A Phase-3, Open-Label, Randomized Study of Dato-DXd Versus Investigator's Choice of Chemotherapy (ICC) in Participants With Inoperable or Metastatic HR-Positive, HER2-Negative Breast Cancer Who Have Been Treated With One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01)
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: AstraZeneca

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Clinical Study Report Addendum 1 Appendix 
16.1.1 
Drug Substance 
Datopotamab deruxtecan 
(Dato-DXd, DS-1062a) 
Study Code 
D9268C00001 
Appendix 16.1.1 
Protocol and Protocol Amendments  
 

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VERSION OF PROTOCOL OR PROTOCOL AMENDMENT  
Global Document Name 
Version No 
Version Date 
Amended CSP 
Version 5 
11 Dec 2023 
Local Amendment 1 European Union 
Version 1 
22 Apr 2024 
 

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Clinical Study Protocol 
Study Intervention
Datopotamab deruxtecan 
(Dato-DXd, DS-1062a)
Study Code
D9268C00001
Version
V5.0 (Amendment 4)
Date
11 December 2023
EudraCT Number
2020-005620-12
EU CT Number
2023-509631-37
A Phase 3, Open-label, Randomized Study of Dato-DXd Versus 
Investigator’s Choice of Chemotherapy in Participants With 
Inoperable or Metastatic Hormone Receptor-Positive, HER2-
Negative Breast Cancer Who Have Been Treated With One or Two 
Prior Lines of Systemic Chemotherapy (TROPION-Breast01)
Sponsor Name: AstraZeneca
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden. 
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2020-005620-12; EU CT number: 2023-509631-37; IND Number: 155696
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. 
The CSP is publicly registered, and the results are disclosed and/or published according to the AstraZeneca 
Global Policy on Bioethics and in compliance with prevailing laws and regulations.

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Protocol Number: D9268C00001
Amendment Number: 4
Study Intervention: Datopotamab deruxtecan (Dato-DXd, DS-1062a)
Study Phase: Phase 3
Short Title: A Study of Dato-DXd Versus Investigator's Choice Chemotherapy in Inoperable 
or Metastatic Hormone Receptor-positive, HER2-negative Breast Cancer
Acronym: TROPION-Breast01 
Study Clinical Lead Name and Contact Information will be provided separately.
International Co-ordinating Investigator:
Massachusetts General Hospital Cancer Center
55 Fruit Street, Boston, MA 02114-2696.
PPD

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VERSION HISTORY
DOCUMENT HISTORY
Document
Date
Amendment 4 (Version 5.0)
11 December 2023
Amendment 3 (Version 4.0)
10 October 2022
Amendment 2 (Version 3.0)
19 April 2022
Amendment 1 (Version 2.0)
27 August 2021
Original Protocol (Version 1.0)
01 July 2021
Amendment 4 (11 December 2023)
Overall Rationale for the Amendment:
The overall rationale for the amendment is to update the protocol for EU CTR requirements 
and to align with the latest Dato-DXd program standards.
Other important administrative and operational clarifications have also been made.
The rationale for each of these changes is provided in the table below:
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Title page
EU CT number added
To meet EU CTR 
requirements.
Non-substantial
Synopsis
Regulatory Agency Identifiers added
For completeness of the 
Synopsis and to meet EU 
CTR requirements.
Non-substantial
1.3 Schedule of 
Activities Table 1 and 
Table 2, 
8.2.5.3 ILD/Pneumonitis 
Investigation, 
8.6.2 Collection of 
Optional Biomarker 
Samples
Optional lung biopsy specimen 
removed
To reflect that lung 
biopsy is no longer an 
optional biomarker 
sample.
Non-substantial
1.3 Schedule of 
Activities Table 1
Reference to the Dato-DXd Site 
Ophthalmologic Assessment Manual 
was added.
To clarify that the 
Ophthalmologic 
Assessment form is now 
included in the Dato-
DXd Site 
Ophthalmologic 
Assessment Manual.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
1.3 Schedule of 
Activities Table 1
Oral care plan row, arrow from Cycle 
1 through Safety FU assessment was 
replaced with wording “Daily before 
dosing, throughout treatment, and up 
to the first follow-up visit”.
To ensure clarity of the 
oral care protocol and 
avoid footnote details 
being missed.
Non-substantial
1.3 Schedule of 
Activities Table 1, 8.6.2 
Collection of Optional 
Biomarker Samples
Optional bronchoalveolar lavage and 
lung biopsy sample on suspected 
ILD/diagnosis of ILD row was 
deleted.
The lung biopsy will not 
be collected. The lavage 
sample will not be 
collected centrally 
anymore and is specified 
in Table 2.
Non-substantial
1.3 Schedule of 
Activities Table 2
Table for assessments to be 
performed if ILD/pneumonitis 
suspected during the intervention 
period was updated to match the 
corresponding Section 8.2.5.3 for 
clarity and consistency eg, physical 
examination including auscultation of 
lung field, arterial blood gases if 
clinically indicated were added to 
Table 2.
To clarify assessments in 
case of suspected and/or 
confirmed 
ILD/pneumonitis and 
ensure consistency 
across protocol sections. 
Non-substantial
2.3.1.1 Dato-DXd 
Table 3 Risk 
Assessment, 
2.2.3 Overall Benefit: 
Risk Conclusion
IRR was downgraded from important 
identified risk to the identified risk 
category. Embryo-fetal toxicity was 
added as an important potential risk. 
A sentence was added to clarify that 
Dato-DXd has not been studied in 
participants with renal or hepatic 
impairment. The Summary of 
Data/Rationale for Risk was updated 
with the latest safety data from the 
IB. The Mitigation Strategy was 
updated to list out the AESIs.
To reflect clinical data 
for Dato-DXd in 
alignment with Dato-
DXd IB Edition 7.0.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
2.3.3 Overall Benefit: 
Risk Conclusion, 
6.5 Concomitant 
Therapy, 6.6 Dose 
Modification, 8.3 
Adverse Events and 
Serious Adverse Events, 
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis, 
8.6.3 Other Study 
Related Biomarker 
Assessments, 9.4.1 
General Considerations, 
Appendix I2 (Table 18), 
Appendix J
COVID-19 specific text was deleted 
throughout the protocol.
No specific safety 
concerns have been 
identified in patients with 
COVID-19 who have 
been treated with Dato-
DXd.
Non-substantial
4.1 Overall Design, 
5 Study Population
A reference for country-specific 
study requirements provided in 
Appendix L was added.
Country-specific 
addendums were added 
to the appendices to 
create one global 
protocol for EU CTR 
submission.
Non-substantial
4.4 End of Study 
Definition
The end of study definition was 
updated to distinguish between end of 
study (EU definition) and study 
completion (FDA definition).
To provide a clear 
definition of end of the 
study for results 
disclosure purposes.
Non-substantial
6.1.1 Investigational 
Products
In Table 5, AxMP was added to the 
IMP and NIMP row. For the unit 
dose strength row, ‘vial’ was deleted 
from ‘100 mg vial’. Reference to 
GMP Annex 13 was removed from 
labelling information.
To ensure all 
interventions are 
designated as an 
investigational medicinal 
product or a non-
investigational medicinal 
product/auxiliary 
medicinal product. To 
omit repetition of 
packaging details in dose 
unit dose strength 
information. To ensure 
country-specific labelling 
requirements are 
followed.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
6.2.1 Dato-DXd
Density of Dato-DXd was added.
Reference to the Pharmacy Manual 
was moved to Section 6.2.1.1 and 
corrected.
To ensure the latest 
available information is 
reflected in the protocol
and to align with the 
Pharmacy Manual.
Non-substantial
6.2.1.1 Preparation of 
Dato-DXd
Guidance for preparation of Dato-
DXd has been updated with 
additional details. A reference to the 
Pharmacy Manual for administration 
details provided separately was 
added.
To ensure the latest
available information is 
reflected in the protocol 
and to align with the 
Pharmacy Manual.
Non-substantial
6.2.1.2 Administration of 
Dato-DXd
Guidance for administration of Dato-
DXd has been updated additional 
details.
To ensure the latest 
available information is 
reflected in the protocol 
and to align with the 
Pharmacy Manual.
Non-substantial
6.6 Dose Modification
Subheadings were added: 6.6.1 Dose 
Delays, 6.6.2 Dose Delays for 
Reasons Other than Treatment-
related Toxicity, 6.6.3 Dose 
Reductions and the text restructured 
accordingly. 
Clarification was added around doses 
delayed for up to 3 consecutive 
cycles (63 days) from the planned 
date of administration (ie, 84 days 
from the last infusion date).
Figure 3 Dose Delay Schema for 
Dato-DXd was added. 
Section 6.6.2 Dose Delays for 
Reasons Other Than 
Treatment-related Toxicity guidance 
as included.
To clarify dose 
modification guidance.
Non-substantial
6.7 Intervention after the 
End of the Study
Section heading was updated to 
Continued Access to Study 
Intervention after the End of the 
Study. Language was added to 
describe methods of providing 
participants with access to treatment 
after data collection in the study has 
ended.
To clarify intervention 
available to participants 
after the end of the study.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
8.2.2 Vital Signs
End of infusion vital signs collection 
window restriction of ±5 minutes was 
removed.
To avoid unnecessary 
protocol deviations since 
vital signs measurements 
timing can be more 
flexible. 
Non-substantial
8.2.5.3 ILD/Pneumonitis 
Investigation
ILD/pneumonitis investigation 
paragraph was updated for clarity. 
Signs and symptoms entry was 
deleted from the list of evaluations. 
Optional bronchoscopy and 
bronchoalveolar lavage if clinically 
indicated text was updated for clarity. 
Acceptable CT scan was clarified to 
include non-contrast chest CT with 1 
to 2 mm slice thickness 
recommended. Differential white 
blood cell count was specified with 
blood tests for clarification.
The additional blood sample for 
exploratory biomarker analysis was 
clarified as an optional serum sample 
when ILD/pneumonitis is suspected 
and/or diagnosed.
An example of other tests that may be 
needed was added.
Text was updated to match the 
corresponding Section 8.2.5.3 for 
clarity and consistency.
To clarify 
ILD/pneumonitis 
investigations. Signs and 
symptoms are not 
assessments and covered 
under adverse events 
reporting. 
To clarify what 
constitutes an acceptable 
CT and biomarker 
sample requirements.
Non-substantial
8.2.5.5 Ophthalmologic 
Assessments, 8.3.11 
Adverse Events of 
Special Interest
A reference to the Dato-DXd 
Ophthalmologic Assessment Manual 
was added. The frequency of use of 
artificial tears was specified as 4 
times daily as preventative measures 
and up to 8 times daily as clinically 
needed.
To clarify the frequency 
of use of artificial tears.
Non-substantial
8.2.5.6 Oral Care Plan
Oral care guidance for participants 
was updated to state participants 
receiving ICC are recommended 
daily use of alcohol-free mouthwash 
while participants receiving Dato-
DXd are recommended to use a 
steroid-containing mouthwash. A 
reference to the Dato-DXd TMGs 
was added.
To specify the 
recommended 
mouthwash for oral care 
with study treatments. To 
direct reader to TMGs 
should oral mucosal 
toxicity arise despite 
prophylaxis measures.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
8.3 Adverse Events and 
Serious Adverse Events
The section title was updated to 
Adverse Events, Serious Adverse 
Events, and Other Safety Reporting.
To clarify that other 
safety reporting is also 
captured in this section. 
Non-substantial
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information
The reporting period for 
ILD/pneumonitis events was clarified 
to extend beyond the 28 + 7 day 
safety follow-up period. The 
reporting period for all AESIs was 
clarified. Reporting instructions for 
pre-existing medical conditions was 
included. Clarification was provided 
for reporting details of hepatic events.
To ensure appropriate 
data collection on 
ILD/pneumonitis events 
and all other AEs and 
SAEs.
Non-substantial
8.3.11 Adverse Events of 
Special Interest
Reporting requirements for 
concomitant medication administered 
as treatment for drug-related AESIs 
was specified.
IRR was changed from important 
identified risk to identified risk.
To ensure that 
concomitant medications 
for drug-related AESIs 
are appropriately 
recorded.
Non-substantial
8.3.15 Medication Error
Section heading was updated to 
Medication Error, Drug Abuse, and 
Drug Misuse. Subsections including 
relevant definitions were added for 
Medication Error, Drug Abuse, Drug 
Misuse. A reference to Appendix B4 
was added. 
To clarify what 
constitutes a medication 
error, drug abuse, and 
drug misuse in the study.
Non-substantial
8.5 Human Biological 
Samples
For PK and ADA samples retention, 
the wording “unless consented for 
future analysis” was deleted.
It was clarified that remaining ADA 
sample aliquots will be retained for a 
maximum of 5 years after CSR 
publication. Wording was added to 
clarify ADA samples collected in 
China will be disposed of 1 year after 
CSR publication.
The samples will be used 
for study analysis only. 
To clarify sample 
retention periods.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis, 
1.3 Schedule of 
Activities Table 1
Additional blood samples for 
exploratory biomarker analysis to be 
collected as soon as ILD/pneumonitis 
is suspected, if feasible was moved to 
Section 8.6.2 since these are optional 
samples. In Table 1, It was clarified 
that the additional exploratory 
biomarker blood samples are 
optional.
The retention time for residual tumor 
samples collected for TROP2 IHC 
testing from Chinese participants was 
corrected to state samples will be 
destroyed or repatriated within 1 year 
after CSR completion.
To clarify that the 
additional exploratory 
biomarker samples are 
optional. To correct 
residual tumor sample 
retention for Chinese 
participants.
Non-substantial
9.3 Populations for 
Analyses Table 9
ITT and Safety Analysis Set 
descriptions were updated to specify 
clinical outcomes assessments 
included in each set. 
To clarify the 
populations definitions 
and align with objectives 
and endpoints.
Non-substantial
Appendix A1 Regulatory 
and Ethical 
Considerations
Investigator oversight of the conduct 
of the study and adherence to 
regulatory requirements was clarified.
A subsection for Regulatory 
Reporting Requirements of Serious 
Breaches was added.
To clarify investigator 
responsibilities and 
include guidance on 
reporting serious 
breaches during study 
conduct.
Non-substantial
Appendix A6 
Dissemination of 
Clinical Study Data
The timeframe for submitting results 
summaries to EU CTIS was included. 
The AstraZeneca website for a
description of the study was updated.
To clarify study result 
submission timelines and 
include the current 
AstraZeneca website.
Non-substantial
Appendix A7 Data 
Quality Assurance
It was clarified that clinical reviews 
of data from a medical perspective 
form part of the monitoring strategy. 
The record and document retention 
period was clarified.
To clarify the monitoring 
process and record 
retention policy.
Non-substantial
Appendix B4 Medication 
Error
Section heading was updated to 
Medication Error, Drug Abuse, and 
Drug Misuse. Subheading for 
Medication Error as well as a range 
for dose error was added. Subsections 
for Drug Abuse and Drug Misuse 
were added.
To clarify what 
constitutes a medication 
error, drug abuse, and 
drug misuse in the study.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Appendix I2 Restricted, 
Prohibited, and 
Permitted Concomitant 
Medications/Therapies
In Table 17 was updated to include 
instructions regarding Dato-DXd 
therapy when palliative radiotherapy 
is given. It was clarified that curative 
radiotherapy prohibited.
To clarify Dato-DXd 
therapy delays in the 
case of palliative 
radiotherapy.
Non-substantial
Appendix I2 Supportive 
Medications/Therapies
Table 19: ‘Antihistamines and 
acetaminophen’ was re-labeled as 
‘pre-medications for prevention of 
IRR or as supportive treatment of 
Dato-DXd’. Examples of 
prophylactic anti-emetic agents was 
deleted from text in the supportive 
medication column.
Text was updated to 
mention examples in the 
Usage column instead of 
in the medications/class 
of drug/therapy column.
Non-substantial
Appendix K Protocol 
Version History
Previous protocol amendments were 
moved to Appendix K.
To focus protocol text on 
current information with 
additional information 
provided in appendices.
Non-substantial
Appendix L
Country-specific addendums to the 
protocol were added in Appendix L. 
Country-specific 
addendums were added 
to the appendices to 
create one global 
protocol for EU CTR 
submission.
Non-substantial
Throughout
Minor editorial and formatting 
revisions.
To further clarify.
Non-substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS .................................................................................................... 11
LIST OF FIGURES ............................................................................................................ 14
LIST OF TABLES .............................................................................................................. 15
1
PROTOCOL SUMMARY ................................................................................ 17
1.1
Synopsis ........................................................................................................... 17
1.2
Schema............................................................................................................. 24
1.3
Schedule of Activities ....................................................................................... 26
2
INTRODUCTION............................................................................................ 34
2.1
Study Rationale ................................................................................................ 35
2.2
Background ...................................................................................................... 36
2.2.1
HR-positive, HER2-negative, inoperable/metastatic breast cancer..................... 36
2.2.1.1
Unmet medical need ......................................................................................... 37
2.2.2
Dato-DXd......................................................................................................... 38
2.2.2.1
TROPION-PanTumor01 study.......................................................................... 38
2.3
Benefit/Risk Assessment................................................................................... 39
2.3.1
Risk Assessment ............................................................................................... 39
2.3.1.1
Dato-DXd......................................................................................................... 39
2.3.2
Benefit Assessment........................................................................................... 40
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 41
3
OBJECTIVES AND ENDPOINTS................................................................... 43
4
STUDY DESIGN ............................................................................................. 48
4.1
Overall Design.................................................................................................. 48
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 51
4.2
Scientific Rationale for Study Design ............................................................... 51
4.2.1
Rationale for Study Design ............................................................................... 51
4.2.2
Rationale for Choice of Comparator Treatments................................................ 52
4.2.3
Rationale for Stratification Factors.................................................................... 53
4.2.3.1
Stratification based on previous lines of chemotherapy ..................................... 53
4.2.3.2
Stratification based on prior CDK4/6 inhibitor use............................................ 53
4.2.3.3
Stratification based on geographical region....................................................... 53
4.2.4
Rationale for Primary Efficacy Endpoints ......................................................... 53
4.2.5
Rationale for Other Study Endpoints................................................................. 54
4.3
Justification for Dose........................................................................................ 55
4.3.1
Dato-DXd......................................................................................................... 55
4.3.2
Investigator Choice of Chemotherapy (ICC) ..................................................... 55
4.4
End of Study Definition.................................................................................... 56
5
STUDY POPULATION.................................................................................... 56

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5.1
Inclusion Criteria .............................................................................................. 57
5.2
Exclusion Criteria ............................................................................................. 60
5.3
Lifestyle Considerations ................................................................................... 64
5.4
Screen Failures ................................................................................................. 64
6
STUDY INTERVENTION ............................................................................... 65
6.1
Study Intervention(s) Administered................................................................... 65
6.1.1
Investigational Products.................................................................................... 65
6.1.1.1
Duration of Treatment....................................................................................... 66
6.1.2
Medical Devices ............................................................................................... 66
6.2
Preparation, Handling, Storage, Accountability of Interventions........................ 66
6.2.1
Dato-DXd......................................................................................................... 67
6.2.1.1
Preparation of Dato-DXd.................................................................................. 67
6.2.1.2
Administration of Dato-DXd............................................................................. 68
6.2.1.3
Monitoring of Dato-DXd Administration .......................................................... 69
6.2.1.4
Storage of Dato-DXd........................................................................................ 69
6.2.2
Investigator’s Choice of Chemotherapy ............................................................ 69
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 70
6.3.1
Participant Enrolment and Randomization ........................................................ 70
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized Participants........ 71
6.3.3
Methods for Assigning Treatment Groups......................................................... 71
6.3.4
Methods for Ensuring Blinding......................................................................... 72
6.4
Study Intervention Compliance......................................................................... 72
6.5
Concomitant Therapy........................................................................................ 72
6.6
Dose Modification ............................................................................................ 74
6.6.1
Dose Delays...................................................................................................... 74
6.6.2
Dose Delays for Reasons Other Than Treatment-related Toxicity...................... 75
6.6.3
Dose Reductions............................................................................................... 76
6.6.4
Management of Toxicities................................................................................. 76
6.7
Continued Access to Study Intervention After the End of the Study .................. 77
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 78
7.1
Discontinuation of Study Intervention............................................................... 78
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention............... 79
7.1.2
Follow-up of Participants to PFS2..................................................................... 79
7.1.3
Follow-up for Survival...................................................................................... 79
7.2
Participant Withdrawal from the Study.............................................................. 80
7.3
Lost to Follow-up ............................................................................................. 80
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 81
8.1
Efficacy Assessments........................................................................................ 82
8.1.1
Imaging Tumor Assessments............................................................................. 82
8.1.2
Central Reading of Scans.................................................................................. 84
8.1.3
Time to Second Progression or Death................................................................ 84

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8.1.4
Overall Survival................................................................................................ 84
8.1.5
Clinical Outcome Assessments (COA).............................................................. 85
8.1.5.1
EORTC QLQ-C30 ............................................................................................ 85
8.1.5.2
EORTC IL116: selected breast and arm symptom scales from EORTC QLQ-
BR45/IL ........................................................................................................... 86
8.1.5.3
PRO-CTCAE.................................................................................................... 86
8.1.5.4
EORTC IL117: selected symptomatic AE items from EORTC IL...................... 86
8.1.5.5
PGI-TT............................................................................................................. 87
8.1.5.6
PGIS................................................................................................................. 87
8.1.5.7
PGIC ................................................................................................................ 87
8.1.5.8
EQ-5D-5L ........................................................................................................ 87
8.1.5.9
Administration of Electronic PRO (ePRO) Questionnaires................................ 88
8.2
Safety Assessments........................................................................................... 90
8.2.1
Physical Examinations...................................................................................... 90
8.2.2
Vital Signs ........................................................................................................ 91
8.2.3
Electrocardiograms........................................................................................... 91
8.2.4
Clinical Safety Laboratory Assessments............................................................ 92
8.2.5
Other Safety Assessments ................................................................................. 93
8.2.5.1
Echocardiogram/Multigated Acquisition Scan................................................... 93
8.2.5.2
Pulmonary Function Tests................................................................................. 94
8.2.5.3
ILD/Pneumonitis Investigation ......................................................................... 94
8.2.5.4
ECOG Performance Status................................................................................ 95
8.2.5.5
Ophthalmologic Assessments............................................................................ 96
8.2.5.6
Oral Care Plan .................................................................................................. 97
8.3
Adverse Events, Serious Adverse Events, and Other Safety Reporting .............. 98
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 98
8.3.2
Follow-up of AEs and SAEs ........................................................................... 100
8.3.3
Causality Collection........................................................................................ 101
8.3.4
Adverse Events Based on Signs and Symptoms .............................................. 101
8.3.5
Adverse Events Based on Examinations and Tests .......................................... 101
8.3.6
Hy’s Law........................................................................................................ 102
8.3.7
Disease Progression........................................................................................ 102
8.3.8
Disease Under Study....................................................................................... 102
8.3.9
New Cancers................................................................................................... 102
8.3.10
Deaths ............................................................................................................ 102
8.3.11
Adverse Events of Special Interest.................................................................. 103
8.3.12
Safety Data to be Collected Following the Final Data Cutoff of the Study....... 105
8.3.13
Reporting of Serious Adverse Events .............................................................. 106
8.3.14
Pregnancy....................................................................................................... 106
8.3.14.1
Maternal Exposure.......................................................................................... 107
8.3.14.2
Paternal Exposure........................................................................................... 107
8.3.15
Medication Error, Drug Abuse, and Drug Misuse............................................ 108
8.3.15.2
Medication Error............................................................................................. 108
8.3.15.3
Drug Abuse..................................................................................................... 108
8.3.15.4
Drug Misuse ................................................................................................... 108
8.3.16
Medical Device Deficiencies........................................................................... 109

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8.4
Overdose ........................................................................................................ 109
8.5
Human Biological Samples............................................................................. 109
8.5.1
Pharmacokinetics............................................................................................ 110
8.5.1.1
Determination of Drug Concentration ............................................................. 110
8.5.2
Immunogenicity Assessments ......................................................................... 110
8.6
Human Biological Sample Biomarkers ............................................................111
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ...............................111
8.6.2
Collection of Optional Biomarker Samples ..................................................... 113
8.6.3
Other Study Related Biomarker Assessments.................................................. 114
8.7
Optional Genomics Initiative Sample.............................................................. 114
8.8
Medical Resource Utilization and Health Economics...................................... 115
9
STATISTICAL CONSIDERATIONS.............................................................. 115
9.1
Statistical Hypotheses..................................................................................... 115
9.2
Sample Size Determination............................................................................. 116
9.3
Populations for Analyses................................................................................. 118
9.4
Statistical Analyses ......................................................................................... 119
9.4.1
General Considerations................................................................................... 119
9.4.2
Efficacy .......................................................................................................... 119
9.4.2.1
Primary Endpoints .......................................................................................... 119
9.4.2.2
Secondary Endpoint(s).................................................................................... 124
9.4.2.3
Exploratory Endpoints .................................................................................... 128
9.4.3
Safety ............................................................................................................. 129
9.4.4
Other Analyses................................................................................................ 131
9.4.4.1
Optional Exploratory Genetic Sample............................................................. 131
9.4.4.2
Ophthalmologic Analysis................................................................................ 131
9.5
Interim Analyses............................................................................................. 131
9.6
Data Monitoring Committees.......................................................................... 132
9.6.1
Independent Data Monitoring Committee ....................................................... 132
9.6.2
ILD Adjudication Committee.......................................................................... 133
9.6.3
Ophthalmologic Data Review Committee ....................................................... 133
9.7
Mainland China Cohort................................................................................... 133
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 135
Amendment 3 (10 October 2022)...................................................................................... 194
Amendment 2 (19 April 2022) .......................................................................................... 197
Amendment 1 (27 August 2021)........................................................................................ 204
11
REFERENCES............................................................................................... 234
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 25

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Figure 2
Study Flow Chart..................................................................................... 50
Figure 3
Dose Delay Schema for Dato-DXd .......................................................... 75
Figure 4
Prophylactic Mouthwash Algorithm......................................................... 98
Figure 5
Multiple Testing Procedure.................................................................... 116
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 27
Table 2
Assessments if ILD/Pneumonitis is Suspected during the Intervention 
Period...................................................................................................... 34
Table 3
Risk Assessment...................................................................................... 39
Table 4
Objectives and Endpoints......................................................................... 43
Table 5
Investigational Products........................................................................... 65
Table 6
Dose Reduction Levels of Dato-DXd....................................................... 76
Table 7
Laboratory Safety Variables..................................................................... 93
Table 8
Spirometry Component............................................................................ 94
Table 9
Populations for Analysis ........................................................................ 118
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Primary Endpoints ................................................................................. 119
Table 11
Summary of planned timings of the interim and final OS analyses......... 131
Table 12
Summary of Imaging Modalities for Tumor Assessment........................ 162
Table 13
RECIST 1.1 Evaluation of Target Lesions ............................................. 169
Table 14
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 170
Table 15
RECIST 1.1 Overall Visit Response ...................................................... 171
Table 16
Highly Effective Methods of Contraception (< 1% Failure Rate) ........... 175
Table 17
Restricted medications/therapies............................................................ 189
Table 18
Prohibited medications/therapies............................................................ 190
Table 19
Supportive medications/therapies........................................................... 191
Table L20
Country-specific Requirements for Brazil (Effective 15 September 2022)208
Table L21
Country-specific Requirements for Canada (Effective 13 December 
2022)..................................................................................................... 212
Table L22
Country-specific Requirements for France (Effective 10 November 
2022)..................................................................................................... 213
Table L23
Country-specific Requirements for France (Effective 21 January 2022). 215
Table L24
Country-specific Requirements for Germany (Effective 
15 November 2022)............................................................................... 219

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Table L25
Country-specific Requirements for India (Effective 02 November 2021)222
Table L26
Country-specific Requirements for United Kingdom (Effective 
19 May 2022) ........................................................................................ 227
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 136
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 142
Appendix C
Handling of Human Biological Samples ................................................ 148
Appendix D
Optional Genomics Initiative Sample..................................................... 151
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 155
Appendix F
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors).................. 162
Appendix G
Contraception Requirements.................................................................. 173
Appendix H
Patient-reported Outcomes..................................................................... 176
Appendix I
Concomitant Medications ...................................................................... 189
Appendix J
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 192
Appendix K
Protocol Version History ....................................................................... 194
Appendix L
Country-Specific Addendums to the Protocol ........................................ 208
Appendix M
Abbreviations ........................................................................................ 228

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:  A Phase 3, Open-label, Randomized Study of Dato-DXd Versus 
Investigator’s Choice of Chemotherapy in Participants With Inoperable or Metastatic 
Hormone Receptor-Positive, HER2-Negative Breast Cancer Who Have Been Treated With 
One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01).
Short Title: A Study of Dato-DXd Versus Investigator's Choice Chemotherapy in Inoperable 
or Metastatic Hormone Receptor-positive, HER2-negative Breast Cancer.
Regulatory Agency Identifier Number(s):
EudraCT Number: 2020-005620-12; IND Number: 155696; EU CT number: 2023-509631-37
Rationale: 
Single agent chemotherapy remains the cornerstone of therapy for patients with HR-positive, 
HER2-negative metastatic breast cancer who have exhausted endocrine therapy options. 
However, patient prognosis is poor, and durable antineoplastic therapy options are necessary 
to improve outcomes in this patient population.
Dato-DXd is a TROP2 antibody-drug conjugate (administered via IV infusion, Q3W). Within 
the Dato-DXd clinical development program, preliminary data supporting the use of 
Dato-DXd in participants with HR-positive, HER2-negative breast cancer are available from 
an ongoing phase 1 first-in-human study, TROPION-PanTumor01 (NCT03401385), which is 
evaluating Dato-DXd in participants with advanced non-small cell lung cancer and triple-
negative breast cancer, relapsed or refractory to standard-of-care therapy. These data have 
demonstrated highly encouraging efficacy across dose groups, with tumor responses observed 
at doses of 4, 6, and 8 mg/kg and an acceptable and manageable toxicity profile. 
Given these encouraging preliminary safety and efficacy data, the current study is designed to 
provide a robust and detailed understanding of the efficacy and safety of Dato-DXd when 
compared with Investigator’s choice of standard-of-care single-agent chemotherapy (eribulin, 
capecitabine, vinorelbine, or gemcitabine; henceforth referred to as ICC) in participants with 
inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated 
with one or two prior lines of systemic chemotherapy, for which an unmet medical need 
remains.

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Objectives and Endpoints
Objectives
Endpoints
Dual Primary
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR.
PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by BICR, or 
death due to any cause. 
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinicallyprogresses prior to RECIST 1.1. 
The measure of interest is the hazard ratio of PFS.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of OS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
OS is defined as time from randomization until the date of 
death due to any cause. 
The comparison will include all randomized participants as 
randomized, regardless of whether the participant withdraws 
from therapy or receives another anticancer therapy.
The measure of interest is the hazard ratio of OS.
Secondary
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of ORR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment.
ORR is defined as the proportion of participants who have a 
confirmed CR or PR, as determined by the 
BICR/Investigator assessment, per RECIST 1.1.
The analysis will include all randomized participants as 
randomized. 
Data obtained from randomization up until 
progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR, 
regardless of whether the participant withdraws from therapy. 
Participants who go off treatment without a response or 
progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR.
The measure of interest is the odds ratio of the ORR.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DoR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
DoR is defined as the time from the date of first documented 
confirmed response until date of documented progression 
per RECIST 1.1, as assessed by BICR/Investigator 
assessment or death due to any cause.
The analysis will include all randomized participants as 
randomized who have a confirmed response, regardless of 
whether the participant withdraws from therapy, receives 
another anticancer therapy or clinically progresses prior to 
RECIST 1.1 progression.
The measure of interest is the median of DoR.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per investigator assessment.
PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by investigator 
assessment, or death due to any cause. 
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinicallyprogresses prior to RECIST 1.1.
The measure of interest is the hazard ratio of PFS.

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Objectives
Endpoints
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DCR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment.
DCR at 12 weeks is defined as the percentage of 
participants who have a confirmed CR or PR or who have 
SD, per RECIST 1.1, as assessed BICR/per investigator 
assessment and derived from the raw tumor data for at least 
11 weeks after randomization. 
Data obtained from randomization up until progression, or the 
last evaluable assessment in the absence of progression, will 
be included in the assessment of DCR, regardless of whether 
the participant withdraws from therapy. Participants who 
receive a subsequent therapy prior to week 11 will not be 
considered to have disease control in the analysis.
The analysis will include all randomized participants as 
randomized.
The measure of interest is the odds ratio of the DCR.
To assess pain in participants treated with 
Dato-DXd compared to ICC.
TTD in pain as measured by the pain scale from EORTC 
QLQ-C30
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants. 
The measure of interest is the hazard ratio of TTD in pain. 
To assess physical functioning in 
participants treated with Dato-DXd 
compared to ICC.
TTD in physical functioning as measured by the physical 
functioning scale from EORTC QLQ-C30
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants. 
The measure of interest is the hazard ratio of TTD in physical 
functioning.
To assess global health status/quality of life 
(GHS/QoL) in participants treated with
Dato-DXd compared to ICC.
TTD in GHS/QoL as measured by the GHS/QoL scale from 
EORTC QLQ-C30
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants. 
The measure of interest is the hazard ratio of TTD in 
GHS/QoL.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TFST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
TFST is defined as the time from randomization until the 
start date of the first subsequent anticancer therapy after 
discontinuation of randomized treatment, or death due to 
any cause.
The analysis will include all randomized participants as 
randomized, regardless of progression status.
The measure of interest is the hazard ratio of TFST.

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Objectives
Endpoints
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TSST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
TSST is defined as the time from randomization to until the 
start date of the second subsequent anticancer therapy after 
discontinuation of first subsequent treatment, or death due to 
any cause.
The analysis will include all randomized participants as 
randomized, regardless of progression status on study 
treatment or first subsequent treatment.
The measure of interest is the hazard ratio of TSST. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS2 in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
PFS2 will be defined as the time from the randomization to 
the earliest of the progression event (following the initial 
progression), subsequent to first subsequent therapy, or 
death. The date of second progression will be recorded by 
the Investigator in the eCRF and defined according to local 
standard clinical practice.
The comparison will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from subsequent therapy and regardless of missed visits.
The measure of interest is the hazard ratio of PFS2.
To assess the PK of Dato-DXd 6mg/kg IV 
Q3W.
Plasma concentrations of Dato-DXd, total anti-TROP2 
antibody, and MAAA-1181a (payload). 
To investigate the immunogenicity of 
Dato-DXd 6mg/kg IV Q3W.
Presence of ADA.
Safety
To assess the safety and tolerability profile 
of Dato-DXd compared to ICC.
Safety and tolerability will be evaluated in terms of adverse 
events (graded by CTCAE version 5.0), and also in terms of:

ECOG PS

Vital signs, body weight, physical examination 

Clinical chemistry, hematology, and urinalysis assessments

ECG, ECHO/MUGA and Ophthalmologic assessments
For exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design
Disclosure Statement: This is a Phase 3, randomized, open-label, 2 arm, multicenter, 
international study assessing the efficacy and safety of Dato-DXd compared with ICC in 
participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who 
have been treated with one or two prior lines of systemic chemotherapy in the inoperable or 
metastatic setting.
Participant Population: The target population of interest in this study is male or female adult 
(≥18 years participants with inoperable or metastatic HR-positive, HER2 negative breast 
cancer (per ASCO/CAP guidelines, on local laboratory results) who have progressed on and 
are not suitable for endocrine therapy per investigator assessment, and have been treated with 
1 to 2 lines of prior chemotherapy in the inoperable/metastatic setting. Participants must have 
documented progression on their most recent line of chemotherapy, and be eligible for one of 

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the chemotherapy options listed as ICC (eribulin, capecitabine, vinorelbine, gemcitabine), per 
investigator assessment.
To be eligible for randomization, availability of a FFPE tumor sample (block preferred, or a 
minimum of 20 freshly cut slides) is required, at the time of screening. This sample can be 
from either the primary disease setting (surgical resection or diagnostic sample), or from a 
metastatic lesion (excluding bone). If neither an adequate FFPE block nor the minimum of 
20 slides are available, a patient may still be considered eligible. In this situation, approval by 
the Study Team for patient’s entry into the study is required. If there is no written 
confirmation of the availability of an appropriate tumor sample prior to enrolment, the 
participant will not be eligible for the study. At the time of enrolment all participants must 
have an ECOG PS of 0 or 1, and have at least 1 measurable lesion not previously irradiated 
that qualifies as a RECIST 1.1 target lesion. Participants with clinically inactive brain 
metastases may be included in the study.
Number of Participants: Approximately 1000 participants will be enrolled to achieve 
approximately 700 randomly assigned participants to study intervention. If required for 
regulatory submission purposes, the recruitment of participants in mainland China may 
continue beyond the close of the global cohort, to include approximately an additional 20 
randomized participants in the mainland China cohort. The mainland China cohort is defined 
as all participants from sites in mainland China randomized into the study. A participant 
randomized in the mainland China cohort prior to the last participant randomized in the global 
cohort will be included in both the global and mainland China cohorts. A participant 
randomized in mainland China after the last participant was randomized in the global cohort 
will be included only in the mainland China cohort.
Note: "Enrolled" means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned in the study, are considered “screen failures”, unless otherwise 
specified by the protocol. 
Intervention Groups and Duration: Participants will be randomized in a 1:1 ratio to one of 
the following intervention groups:

Arm 1: Dato-DXd (6 mg/kg IV on Day 1, Q3W)

Arm 2: ICC:
Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W); choice between 
the 2 doses will be determined by standard institutional practice.
Gemcitabine (1000 mg/m2 IV on Day 1 and Day 8, Q3W)

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Eribulin mesylate (1.4 mg/m2 IV on Days 1 and 8, Q3W)
Vinorelbine (25 mg/m2 IV on Days 1 and 8, Q3W)
Randomization will be stratified by the following prognostic and/or predictive factors:

Number of previous lines of chemotherapy (1 versus 2)

Geographic region (Region 1 [US, Canada, Europe] versus Region 2 [Rest of World])

Prior use of CDK4/6 inhibitor (Yes versus No)
A 50% cap will be applied to participants who have had 2 prior lines of chemotherapy in the 
inoperable/metastatic setting, while a 49% cap will be applied to participants who have not 
received prior CDK4/6 inhibitor therapy.
All participants will receive study intervention until Investigator-defined disease progression 
according to RECIST 1.1, or until unacceptable toxicity, withdrawal of consent, or another 
criterion for discontinuation is met. Continued treatment with the same study drug post-
progression may be allowed, based on prior discussion with study physician on case-by-case 
basis. No crossover between study treatment arms will be allowed. 
Follow-up of participants post discontinuation of study intervention
After study intervention discontinuation, all participants will undergo an end-of-treatment visit 
(to be conducted +7 days of the decision to discontinue treatment) and will be followed up for 
safety assessments 28 (+7) days after their last dose of study intervention (ie, the safety 
follow-up visit). If the date of discontinuation is over 35 days from last study intervention 
administration, then the EoT assessments can also function as the Safety Follow-up visit.
Participants who have discontinued study intervention in the absence of RECIST 1.1-defined 
radiological progression (by investigator assessment) will be followed up with tumor 
assessments according to the Schedule of Activities (SoA) until RECIST 1.1-defined PD (as 
assessed by the Investigator) or death regardless of whether or not the participant started a 
subsequent anticancer therapy, unless they have withdrawn all consent to study related 
assessments. Following disease progression, 1 additional follow-up scan should also be 
performed as per imaging schedule (ie, either 6 weeks or 9 weeks later). In the event the 
investigator identified progression does not match with the BICR evaluation, this additional 
scan may identify progression by BICR.
In addition, all participants will be followed up for survival status after intervention 
discontinuation every 3 months (±14 days) from the date of the date of the Safety Follow-up 
Visit until death, withdrawal of consent, or the end of the study (ie, progression/survival 
follow-up), as per the SoA. Participants will be followed up for time to second progression or 
death (PFS2) and subsequent anticancer therapy use after intervention discontinuation every 

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3 months (±14 days) from the date of randomization until death, withdrawal of consent, or the 
end of the study (ie, progression/survival follow-up), as per SoA. The study may continue 
monitoring participants for OS up to the scheduled final analysis, beyond planned interim 
analyses, to provide more refined estimates of treatment effects for survival.
See Section 6.7 for a description of assessments following study DCOs.
Independent Data Monitoring Committee (IDMC): An IDMC comprised of independent 
experts will be convened to review unblinded safety data and make recommendations to 
continue, amend, or stop the study based on safety findings. In addition, the IDMC may be 
requested to review efficacy data. For the interim analyses, the IDMC will review unblinded 
interim data and inform the Sponsor whether the interim boundaries specified in Section 9.5 
are crossed. Full details of the IDMC procedures, processes, and interim analyses can be 
found in the IDMC Charter.
Statistical methods
The study is sized for dual primary endpoints to characterize the PFS and OS benefit of 
Dato-DXd versus ICC in intent-to-treat (ITT) population. This comprises all participants 
randomized into the study, excluding participants randomized in mainland China after the 
global cohort last participant randomized, and will be analyzed according to randomized 
treatment regardless of the treatment received (ITT principle). The study will be considered 
positive (a success) if either the PFS analysis results and/or the OS analysis results are 
statistically significant.
The primary, final analysis of PFS will be performed when approximately 419 PFS BICR 
events occur, approximately 2 months after the last participant is randomized in the study; 419 
PFS BICR events from the ITT population across the Dato-DXd and ICC treatment groups 
will represent 60% maturity of data. Assuming the true PFS hazard ratio is 0.55 for Dato-DXd 
versus ICC, the study will have a greater than 99% power to demonstrate statistical 
significance at the 1.0% level (using a 2-sided test). This assumes median PFS times of 
4.7 months and 8.5 months in ICC and Dato-DXd, respectively when the PFS times are 
exponentially distributed. The smallest treatment difference that could be statistically 
significant at the final analysis is a hazard ratio of 0.775. 
The final analysis of OS will be performed when approximately 444 OS events have occurred 
across the Dato-DXd and ICC treatment groups (63% maturity). Assuming the true OS hazard 
ratio is 0.75 for Dato-DXd versus ICC, the study will have 85% power to demonstrate 
statistical significance at the 5.0% level (using a 2-sided test). This assumes the PFS primary 
analysis crosses the efficacy threshold, and allowing 2 interim analyses to be conducted at 
information fractions of approximately 40% and 80% of the target events, respectively (per 
the O’Brien and Fleming approach). The smallest treatment difference that could be 

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statistically significant at the final analysis is a hazard ratio of 0.824. If the PFS primary 
analysis does not cross the efficacy threshold, the OS analysis will have 83% power to 
demonstrate statistical significance at the 4.0% level (using a 2-sided test). The smallest 
treatment difference that could be statistically significant at the final analysis is a hazard ratio 
of 0.817. Calculations assume median OS times of 19.0 months and 25.3 months in ICC and 
Dato-DXd, respectively when the survival times are exponentially distributed. 
The study may continue monitoring participants for OS up to the scheduled final analysis, 
beyond planned interim analyses, to provide more refined estimates of treatment effects for 
survival. 
A nonuniform accrual of participants (with k = 1.5) is assumed when estimating the analysis 
times. The total proportion of participants randomized at time t [t ≤ 19 months] following the 
start of the study is assumed to be (t/19)k. 
Hypotheses will be tested using a multiple testing procedure (MTP) with an alpha-exhaustive 
recycling strategy. To strongly control the familywise type I error rate at the 5.0% level 
(2-sided), an alpha level of 1.0% will be allocated to the PFS dual primary analysis and the 
remaining 4.0% alpha level will be allocated to the OS analyses. If the PFS dual primary 
analysis crosses the efficacy threshold, the 1.0% type I error allocated to the PFS endpoint will 
be reallocated to the OS endpoint for a total 2-sided type I error of 5.0%.
Safety data will be summarized descriptively and will not be formally analyzed unless 
otherwise specified.
1.2
Schema
The study schema is presented in Figure 1.

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Figure 1
Study Design

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1.3
Schedule of Activities
The procedures for this study are presented in the SoA (Table 1). Assessments in the event of 
suspected ILD/pneumonitis are presented separately in Table 2.

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g
Includes ocular history (since prior ocular events may predispose to or cause dry eye/keratitis), as well as history, type and frequency of tobacco use, e-cigarette use, vaping 
(including dates).
h
Triplicate ECGs will be taken at screening and EoT. Triplicate ECGs will be taken in close succession, while in a supine/semi-recumbent position. Single ECGs should be 
taken during treatment as clinically indicated. 
i
The same test must be used for the participant throughout the study. ECHO/MUGA not required at EoT unless clinically indicated.
j
Vital signs and SpO2 should be performed both before and after study intervention administration (where applicable), and as clinically indicated during treatment. Participant 
should remain at the site for at least 1-hour post-infusion (where applicable) for close observation for IRRs. 
k
Pulmonary function tests at a minimum should include spirometry (minimum requirement of: FVC [L], FVC % predicted, FEV1 [L], FEV1 % predicted, FEV1/FVC %). 
DLCO will be performed (when feasible); however, for participants with prior severe and/or clinically significant pulmonary disorders, DLCO is a requirement.
l
Ophthalmologic assessments (by a licensed eye care provider) including but not limited to visual acuity testing, fluorescein staining, intraocular pressure, slit-lamp 
examination and fundoscopy will be performed at screening, and then every 3 cycles from C1D1 onwards (eg, C4D1, C7D1, C10D1 etc) within 14 days prior to scheduled 
cycle Day 1 visit (but not after the scheduled visit), in addition to as clinically indicated while on trial, and at EoT. (see Section 8.2.5.5 for additional information). Please 
refer to the Dato-DXd Site Ophthalmologic Assessment Manual for further details.
m
A daily Oral Care Protocol (OCP) will be started before study drug initiation, and it must be maintained throughout the study until 28 days after last dose. An oral care kit will 
be provided at study enrolment and monthly thereafter until the safety FU visit, which will include a toothbrush, toothpaste, dental floss, and an alcohol-free mouthwash. An oral care plan 
participant information guide should be given to each randomized participant before study drug initiation. Strongly consider initiation of dexamethasone oral solution (see Section 
8.2.5.6 for details).
n
Data collection may be conducted by phone if not tied to a visit.
o
All AEs occurring after the participant signs the ICF and up to 28 (+7) days after the last dose of study drug (ie, the safety follow-up period), whether observed by the 
Investigator or reported by the participant, will be recorded on the AE eCRF page (see Section 8.3 for additional information).
p
Negative serum pregnancy test performed within 72 hours before study intervention at screening and repeat urine or serum pregnancy tests (per institutional guideline) 
performed within 72 hours before infusion of each cycle and at EoT and during safety follow-up. A positive urine pregnancy test result must immediately be confirmed using 
a serum test.
q
Prior HIV serology (anti-HIV with or without HIV RNA, as appropriate), hepatitis B serology (HBsAg, anti-HBs, and anti-HBc with or without HBV DNA, as appropriate),
and hepatitis C serology (anti-HCV antibody with or without HCV RNA, as appropriate) testing results can be used if performed within 120 days before enrolment. In this 
case, there is no need for a repeat test during the 28-day screening period.
r
Participants must be tested for HIV if acceptable by local regulations or an IRB/EC. If an HIV infection meets the criteria outlined in Section 5.2, monitoring of the 
participants’ viral RNA load and CD4+ cell count should be monitored per local SoC (eg, every 3 months).
s
To be performed within 8 hours prior to the start of Dato-DXd infusion, except for the EoT visit, during which samples can be collected anytime during this visit. 
t
To be performed within 1 hour after the end of Dato-DXd infusion.
u
An additional PK sample should be taken 5 hours (±1 hour) from the start of Dato-DXd infusion on C1D1.
v
Not applicable to participants in mainland China. 
w
The sample for genetic research will be obtained at Day 1 pre-dose. If, for any reason, the sample is not drawn at Day 1, it may be taken at any visit until the last study visit. 
Only 1 sample should be collected per participant for genetics during the study.

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x
The baseline tumor assessment must be performed within 28 days before randomization and as close as possible to the start of treatment. The assessment should include CT 
(preferred) or MRI, with IV contrast, of the chest, abdomen (including the entire liver and both adrenal glands), and pelvis. Any other areas of disease involvement should be 
additionally imaged at screening based on known metastasis sites or by the signs and symptoms of individual participants. The follow-up assessments should include 
CT/MRI with IV contrast of the chest, abdomen and pelvis and any other area where disease was identified at baseline. The assessment must continue until 1 visit (per 
original schedule) after radiographic disease progression (as assessed by Investigator), whether or not the participant is still on treatment. The same imaging technique (CT 
or MRI) used to characterize each identified and reported lesion at baseline will be used in the subsequent tumor assessments.
y
Participants with brain metastases at baseline must have the lesions recorded as part of the RECIST assessment and must have a brain scan performed per the tumor imaging 
schedule until radiological progression per RECIST. For participants in whom CNS metastases are first discovered at the time of screening, the treating investigator should 
consider delay of randomization and study intervention to document stability of CNS metastases with repeat imaging at least 4 weeks later (in which case, repeat of all 
screening activity may be required).
z
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-ray should be recorded as NTLs and followed by the same method (CT, MRI, 
or X-ray), as indicated in the SoA.
aa
The site should complete the “Hospital Admission (HOSPAD)” form at the site at every scheduled clinic visit up to and including the post study treatment discontinuation 
follow up visit. If the participant discontinues study treatment for reasons other than RECIST progression, the HOSPAD form should continue to be administered until 
progression has been confirmed. Study mandated visits should not be included as a hospital admission.
bb
Only applicable to participants who are required to attend study visits on Day 8 of each cycle (ie, those randomized to receive Investigators Choice of Chemotherapy which 
are administered by IV infusion).
Note: All assessments on treatment days are to be performed prior to study intervention administration, unless otherwise indicated. Following the DCO for the primary analysis, 
PK assessments will be discontinued. Data collection following final study analysis until the end of the study is described in Section 8.

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Table 2
Assessments if ILD/Pneumonitis is Suspected during the Intervention 
Period
Procedure
Details in CSP Section
ILD/pneumonitis investigation
Section 8.2.5.3
Detailed past medical history and concomitant medications
Section 8.2.5.3
Physical examination, including auscultation of lung field
Section 8.2.5.3
HRCT of the chest if feasible (otherwise non-contrast chest CT is acceptable)
Section 8.2.5.3
Arterial blood gases if clinically indicated
Section 8.2.5.3
Pulmonary function tests and pulse oximetry (SpO2)
Sections 8.2.5.2 and 8.2.5.3
Bronchoscopy and bronchoalveolar lavage should be considered if clinically 
indicated and feasible
Sections 8.2.5.3
Pulmonologist consultation (infectious diseases consultation, as clinically 
indicated)
Section 8.2.5.3
Blood culture, complete blood count, and differential white blood cell count; 
other blood tests could be considered as needed
Section 8.2.5.3
Troponin measurements to rule out cardiac etiology
Section 8.2.5.3
Additional optional blood sample for plasma exploratory ILD/pneumonitis 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed a
Sections 8.2.5.3 and 8.6.1
Additional optional blood sample for serum exploratory ILD/pneumonitis 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed a
Sections 8.2.5.3 and 8.6.1
Note: Other tests could be considered, as needed (eg, COVID-19 test).
a
Whenever ECGs, vital signs and blood draws are scheduled for the same day, the assessments should occur 
in the following order: ECG, vital signs and then blood draws. The timing of the ECG and vital signs 
assessments must allow for the blood draw (eg, PK blood sample) to occur at the scheduled time points 
specified in Table 1. Pulse oximetry (SpO2) will be performed at the same time as vital signs.
2
INTRODUCTION
Datopotamab deruxtecan (Dato-DXd, DS-1062a) is an antibody-drug conjugate (ADC) that 
comprises a recombinant humanized anti-TROP2 IgG1 monoclonal antibody, which is 
covalently conjugated to a drug linker via thioether bonds.
Antibody-drug conjugates are targeted anticancer medicines that deliver cytotoxic 
chemotherapy (‘payload’) to cancer cells via a linker attached to a monoclonal antibody that 
binds to a specific target expressed on cancer cells. Antibody-drug conjugates provide a 
unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue. 
Dato-DXd binds to trophoblast cell surface protein 2 (TROP2), also known as 
tumor-associated calcium signal transducer 2. Dato-DXd is in development as a candidate 
therapy for cancer.

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2.1
Study Rationale
Single agent chemotherapy remains the cornerstone of therapy for patients with HR-positive, 
HER2-negative metastatic breast cancer who have exhausted endocrine therapy options. 
However, patient prognosis is poor, and durable antineoplastic therapy options are necessary 
to improve outcomes in this patient population (see Section 2.2.1 for further details).
TROP2 is a type I transmembrane glycoprotein originally identified in human trophoblast 
cells (Fornaro et al 1995, Alberti et al 1992, Lipinski et al 1981). TROP2 is highly expressed 
in a number of normal tissues and several cancers and has been recognized as a novel 
promising antigen for ADCs due to its high expression in breast tumors (Pau Ni et al 2010). 
Furthermore, increased TROP2 mRNA in breast cancer has been shown to be a predictor of 
lymph node involvement, distant metastasis, and poor OS (Zhao et al 2018). 
The potential for TROP2 ADCs in the treatment of breast cancer has been demonstrated with 
the FDA approval of sacituzumab govitecan (TRODELVY; IMMU-132; Gilead Sciences, 
Inc.) for patients with locally advanced and metastatic TNBC who have received at least
2 prior systemic therapies, at least one of them for metastatic disease. Most recent data in 
HR-positive, HER2-negative metastatic breast cancer population treated with sacituzumab 
govitecan, who have received at least 2 prior lines of therapy, with a median follow-up of 
11.5 months, has shown that the ORR was 31.5% (95% CI: 19.5, 45.6; 17 partial responses); 
median DoR was 8.7 months (95% CI: 3.7, 12.7), median PFS was 5.5 months (95% CI: 3.6, 
7.6), and median OS was 12 months (95% CI: 9.0, 18.2) (Kalinsky et al 2020). Of note, 
significant toxicities in sacituzumab govitecan treated participants have been reported, which 
include myelosuppression and diarrhea (Bardia et al 2020). Furthermore, the efficacy of ADCs 
in breast cancer has been demonstrated from the approval of ENHERTU (T-DXd) and 
KADCYLA (T-DM1), two HER2-targeted ADCs indicated for HER2-positive breast cancer 
(Modi et al 2020, Von Minckwitz et al 2019).
Dato-DXd is a TROP2 ADC (administered via IV infusion, Q3W) that binds to TROP2, is 
internalized, and after enzymatic processing, the topoisomerase I inhibitor, MAAA-1181a, is 
released, leading to inhibition of tumor growth, DNA damage, and apoptosis of target cells. 
The cytotoxic payload of Dato-DXd is the same as T-DXd. Preclinical data has demonstrated 
that Dato-DXd exerts specific cell growth inhibitory activity against TROP2-expressing cells, 
but it does not have cell growth inhibitory against TROP2-negative cells. 
Within the Dato-DXd clinical development program, preliminary data supporting the use of 
Dato-DXd in participants with HR-positive, HER2-negative breast cancer are available from 
an ongoing phase 1 FIH study, TROPION-PanTumor01 (NCT03401385), which is evaluating 
escalating doses of Dato-DXd (0.27 mg/kg to 10 mg/kg) in participants with advanced 
NSCLC and TNBC, relapsed or refractory to SoC therapy. These data have demonstrated 
highly encouraging efficacy across dose groups, with tumor responses observed at doses of 4, 

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6, and 8 mg/kg and an acceptable and manageable toxicity profile (see Section 2.2.2.1). An 
additional cohort of participants with HR-positive, HER2-negative breast cancer is currently 
recruiting as of March 2021.
Given the biological rationale and encouraging preliminary safety and efficacy data obtained 
from the TROPION-PanTumor01 study, the current study is designed to provide a robust and
detailed understanding of the efficacy and safety of Dato-DXd when compared with 
Investigator’s choice of standard-of-care single-agent chemotherapy (eribulin, capecitabine, 
vinorelbine, or gemcitabine; henceforth referred to as ICC) in participants with inoperable or 
metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two 
prior lines of systemic chemotherapy, for which an unmet medical need remains.
2.2
Background
2.2.1
HR-positive, HER2-negative, inoperable/metastatic breast cancer 
Breast cancer is the most common cancer in the world, with an estimated 2.2 million new 
cases in 2020 globally (11.7% of all new cancers). Breast cancer is also the fifth most 
common cause of death from cancer, with an estimated 684000 deaths in 2020 (Sung et al 
2021). In Europe, an estimated 531000 patients were diagnosed with breast cancer in 2020, 
and 141000 died from the disease. Despite advances in the diagnosis and treatment of breast 
cancer, around 6% of women diagnosed with breast cancer in the US have metastatic disease 
at time of diagnosis, and up to 30% of women with early-stage non-metastatic breast cancer 
will develop metastatic disease (O'Shaughnessy 2005). Although treatable, metastatic breast 
cancer remains virtually incurable, with a median survival of approximately 3 years and a 
5-year survival rate of approximately 25% (Cardoso et al 2018). 
Currently, clinical practice typically uses a surrogate classification of three breast cancer 
subtypes, based on molecular characteristics: HER2-positive, HR-positive but HER2-negative, 
and triple-negative. Tumors expressing ER and/or PR are considered HR-positive breast 
cancers, whereas tumors that do not express ER, PR or HER2 are defined as TNBC (Harbeck 
et al 2019). Approximately 70% of all breast cancers are HR-positive, HER2-negative 
(Howlader et al 2014). 
In patients with metastatic HR-positive, HER2-negative breast cancer, the preferred initial 
treatment of choice is endocrine therapy, given either alone or in combination with targeted 
therapies such as CDK4/6 inhibitors, PI3-K, and mTOR inhibitors (Matutino et al 2018, André 
et al 2019). Within these, CDK4/6 as a class has shown to improve both PFS and OS in a 
meta-analysis (Cardoso et al 2018); however, the optimal sequence and integration of the 
agents is not fully established and is largely determined by geographic availability, which 
treatments were previously administered, the response obtained, and individual patient and 
disease characteristics.

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In patients with metastatic HR-positive, HER2-negative breast cancer, who have exhausted or 
are not suitable for endocrine therapy, first-line chemotherapy is the SoC, with sequential 
single-agent chemotherapy (such as eribulin, capecitabine, gemcitabine, vinorelbine) generally 
preferred over combination therapy due to lack of consistent OS benefit and poor tolerability 
with combination therapy (Cardoso et al 2020, NCCN Guidelines 2020).
The following baseline clinico-pathological characteristics/factors could be clinically relevant 
to the targeted study population of interest for this study: 

Proportion of patients with 1 versus 2 prior lines of chemotherapy in the metastatic or 
inoperable setting 

Prior CDK4/6 inhibitor use (yes versus no)

History of brain metastasis (yes versus no).
These and other factors may be recorded in IRT and could be included as part of routine 
monitoring throughout enrolment of the study. Unexpected variations could be evaluated by 
the Sponsor (see Appendix A).
2.2.1.1
Unmet medical need
The SoC of single agent chemotherapy in the HR-positive, HER2-negative metastatic breast 
cancer population has led to reported response rates of approximately 23%, a median PFS of 
7 to 10 months, and a median OS of 26 to 36 months (Jerusalem et al 2018, Kaufman et al 
2015, Twelves et al 2016). After two prior lines of chemotherapy, a median PFS of between 4 
and 5 months and a median OS of between 14 and 24 months has been reported (Twelves et al 
2016, Brufsky 2011, Miller et al 2005, Sparano et al 2010, Barrios 2010, Thomas et al 2007). 
Data after three lines of chemotherapy report a median PFS of approximately 3 to 4 months 
and median OS of between 11 to 16 months (Cortes et al 2011, Yardley et al 2013, Martín et al 
2007, Yuan et al 2019). These data indicate that patients who are not suitable for, or who have 
exhausted, endocrine treatment options have an increasingly poor prognosis, with the greatest 
unmet medical need arising in patients who have received two or three prior lines of 
chemotherapy, for whom median survival is currently less than 2 years.
Chemotherapy is also associated with significant toxicities, including hematologic adverse 
effects, gastrointestinal toxicities including diarrhea, nausea, vomiting, alopecia, and skin 
reactions (Gradishar et al 2005, Miller et al 2007, Piccart-Gebhart et al 2008), which can have 
a significant impact on patient quality of life. Consequently, new and novel treatments for 
participants with HR-positive, HER2-negative advanced breast cancer are still needed to 
improve prognosis, control disease and prevent symptoms while minimizing toxicity, and 
therefore represents an area of considerable unmet medical need. A new class of therapy with 
better efficacy and relatively fewer side effects would therefore be a preferred option in this 

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treatment setting, to offer an alternative after traditional standard chemotherapies.
2.2.2
Dato-DXd
Dato-DXd is being co-developed by Daiichi Sankyo and AstraZeneca as an anticancer agent. 
To date, clinical (preliminary safety and efficacy) data is currently available from one ongoing 
study (TROPION-PanTumor01; sponsored by Daiichi Sankyo). A summary of recent data 
from this study is presented in Section 2.2.2.1. Please refer to the Dato-DXd IB for a list of all 
studies in the Dato-DXd clinical development program, including participant exposure.
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of Dato-DXd is provided in the IB.
2.2.2.1
TROPION-PanTumor01 study
This ongoing Phase I FIH study evaluated escalating doses (0.27 to 10 mg/kg) of Dato-DXd in 
advanced solid tumors in participants with unresectable advanced NSCLC, and is currently in 
the dose expansion phase evaluating selected doses of Dato-DXd in participants with NSCLC, 
TNBC, and ER-positive, HER2-negative breast cancer who have been refractory to or 
relapsed on standard treatment or for which no standard treatment is available.
At the efficacy DCO date, 30 July 2021, preliminary efficacy data from the ongoing 
DS1062-A-J101 study were available. A total of 254 participants were evaluable for response 
assessments (210 with NSCLC and 44 with TNBC), defined as participants who received at 
least 1 dose of Dato-DXd and had pre-treatment and at least 1 post-treatment tumor 
assessment or discontinued from study drug. For participants with TNBC, the DCR was 
76.2% (13 PRs and 16 SDs in 42 participants) in the 6 mg/kg dose group and 100% (1 PR and 
1 SD in 2 participants) in the 8 mg/kg dose group.
Preliminary safety summary, as of 30 July 2021, in participants with breast cancer (TNBC and 
HR+/HER2-breast cancer) are summarized below. A total of 75 (93.8%) participants 
experienced at least 1 TEAE. The most frequently (≥15% of participants) reported TEAEs 
were nausea (45 [56.3%] participants), stomatitis (37 [46.3%] participants), alopecia 
(24 [30.0%] participants), fatigue (24 [30.0%] participants), vomiting (22 [27.5%] 
participants), constipation (16 [20.0%] participants), mucosal inflammation (18 [22.5%] 
participants), and headache (17 [21.3%] participants).
A total of 28 (35.0%) participants experienced ≥Grade 3 TEAEs. The most commonly 
(> 2.5% of participants) reported ≥Grade 3 events by investigator-reported PT were 
lymphocyte count decreased (4 [5.0%] participants), stomatitis (4 [5.0%] participants), fatigue 
(3 [3.8%] participants), and lymphopenia (3 [3.8%] participants). A total of 1 (1.3%) 
participant had TEAEs associated with study treatment discontinuation due to 
investigator-reported PT of pneumonitis. A total of 1 (1.3%) participant experienced TEAEs 

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biopsy, which will provide real-time next-generation sequencing results from the 
FoundationOne®CDx, that may help guide next treatment options.
Overall, participants enrolling onto this study will have a 1:1 chance of the receiving either the 
experimental drug Dato-DXd, or a standard chemotherapy agent. All participants will be 
contributing to the process of developing new therapies in an area of great unmet medical 
need.
2.3.3 Overall Benefit: Risk Conclusion
There is an unmet medical need for efficacious and safe therapies in treatment of HR-positive, 
HER2-negative inoperable or metastatic breast cancer in order to improve clinical outcomes. 
The extensive expression of TROP2 in breast cancers and the proof-of-concept shown by 
sacituzumab govitecan in HR-positive, HER2-negative (and TNBC) metastatic breast cancer 
has demonstrated the strong rationale of using an anti-TROP2-ADC in the HR-positive, 
HER2-negative population (Bardia et al 2021, Kalinsky et al 2020).
Preliminary results from the TNBC cohort of the TROPION-PanTumor01 study have shown 
promising efficacy of Dato-DXd at a dose of 6 mg/kg Q3W and support the further evaluation 
of Dato-DXd in the HR-positive, HER2-negative breast cancer population. In this cohort, the 
most common TEAEs were nausea, stomatitis, alopecia, fatigue, vomiting, constipation, 
mucosal inflammation, and headache. The most common Grade ≥3 TEAEs were lymphocyte 
count decreased, stomatitis, fatigue, and lymphopenia. One participant had TEAEs associated 
with study treatment discontinuation and one participant experienced TEAEs associated with 
an outcome of death.
The 2 most relevant risks considered for the benefit/risk assessment are the important 
identified risk of ILD/pneumonitis and the identified risk of IRR. Both of these risks can be 
fatal. Several measures have been put into place within the CSP to mitigate the incidence of 
pulmonary toxicities, including eligibility criteria that prohibit participants with pre-existing 
pulmonary co-morbidities from entering the study. In addition, baseline pulmonary function 
tests will be performed for all participants. Participants will be monitored closely throughout 
the study and clinical and laboratory assessments will be performed before every cycle. 
Toxicity Management Guidelines are also provided to assist with the management of the most 
commonly reported AEs and AESIs (see the Annex document to this CSP). 
Consequently, compared to the safety profile of SoC chemotherapies, Dato-DXd is a potent 
anticancer therapy with the potential to provide an improved meaningful clinical benefit and a 
more favorable safety profile. Furthermore, the long half-life of Dato-DXd also enables a 
single IV, Q3W regimen, providing convenience to patients. It is therefore of key importance 
to evaluate the role of Dato-DXd in the HR-positive, HER2-negative inoperable or metastatic 
breast cancer population who have had progression of disease on 1 or 2 lines of chemotherapy, 

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and considering the measures to minimize risks to participants, the benefit/risk assessment 
supports the proposed study. 

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3
OBJECTIVES AND ENDPOINTS
Table 4
Objectives and Endpoints
Objectives
Endpoints
Dual Primary
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR.
PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by BICR, or 
death due to any cause. 
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinicallyprogresses prior to RECIST 1.1. 
The measure of interest is the hazard ratio of PFS.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of OS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
OS is defined as time from randomization until the date of 
death due to any cause. 
The comparison will include all randomized participants as 
randomized, regardless of whether the participant withdraws 
from therapy or receives another anticancer therapy.
The measure of interest is the hazard ratio of OS.
Secondary
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of ORR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment.
ORR is defined as the proportion of participants who have a 
confirmed CR or PR, as determined by the 
BICR/Investigator assessment, per RECIST 1.1.
The analysis will include all randomized participants as 
randomized. 
Data obtained from randomization up until 
progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR, 
regardless of whether the participant withdraws from therapy. 
Participants who go off treatment without a response or 
progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR.
The measure of interest is the odds ratio of the ORR.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DoR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
DoR is defined as the time from the date of first documented 
confirmed response until date of documented progression 
per RECIST 1.1, as assessed by BICR/Investigator 
assessment or death due to any cause.
The analysis will include all randomized participants as 
randomized who have a confirmed response, regardless of 
whether the participant withdraws from therapy, receives 
another anticancer therapy or clinically progresses prior to 
RECIST 1.1 progression.
The measure of interest is the median of DoR.

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Objectives
Endpoints
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per investigator assessment.
PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by investigator 
assessment, or death due to any cause. 
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinicallyprogresses prior to RECIST 1.1.
The measure of interest is the hazard ratio of PFS.
To demonstrate the superiority of Dato-DXd
compared to ICC by assessment of DCR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment.
DCR at 12 weeks is defined as the percentage of 
participants who have a confirmed CR or PR or who have 
SD, per RECIST 1.1, as assessed BICR/per investigator 
assessment and derived from the raw tumor data for at least 
11 weeks after randomization. 
Data obtained from randomization up until progression, or the 
last evaluable assessment in the absence of progression, will 
be included in the assessment of DCR, regardless of whether 
the participant withdraws from therapy. Participants who 
receive a subsequent therapy prior to week 11 will not be 
considered to have disease control in the analysis.
The analysis will include all randomized participants as 
randomized.
The measure of interest is the odds ratio of the DCR.
To assess pain in participants treated with 
Dato-DXd compared to ICC.
TTD in pain as measured by the pain scale from EORTC 
QLQ-C30
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants. 
The measure of interest is the hazard ratio of TTD in pain. 
To assess physical functioning in 
participants treated with Dato-DXd 
compared to ICC.
TTD in physical functioning as measured by the physical 
functioning scale from EORTC QLQ-C30
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants. 
The measure of interest is the hazard ratio of TTD in physical 
functioning.
To assess global health status/quality of life 
(GHS/QoL) in participants treated with 
Dato-DXd compared to ICC.
TTD in GHS/QoL as measured by the GHS/QoL scale from 
EORTC QLQ-C30
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration
threshold. The analysis will include all randomized 
participants. 
The measure of interest is the hazard ratio of TTD in 
GHS/QoL.

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Objectives
Endpoints
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TFST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
TFST is defined as the time from randomization until the 
start date of the first subsequent anticancer therapy after 
discontinuation of randomized treatment, or death due to 
any cause.
The analysis will include all randomized participants as 
randomized, regardless of progression status.
The measure of interest is the hazard ratio of TFST.
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TSST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
TSST is defined as the time from randomization to until the 
start date of the second subsequent anticancer therapy after 
discontinuation of first subsequent treatment, or death due to 
any cause.
The analysis will include all randomized participants as 
randomized, regardless of progression status on study 
treatment or first subsequent treatment.
The measure of interest is the hazard ratio of TSST. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS2 in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting.
PFS2 will be defined as the time from the randomization to 
the earliest of the progression event (following the initial 
progression), subsequent to first subsequent therapy, or 
death. The date of second progression will be recorded by 
the Investigator in the eCRF and defined according to local 
standard clinical practice.
The comparison will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from subsequent therapy and regardless of missed visits.
The measure of interest is the hazard ratio of PFS2.
To assess the PK of Dato-DXd 6mg/kg IV 
Q3W.
Plasma concentrations of Dato-DXd, total anti-TROP2 
antibody, and MAAA-1181a (payload). 
To investigate the immunogenicity of 
Dato-DXd 6mg/kg IV Q3W.
Presence of ADA.
Safety
To assess the safety and tolerability profile 
of Dato-DXd compared to ICC.
Safety and tolerability will be evaluated in terms of adverse 
events (graded by CTCAE version 5.0), and also in terms of:

ECOG PS

Vital signs, body weight, physical examination 

Clinical chemistry, hematology, and urinalysis assessments

ECG, ECHO/MUGA and Ophthalmologic assessments
Exploratory
To assess participant-reported symptomatic 
AEs and treatment tolerability.
Proportion of participants experiencing different levels of 
symptomatic AEs as measured by selected items from the 
PRO-CTCAE and EORTC Item Library (IL; ie, EORTC 
IL117) and reporting different levels of overall tolerability as 
measured by the PGI-TT.
The analysis will include all dosed participants. 
The measure of interest will be proportion of participants 
reporting different levels of symptomatic AEs and overall 
tolerability.

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Objectives
Endpoints
To assess participant-reported global 
impression of the severity of overall cancer 
symptoms.
Proportion of participants reporting different levels of global 
impression of the severity of overall cancer symptoms as 
measured by PGIS.
The analysis will include all randomized participants.
The measure of interest will be proportion of participants 
reporting different levels of global impression of the severity 
of overall cancer symptoms.
To assess participant-reported global 
impression of change in health status.
Proportion of participants reporting different levels of global 
impression of change in health status as measured by PGIC.
The analysis will include all randomized participants.
The measure of interest will be proportion of participants 
reporting different levels of global impression of change in 
health status. 
To assess participant-reported symptoms, 
functioning and health-related QoL.
TTD in fatigue and other symptoms as measured by EORTC 
QLQ-C30
TTD in other functioning as measured by EORTC 
QLQ-C30
Change from baseline of symptom, functioning and 
GHS/QoL scores as measured by EORTC QLQ-C30 
The analysis will include all randomized participants. 
The measure of interest will be hazard ratio of TTD in fatigue 
and other symptoms, TTD in other functioning, and mean 
change from baseline of symptom, functioning and GHS/QoL 
scores. 
To assess breast and arm symptoms in 
participants treated with Dato-DXd 
compared to ICC.
TTD in breast symptoms as measured by the breast 
symptoms scale from EORTC QLQ-BR45/IL116
TTD in arm symptoms as measured by the arm symptoms 
scale from EORTC QLQ-BR45/IL116
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change 
from baseline that reaches a clinically meaningful 
deterioration threshold. The analysis will include all 
randomized participants. 
The measure of interest is the hazard ratio of TTD in breast 
symptoms/arm symptoms.
To assess participant-reported health status.
VAS score, its change from baseline and 5-dimension scores 
as measured by EQ-5D-5L
The analysis will include all randomized participants. 
The measure of interest will be mean and mean change from 
baseline of VAS score, and proportion of participants 
reporting different levels of each of 5-dimension scores. 
Association of TROP2 or other tumor 
derived biomarkers with response and 
tolerability to Dato-DXd and ICC. a
Correlation of biomarkers with clinical response (BoR, 
DoR, PFS, OS and other relevant efficacy endpoints) and/or
development of cancer 
Correlation of biomarkers with safety and tolerability 
endpoints
Analysis may include, but is not limited to, the analysis of
tumor biomarkers which include DNA, RNA, proteins or 
metabolite analysis

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Objectives
Endpoints
Association of exploratory biomarkers in 
tumor, plasma, whole blood, or serum 
collected before, during treatment or at 
disease progression with disease status 
and/or response and tolerability to 
Dato-DXd. a 
Correlation of biomarkers with clinical response (BoR, 
DoR, PFS, OS and other relevant efficacy endpoints) and/or 
development of cancer 
Correlation of biomarkers with safety and tolerability 
endpoints
Analysis may include, but is not limited to, the analysis of 
tumor biomarkers which include DNA, RNA, proteins or 
metabolite analysis
Assessment of ctDNA mutational profile 
and dynamic changes as an indicator for 
early response and/or relapse on Dato-DXd, 
and assessment of molecular and genomic 
determinants of response to Dato-DXd in 
tumor and blood. a
Assessment of ctDNA levels and mutational status of 
cancer-associated genes in ctDNA, including dynamic 
changes on treatment and correlation with clinical response 
on Dato-DXd and ICC, and correlation of gene expression 
and cancer gene mutational profile with clinical response.
To explore the impact of treatment and 
disease on health care resource use.
The HOSPAD module will be used to collect information on 
key health care resource use beyond study mandated visits.
a Optional biomarker samples will not be collected in mainland China.

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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3, open-label, randomized study of Dato-DXd versus ICC in participants with 
inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated 
with one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. 
For an overview of the study design, see Figure 1.
Approximately 700 participants will be randomized in a 1:1 ratio to one of 2 intervention 
arms. If required for regulatory submission purposes, the recruitment of participants in 
mainland China may continue beyond the close of the global cohort, to include approximately 
an additional 20 randomized participants in the mainland China cohort. The mainland China 
cohort is defined as all participants from sites in mainland China randomized into the study. A 
participant randomized in the mainland China cohort prior to the last participant randomized 
in the global cohort will be included in both the global and mainland China cohorts. A 
participant randomized in mainland China after the last participant was randomized in the 
global cohort will be included only in the mainland China cohort.
Randomization will be stratified by the following prognostic and/or predictive factors:

Number of previous lines of chemotherapy (1 versus 2)

Geographic region (Region 1 [US, Canada, Europe] versus Region 2 [Rest of World])

Prior use of CDK4/6 inhibitor (Yes versus No)
A 50% cap will be applied to participants who have had 2 prior lines of chemotherapy in the 
inoperable/metastatic setting.
CDK4/6 inhibitors are being increasingly utilized as part of standard of care for patients with 
HR+ breast cancer. To ensure that majority of participants have received prior CDK4/6 
inhibitor therapy in the HER2 negative, HR-positive population, a cap of 49% will be applied 
to participants who have NOT received prior CDK4/6 inhibitor therapy.
The study intervention arms are: 

Arm 1: Dato-DXd (6 mg/kg IV on Day 1, Q3W)

Arm 2: ICC:
Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W); choice between 
the 2 doses will be determined by standard institutional practice.
Gemcitabine (1000 mg/m2 IV on Day 1 and Day 8, Q3W)
Eribulin mesylate (1.4 mg/m2 IV on Days 1 and 8, Q3W)
Vinorelbine (25 mg/m2 IV on Days 1 and 8, Q3W)

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Further details of all study interventions are provided in Section 6. All participants will 
receive study intervention until Investigator-defined disease progression according to 
RECIST 1.1, or until unacceptable toxicity, withdrawal of consent, or another criterion for 
discontinuation is met (see Section 7 for further details). Continued treatment with the same 
study drug post-progression may be allowed, based on prior discussion with study physician 
on case-by-case basis. No crossover between study treatment arms will be allowed.
The study is powered to assess the efficacy of Dato-DXd compared to ICC for the dual 
primary objectives of PFS (per RECIST 1.1, as assessed by BICR) and OS. Other measures of 
efficacy (ORR, DoR, DCR, TFST, TSST, PFS2) and HRQoL will also be evaluated during 
the study, in addition to the safety and tolerability profile of Dato-DXd, PK parameters, and 
immunogenicity. Details of all study objectives and corresponding endpoints are provided in 
Section 3.
All participants must have available a FFPE tumor sample (block preferred, or minimum of 20 
freshly cut slides), at the time of screening. This can be from either the primary disease setting 
(surgical resection or diagnostic sample), or from a metastatic lesion (excluding bone) for 
tissue-based analysis (including but not restricted/limited to IHC staining of potential 
predictive biomarkers as well as tumor mutational analysis). The mandatory FFPE tumor 
sample submitted for analysis should be obtained as close to the time of diagnosis of 
metastatic or inoperable disease as possible.
If neither an adequate FFPE block nor the minimum of 20 slides are available, a patient may 
still be considered eligible. In this situation, approval by the Study Team for patient’s entry 
into the study is required. If there is no written confirmation of the availability of an 
appropriate tumor sample prior to enrolment, the participant will not be eligible for the study. 
At the time of enrolment all participants must have an ECOG PS of 0 or 1.
Note: Sample collection in mainland China will follow local regulatory approval.
A summary of the study periods and timings of study visits and main efficacy assessments is 
provided in Figure 2.
Country-specific study requirements are provided in Appendix L.

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Figure 2
Study Flow Chart

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4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection), which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. Where allowable by local health 
authorities, ethics committees, healthcare provider guidelines (eg, hospital policies) or local 
government, these changes may include the following options: 

Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the ICF should be signed at the participant’s next contact with the study 
site).

Rescreening: Extended rescreening period to confirm eligibility to participate in the 
clinical study can be performed in previously screened participants. The investigator 
should confirm this with the designated study physician. 

Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV).

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix J.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design
This randomized, open-label, 2-arm study will investigate Dato-DXd monotherapy versus ICC 
(eribulin, vinorelbine, capecitabine, or gemcitabine). The open-label design was chosen due to 
the differing dosing schedules of the ICC treatments; however, the trial will be conducted as 
“sponsor-blind” and the specific study intervention (Dato-DXd or ICC) to be taken by a 
participant will be assigned in a randomized manner. To maintain the integrity of the study, 
Sponsor personnel directly involved in the study conduct will not undertake or have access to 
efficacy data aggregated by treatment arm prior to final data readout for the dual primary 

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endpoint of PFS. At Sponsor discretion, the sponsor blind may be dropped if the dual primary 
endpoint of PFS achieves statistical significance at its primary analysis.
4.2.2
Rationale for Choice of Comparator Treatments
Chemotherapy (single agent or doublet) is considered the main treatment option for patients 
who have exhausted or are not suitable for endocrine therapy in the metastatic setting. 
Combination chemotherapy has shown higher ORR, however, could not clearly show an OS 
benefit (Schott 2021). In addition, to balance the OS benefits with the toxicities between 
single agent and combination therapy, single agent sequential chemotherapies are 
recommended. Preferred agents in this setting include capecitabine, gemcitabine, vinorelbine, 
and eribulin (NCCN Guidelines 2020, Cardoso et al 2020). 
Capecitabine is frequently the first choice because of oral administration and low risk of 
alopecia and myelotoxicity. In the large phase 2 study in participants with metastatic breast 
cancer, capecitabine monotherapy achieved an ORR of 20% and median OS of 12.6 months 
(Blum et al 1999). Gastrointestinal side effects and hand-foot syndrome were the most 
commonly occurring adverse events. 
Eribulin has demonstrated anti-tumor activity as single-agent in metastatic breast cancer 
participants. In the EMBRACE trial, eribulin significantly improved OS in heavily pre-treated 
metastatic breast cancer participants as compared to SoC (median OS of 13.1 months versus 
10.6 months). The primary toxicity with eribulin was neutropenia whereas peripheral 
neuropathy was the most common adverse event leading to discontinuation of eribulin (Cortes 
et al 2011).
Vinorelbine has demonstrated activity even in heavily pre-treated participants with metastatic 
breast cancer. In a Phase 3 study of vinorelbine monotherapy versus gemcitabine plus 
vinorelbine, median PFS in the single-agent vinorelbine arm was 4.0 months and OS was 
16.4 months (Martín et al 2007). Vinorelbine rarely induces total alopecia or severe 
gastrointestinal events or symptomatic cardiac events. The major dose-limiting hematological 
toxicity associated with vinorelbine is neutropenia (Domenech and Vogel 2001).
Gemcitabine is active in metastatic breast cancer, with a response rate of approximately 25% 
and a median DoR of 13.5 months. A median OS of 15.2 months has also been reported 
(Possinger et al 1999). The drug is relatively well tolerated; alopecia and gastrointestinal 
toxicity are mild, and its use is not associated with significant neuropathy. Thrombocytopenia 
can be a dose-limiting toxicity. Gemcitabine appears to cross the blood brain barrier and may 
be a good option in participants with a history of CNS metastases (Gridelli et al 1999).

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4.2.3
Rationale for Stratification Factors 
4.2.3.1
Stratification based on previous lines of chemotherapy
The proposed dual primary endpoints of this study are PFS and OS, which are expected to 
differ in their magnitude dependent on whether a participant has received 1 or 2 lines of prior 
chemotherapy (see Section 2.2.1.1 for further details). Therefore, stratification by lines of 
chemotherapy (1 versus 2) has been chosen. Additionally, the study will also cap enrolment at 
50% for participants who have received 2 prior lines of chemotherapy.
4.2.3.2
Stratification based on prior CDK4/6 inhibitor use
Differences in the magnitude of benefit in PFS and OS are also expected in participants 
receiving TROP2 inhibitors, dependent on whether treatment with a prior CDK4/6 inhibitor 
has been received. In HR-positive, HER2-negative participants treated with sacituzumab 
govitecan (a TROP2 ADC approved for use in metastatic TNBC by in the US), a subgroup 
analysis performed on prior CDK4/6 inhibitor use (no prior use versus prior use) demonstrated 
notable differences in median PFS, OS, and ORR (Kalinsky et al 2020). It is expected that the 
majority of study participants will have received CDK4/6 inhibitors. There are however global 
regions where CDK4/6 inhibitors are not yet adopted, and as such patients may be enrolled, 
stratification based on prior CDK4/6 inhibitor use are proposed.
4.2.3.3
Stratification based on geographical region
Mortality rates from breast cancer vary by geographic region, due to regional differences in 
drug availability and medical practice. In many western countries, mortality rates due to breast 
cancer are decreasing, which has been attributed to a combination of early detection using 
mammographic screening and improved treatment options. In contrast, mortality rates in many 
South American, African, and Asian countries increased (Youlden et al 2012). Given these 
examples of differences in outcomes in various regions, stratification based on geographical 
region is proposed.
4.2.4
Rationale for Primary Efficacy Endpoints
The primary dual endpoints of the study are OS and PFS by BICR, according to RECIST 1.1 
in the ITT. These endpoints are in line with the guidelines outlined by the NCI Breast Cancer 
Steering Committee Working Group Report (Seidman et al 2018), which recommends OS to 
be a primary endpoint in poor prognosis disease settings, and PFS to be a most robust and 
appropriate endpoint in HR-positive, HER2-negative disease, which has longer post-
progression survival. 
Overall survival is a clinically meaningful and direct measure of overall efficacy in metastatic 
breast cancer disease, and both the EMA (EMA 2017) and FDA (FDA 2018) advice consider 
OS as the most persuasive and reliable endpoint. However, both Agencies also consider PFS 
as an acceptable endpoint, dependent on the disease under study and other factors. For a 
randomized Phase 3 study, PFS is a relevant measure of clinical benefit that demonstrates 

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superiority of a new antineoplastic therapy, particularly in a setting where patients may 
frequently change chemotherapy agents due to side effects or progressive disease. 
Progression-free survival is an objective endpoint and is potentially less affected by post 
discontinuation therapies (as opposed to OS). A sufficiently prolonged PFS may therefore be 
considered in itself a clinically relevant effect, provided detriments on other important 
endpoints can be excluded, particularly if the magnitude of effect is large and the therapy has 
an acceptable risk/benefit profile. When rigorously tested, a robust treatment effect based on 
PFS complemented by no detriment in OS, can offer treatments to be made available early for 
patients with limited options especially in studies with long OS.
Given these factors, and in recognizing the value of both PFS and OS as measures of overall 
efficacy, both are planned as dual primary endpoints.
4.2.5
Rationale for Other Study Endpoints
The secondary endpoints of this study are in line with the recommendations outlined in the 
NCI Breast Cancer Steering Committee Working Group Report (Seidman et al 2018).
The secondary participant-reported pain, physical functioning and global health status/quality 
of life endpoints, assessed using EORTC QLQ-C30, as well as participant-reported 
symptomatic AEs measured by selected items from the PRO-CTCAE/EORTC IL117 will 
show the overall influence of the benefits and toxicity of the treatment from the participant’s 
perspective and will aid in understanding the benefit/risk evaluation. These PRO 
questionnaires are well-established instruments that have been previously included in cancer 
clinical studies.
Biological samples will be used to explore potential biomarkers in tumor, plasma, and/or 
serum, which may predict the progression of cancer (and associated clinical characteristics) 
and/or tumor response. By mandating tumor sample collection as part of the study design, 
TROP2 expression will be tested retrospectively by IHC, to explore correlation with treatment 
response. Increased TROP2 mRNA in breast cancer has been shown to be a predictor of 
lymph node involvement, distant metastasis, and poor OS (Zhao et al 2018). In one 
heterogenous breast cancer series, TROP2 analysis by IHC showed 92.6% (38/42) of tumors 
expressed TROP2 (Yang et al 2021). Internal AstraZeneca analysis of TROP2 expression also 
shows broad levels of expression in > 90% of HR-positive breast cancer clinical samples 
(unpublished data).
The safety and tolerability of Dato-DXd will be assessed by the standard safety endpoints. 
Careful consideration has been given to the mitigation of risks related to the mode of action 
and the nature of the target, which will be closely monitored during the study. 

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4.3
Justification for Dose
4.3.1
Dato-DXd
The 6.0 mg/kg IV dose of Dato-DXd was selected based on preliminary results of the ongoing 
Phase 1, 2-part (dose escalation and dose expansion), multicenter, nonrandomized, open-label, 
multiple dose, first-in-human study (Study DS1062-A-J101) in participants with solid tumors. 
In this study, Dato-DXd showed a generally tolerable safety profile in participants with 
NSCLC across a dose range of 0.27 mg/kg to 8.0 mg/kg. During the dose escalation phase, the 
non-tolerated dose for Dato-DXd was 10.0 mg/kg, where 2 participants had Grade 3 
dose-limiting toxicities of mucosal inflammation and stomatitis. One participant at 6.0 mg/kg 
had a dose-limiting toxicity of Grade 3 maculopapular rash. The maximum tolerated dose 
(8.0 mg/kg) was determined during the dose escalation phase.
However, an ongoing review of emerging Phase 1 study data has allowed a closer evaluation 
of the benefit/risk balance by dose. Based on these data, the Dato-DXd 6 mg/kg dose has a 
more favorable benefit/risk balance than the 8 mg/kg dose; thus, the 6 mg/kg is the optimal 
monotherapy dose for further development of Dato-DXd in clinical studies.
Based on review of the safety data as of 16 November 2021, Dato-DXd exhibited an 
acceptable safety profile with established risk monitoring and risk mitigation measures for the 
important identified risks of ILD/pneumonitis and IRR as well as the AESIs of 
ILD/pneumonitis, IRR, oral mucositis/stomatitis, mucosal inflammation other than oral 
mucositis/stomatitis, and ocular surface toxicity.
Overall, the safety and tolerability profile of Dato-DXd 6 mg/kg remains acceptable and 
manageable. The 6 mg/kg dose has a better benefit/risk profile than the 8 mg/kg dose and thus 
supports continued clinical development of Dato-DXd at this dose.
The mean terminal half-life of Dato-DXd was 4.82 days at the 6.0 mg/kg dose, thus 
supporting a Q3W dosing schedule.
For information on dose modifications for Dato-DXd, see Section 6.6.
4.3.2
Investigator Choice of Chemotherapy (ICC)
The dosages of the ICC agents (capecitabine, gemcitabine, vinorelbine, eribulin) to be used in 
the current study are based on recommendations in the Prescribing Information for each agent, 
and are in accordance with current international breast cancer treatment guidelines (NCCN 
Guidelines 2020, Cardoso et al 2020).
In specific relation to capecitabine, 2 dose options have been selected for use (to be 
determined by standard institutional practice), as dose tolerance is different between some 
patients due to pharmacogenetic differences (Midgley and Kerr 2008). For example, in the 
FDA label for capecitabine, Japanese patients had a lower concentration (Cmax) of drug at the 

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same dose given to Caucasian patients (Capecitabine USPI 2015).
4.4
End of Study Definition
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs 
under FDA and EU regulatory requirements:

European Union requirements define study completion as the last visit of the last subject 
for any protocol related activity.

United States FDA requirements defines 2 completion dates:
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified protocol 
or was terminated. In the case of clinical studies with more than one primary outcome 
measure with different completion dates, this term refers to the date on which data 
collection is completed for all the primary outcomes.
Study Completion Date – is defined as the date the final participant is examined or 
receives an intervention for purposes of final collection of data for the primary and 
secondary outcome measure and AEs (for example, last participant’s last visit), 
whether the clinical study concludes according to the pre-specified protocol or is 
terminated.
A participant is considered to have completed the study if they have completed all phases of 
the study, including the last visit shown in the SoA (Section 1.3), and undergone determination 
of OS.
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings.
See Section 6.7 for details on participant management following the final DCO, as well as 
following study completion.
5
STUDY POPULATION
The target population of interest in this study is participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines 
of systemic chemotherapy in the inoperable/metastatic setting. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Participants who do not meet the eligibility criteria requirements are screen failures; refer to 
Section 5.4. 

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Country-specific study requirements are provided in Appendix L.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥18 years at the time of screening. 
Type of Participant and Disease Characteristics
2
Inoperable or metastatic HR-positive, HER2-negative breast cancer (per ASCO/CAP 
guidelines, on local laboratory results); ie, is documented as HR-positive (either ER 
and/or PgR positive [ER or PgR ≥1%]) and HER2-negative. If a participant had multiple 
results after metastatic disease, the most recent local test result will be used to confirm 
eligibility (Allison et al 2020, Wolff et al 2018). 
3
Progressed on and not suitable for endocrine therapy per investigator assessment, and 
treated with 1 to 2 lines of prior standard of care chemotherapy in the 
inoperable/metastatic setting. Participant must have documented progression on their 
most recent line of chemotherapy. 
Note: If a chemotherapy drug is changed within 28 days of use to another drug in the same class (ie, 
antimetabolite to antimetabolite) for any reason, the first drug is not counted as a line.
Targeted agents (such as mTOR inhibitors, PD-1/PD-L1 inhibitors, PARP inhibitors), endocrine therapies, 
and CDK4/6 inhibitors on their own do not contribute to the count of prior lines of chemotherapy; however, 
regimens with such agents in combination with metastatic chemotherapy should be classified as one line of 
chemotherapy.
4
Eligible for one of the chemotherapy options listed as ICC (eribulin, capecitabine, 
vinorelbine, gemcitabine), per investigator assessment. 
Note: Participants who previously received any of these agents are eligible for enrolment to another ICC 
agent in this study.
5
ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to day of first 
dosing.
6
At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 
Target Lesion at baseline and can be accurately measured at baseline as ≥10 mm in the 
longest diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or 
MRI, which is suitable for accurate repeated measurements. 
Note: Participants with bone-only metastases are not permitted.
7
Participants with a history of previously treated neoplastic spinal cord compression, or 
clinically inactive brain metastases, who require no treatment with corticosteroids or 
anticonvulsants, may be included in the study, if they have recovered from the acute toxic 

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effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of 
radiotherapy and study enrolment.
8
Adequate organ and bone marrow function within 7 days before day of first dosing as 
follows:
-
Hemoglobin: ≥ 9.0 g/dL. Red blood cell/plasma transfusion is not permitted within 
1 week prior to screening assessment.
-
Absolute neutrophil count: 1500/mm3. Granulocyte colony-stimulating factor 
administration is not permitted within 1 week prior to screening assessment.
-
Platelet count: 100000/mm3. Platelet transfusion is not permitted within 1 week 
prior to screening assessment.
-
Total bilirubin: ≤ 1.5 × ULN if no liver metastases; or ≤ 3 × ULN in the presence of 
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver 
metastases at baseline.
-
ALT and AST: ≤ 3 × ULN for AST/ALT; however, if elevation is due to liver 
metastases, ≤ 5.0 × ULN is allowed.
-
Calculated creatinine clearance: ≥ 30 mL/min as calculated using the Cockcroft-
Gault equation (using actual body weight):
   Female:  
CrCl = 
    Weight (kg) × (140 - Age)      × 0.85
(mL/min)
72 × serum creatinine (mg/dL)
   Male:  
CrCl = 
    Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
9
LVEF ≥50% by either an echocardiogram or MUGA within 28 days of first dosing.
10 Has had an adequate treatment washout period before Cycle 1 Day 1, defined as:
-
Major surgery: ≥3 weeks.
-
Radiation therapy including palliative radiation to chest: ≥4 weeks (palliative 
radiation therapy to other areas ≥2 weeks).
-
Anticancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule 
targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer).
-
Antibody-based anticancer therapy: ≥4 weeks with the exception of receptor 
activator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumab for 
the treatment of bone metastases).
-
Immunotherapy (non-antibody-based therapy): ≥ 2 weeks or 5 times the terminal 
elimination T½ of the agent, whichever is longer.

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-
Chloroquine/hydroxychloroquine: > 14 days.
11 All participants must have available a FFPE tumor sample (block preferred, or a 
minimum of 20 freshly cut slides), at the time of screening.  This can be from either the 
primary disease setting (surgical resection or diagnostic sample), or from a metastatic 
lesion (excluding bone) for tissue-based analysis (including but not restricted/limited to 
IHC staining of potential predictive biomarkers as well as tumor mutational analysis). 
The mandatory FFPE tumor sample submitted for analysis should be obtained as close to 
the time of diagnosis of metastatic or inoperable disease as possible. If neither an 
adequate FFPE block nor the minimum of 20 slides are available, a patient may still be 
considered eligible. In this situation, approval by the Study Team for patient’s entry into 
the study is required.
Note: Sample collection in mainland China will comply with local regulatory approval.
12 Minimum life expectancy of 12 weeks at screening.
Sex
13 Male or female.
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies; however, oral estrogens 
are not permitted.
Reproduction
14 Negative pregnancy test (serum) for women of childbearing potential.
15 Female participants must be post-menopausal for at least 1 year, surgically sterile, or 
using one highly effective form of birth control (a highly effective method of 
contraception is defined as one that can achieve a failure rate of less than 1% per year 
when used consistently and correctly). For female contraception, please refer to 
Appendix G. Women of childbearing potential who are sexually active with a non-
sterilized male partner must agree to use one highly effective method of birth control. 
They should have been stable on their chosen method of birth control starting at a 
minimum of 3 months before C1D1 to at least 7 months after the last dose (see 
Appendix G for complete list of highly effective birth control methods). Female 
participants must refrain from egg cell donation and breastfeeding while on study and for 
at least 7 months after the last dose of study intervention. Non-sterilized male partners of 
a woman of childbearing potential must use a male condom plus spermicide (condom 
alone in countries where spermicides are not approved) throughout this period.
16 Male participants who intend to be sexually active with a female partner of childbearing 
potential must be surgically sterile or using a highly effective method of contraception 

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(see Appendix G) from the time of screening throughout the total duration of the study 
and the drug washout period (at least 4 months after the last dose of study intervention) to 
prevent pregnancy in a partner. Male participants must not donate or bank sperm during 
this same time period. Not engaging in heterosexual activity (sexual abstinence) for the 
duration of the study and drug washout period is an acceptable practice if this is the 
preferred usual lifestyle of the participant; however, periodic or occasional abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of contraception. 
Female partners of male participants are allowed to use HRT for contraception.
Informed Consent
17 Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
18 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of sample for optional genetic research that supports Genomic 
Initiative. 
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled 
systemic diseases, uncontrolled hypertension, history of allogeneic organ transplant, and 
active bleeding diseases, ongoing or active infection, or significant or cardiac or 
psychological conditions) which, in the investigator’s opinion, makes it undesirable for 
the participant to participate in the study or that would jeopardize compliance with the 
protocol. 
2
History of another primary malignancy except for malignancy treated with curative intent 
with no known active disease within 3 years before the first dose of study intervention 
and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the
skin and squamous cell carcinoma of the skin that has undergone potentially curative 
therapy, adequately resected non-melanoma skin cancer, curatively treated in situ disease, 
or other solid tumors curatively treated.
3
Persistent toxicities caused by previous anticancer therapy (excluding alopecia), not yet 
improved to CTCAE Version 5.0 Grade ≤1 or baseline. Note: participants may be 
enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 
2 for at least 3 months prior to first dosing and managed with SoC treatment) which the 
investigator deems related to previous anticancer therapy, including (but not limited to): 
-
Chemotherapy-induced neuropathy.

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Fatigue.
-
Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 
endocrinopathies which may include:

Hypothyroidism/hyperthyroidism.

Type I diabetes.

Hyperglycaemia.

Adrenal insufficiency
o
Adrenalitis.

Skin hypopigmentation (vitiligo).
4
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected 
infections (eg, prodromal symptoms); or inability to rule out infections.
Note: Participants with localized fungal infections of skin or nails are eligible.
5
Known active or uncontrolled hepatitis B or C infection. Participants are eligible if they:
a.
Have been curatively treated for HCV infection as demonstrated clinically and by 
viral serologies
b. Have received HBV vaccination with only anti-HBs positivity and no clinical signs 
of hepatitis
c.
Are HBsAg- and anti-HBc+ (i.e., those who have cleared HBV after infection) and 
meet conditions i-iii below:
d. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet 
conditions i-iii below:
i.
HBV DNA viral load < 2000 IU/mL
ii.
Have normal transaminase values, or, if liver metastases are present, 
abnormal transaminases, with a result of AST/ALT <3 × ULN, which are 
not attributable to HBV infection
iii.
Start or maintain antiviral treatment if clinically indicated as per the 
investigator
6
Known HIV infection that is not well controlled. All of the following criteria are required 
to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count 
> 350 cells/mm3, no history of AIDs-defining opportunistic infection within the past 
12 months, and stable for at least 4 weeks on same anti-HIV retroviral medications 
(meaning there are no expected further changes in that time to the number or type of 
antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, 
monitoring of viral RNA load and CD4+ count is recommended. Participants must be 
tested for HIV if acceptable by local regulations or an IRB/EC.

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7
Uncontrolled or significant cardiac disease, including myocardial infarction or 
uncontrolled/unstable angina within 6 months prior to C1D1, CHF (New York Heart 
Association Class II to IV), uncontrolled or significant cardiac arrhythmia, or 
uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood 
pressure > 110 mmHg).
8
Investigator judgment of 1 or more of the following:
Mean resting corrected QTcF interval > 470 ms, obtained from triplicate ECGs 
performed at screening.
History of QT prolongation associated with other medications that required 
discontinuation of that medication, or any current concomitant medication known to 
prolong the QT interval and cause Torsades de Pointes.
Congenital long QT syndrome, family history of long QT syndrome, or unexplained 
sudden death under 40 years of age in first-degree relatives.
9
History of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening.
Note: Participants found to have ILD/pneumonitis on baseline screening chest CT are not eligible.
10 Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli 
within three months of first dosing, severe asthma, severe COPD, restrictive lung disease, 
pleural effusion etc), or any autoimmune, connective tissue or inflammatory disorders 
with pulmonary involvement (ie, Rheumatoid arthritis, Sjogren's, sarcoidosis etc), or prior 
pneumonectomy.
11 Leptomeningeal carcinomatosis.
12 Clinically significant corneal disease.
13 Known active tuberculosis infection (clinical evaluation that may include clinical history, 
physical examination and radiographic findings, or tuberculosis testing in line with local 
practice).

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Prior/Concomitant Therapy
14 Any of the following prior anticancer therapies:
Any treatment (including ADC) containing a chemotherapeutic agent targeting 
topoisomerase I
TROP2-targeted therapy
Prior treatment with same ICC agent 
(Note: Participants are eligible for enrolment into this study if they able to receive treatment with another 
ICC agent not previously received; see Inclusion Criterion 4)
15 Any concurrent anticancer treatment, with the exception of bisphosphonates, denosumab, 
for the treatment of bone metastases. 
16 Concurrent use of systemic hormonal replacement therapy (eg, estrogen). However, 
concurrent use of hormones for non-cancer related conditions (eg, insulin for diabetes) is 
acceptable.
17 Major surgical procedure (excluding placement of vascular access) or significant 
traumatic injury within 3 weeks of the first dose of study intervention or an anticipated 
need for major surgery during the study.
18 Receipt of live, attenuated vaccine within 30 days prior to the first dose of study 
treatment.
19 Criterion removed in Protocol version 3.0.
Prior/Concurrent Clinical Study Experience
20 Previous treatment in the present study. 
21 Participation in another clinical study with a study intervention or investigational 
medicinal device administered in the last 4 weeks prior to first dosing, randomization into 
a prior Dato-DXd or T-DXd (trastuzumab deruxtecan) study regardless of treatment 
assignment, or concurrent enrolment in another clinical study, unless it is an observational 
(noninterventional) clinical study or during the follow-up period of an interventional 
study.
22 Participants with a known hypersensitivity to Dato-DXd, or any of the excipients of the 
product (including, but not limited to, polysorbate 80).
23 Known history of severe hypersensitivity reactions to other monoclonal antibodies.

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Other Exclusions
24 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
25 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
26 For women only, currently pregnant (confirmed with positive pregnancy test) or 
breastfeeding, or who are planning to become pregnant. 
5.3
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:

Participants must follow the contraception requirements outlined in Appendix G.

Participants should not donate blood or blood components while participating in this 
study and through 28 (+7) days after the last dose of study intervention. Preservation of 
ova and sperm should be considered prior to enrolment in this study.

Use of tobacco products, e-cigarettes and vaping is strongly discouraged, but not 
prohibited. Any prior or current use of these products should be recorded in the eCRF.
Restrictions relating to concomitant therapies are described in Appendix I 2.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a single time. Rescreened participants should be assigned the same participant 
number (ie, E-code) as for the initial screening. However, rescreening should be documented 
so that any effect on study results can be assessed. 
All assessments must be repeated for rescreening unless they are within 28 days of 
randomization.
Screen failure participants should have the reason for study withdrawal recorded in the eCRF 
as “eligibility criteria not fulfilled” (ie, participant does not meet the required 

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temperature excursion is detected at any time during the study, sites will follow the reporting 
procedures for notifying the sponsor (or designated party); release of study intervention for 
clinical use can only occur once the event has been reviewed and approval is provided by the 
sponsor (or designated party).
Only authorized site staff may prepare, dispense and administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labelled storage conditions with access limited to 
authorized site staff (and investigator, where applicable).
The investigator is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records reflecting destruction or 
return of all unused study intervention); this task may be delegated to study staff members 
identified on the site delegation log. The investigator (or designee) is responsible for ensuring 
that the participant has returned all unused study intervention.
Further guidance and information for the final disposition of unused study interventions are 
provided in the Study Reference Manual.
6.2.1
Dato-DXd
Dato-DXd will be supplied as a 100 mg lyophilized powder for concentrate for solution for 
infusion. The reconstituted solution contains 20 mg/mL Dato-DXd in 
mM 
histidine/histidine HCl, % (w/v) sucrose, 
% (w/v) polysorbate 80; it has a pH of 6.0 and 
density of 1.04 g/mL. The post-reconstitution volume is 5 mL. The reconstituted drug product 
is a clear to slightly opalescent, colorless to slightly yellow liquid and practically free from 
visible particles. 
6.2.1.1
Preparation of Dato-DXd
The dose of Dato-DXd for administration must be prepared by the pharmacy staff members 
(or an appropriate designee trained in study drug preparation), using aseptic technique in 
compliance with local regulations and site requirements.
Dato-DXd should be handled in accordance with practices required for hazardous drugs (i.e., 
chemotherapy). 
Incompatibilities have been identified with 0.9% sodium chloride for injection and must not
be used for dose preparation.
The total time from needle puncture of the Dato-DXd vial to the start of administration must 
not exceed 24 hours at 2 °C to 8 °C (36 °F to 46 °F), otherwise a new dose must be prepared 
from new vials.
Following preparation and during administration, the prepared IV bag must be covered by a 
light protection cover; the cover must be applied immediately after dose preparation and 
CCI
CCI
CCI

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remain on throughout the administration time.
Refer to the Pharmacy Manual for detailed information about preparation and handling of 
Dato-DXd.
6.2.1.2
Administration of Dato-DXd
Pre-medication is required prior to any dose of Dato-DXd and must include antihistamines 
and acetaminophen, with or without glucocorticoids. Participants should remain at the site for 
at least 1-hour post-infusion of every dose of Dato-DXd for close observation for possible 
IRRs.
It is also highly recommended that participants receive prophylactic anti-emetic agents prior 
to infusion of Dato-DXd and on subsequent days as needed. Antiemetics such as 5-HT3 
receptor antagonists, NK1 receptor antagonists and steroids (eg, dexamethasone) should be 
considered and administered in accordance with the prescribing information or institutional 
guidelines.
Dato-DXd must reach room temperature prior to administration.
Incompatibilities have been observed with 0.9% sodium chloride for injection and must not be 
used for drug administration; additionally these solutions must not be co-infused in the same 
IV line as Dato-DXd.
Dato-DXd will be administered using an IV bag containing 5% dextrose injection through an 
IV administration set, using local practices. Do not shake the prepared IV bag.
The infusion must be administered with a 0.2- or 0.22-μm filter; acceptable configurations 
include an IV set containing an in-line filter or the attachment of a separate filter to the distal 
end of the IV tubing.
Dato-DXd infusion time is approximately 90 minutes (±10 minutes) for the first infusion. If 
the first infusion is well tolerated and the participant does not experience an infusion-related 
reaction, then the minimum infusion time for subsequent cycles is 30 minutes. 
In case of interruptions, the total cumulative time from needle puncture of the Dato-DXd vial 
to the end of infusion must not exceed 4.5 hours with the IV bag kept at room temperature, 
otherwise a new dose must be prepared from new vials to complete the dose.
Do not co-administer other drugs through the same IV line.
After the content of the IV bag is administered, the IV line will be flushed with a volume of 
5% dextrose for injection equal to the IV-line volume, at the same rate as infusion according 
to local practices, to ensure the full dose is administered.

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The total infusion time recorded in the EDC system reflects when the infusion IV bag is 
empty; this time does not include the post-infusion flush.
If an IRR (such as fever and chills, with and without nausea/vomiting, pain, headache, 
dizziness, dyspnea, hypotension) is observed during administration, the infusion speed should 
be reduced by 50% and participants should be closely monitored.
The participant’s weight at screening (baseline) will be used to calculate the initial dose. If, 
during the course of treatment, the participant’s weight changes by ≥ ±10%, the participant’s 
dose will be recalculated based on the participant’s updated weight. After the re-calculation, 
the participant’s updated weight will be used as the new baseline weight. The site may follow 
local institutional policy for recalculating dose based on weight changes less than 10%. 
6.2.1.3
Monitoring of Dato-DXd Administration
Participants will be monitored during and after infusion of Dato-DXd. Vital signs will be 
measured according to the SoA and Section 8.2.2.
Management of study intervention-related toxicities are described in the TMGs for Dato-DXd, 
(see the Annex document to this CSP). As with any biologic product, IRRs to dose 
administration are possible. Therefore, appropriate drugs and medical equipment to treat acute 
anaphylactic reactions must be immediately available, and study personnel must be trained to 
recognize and treat anaphylaxis.
6.2.1.4
Storage of Dato-DXd
The investigator, or an appropriate delegate, will ensure that all study intervention is stored in 
a secured area, at appropriate temperatures and as specified on the label, and in accordance 
with applicable regulatory requirements. A calibrated temperature monitoring device will be 
used to record the temperature conditions in the drug storage facility. A temperature log will 
be used to record the temperature of the storage area. Temperature excursions outside the 
permissible range listed in the clinical supply packaging are to be reported to the 
Study Monitor upon detection. Storage conditions stated in the respective IBs may be 
superseded by the label storage instructions.
Investigational product vials are stored at 2 °C to 8 °C (36 °F to 46 °F) and must not be 
frozen. Investigational product must be kept in original packaging until use to prevent 
prolonged light exposure. 
6.2.2
Investigator’s Choice of Chemotherapy
Participants will receive ICC (eribulin, capecitabine, vinorelbine and gemcitabine) at the doses 
specified in Table 5. The choice of chemotherapy must be pre-defined prior to randomization. 
The number of treatment cycles for ICC is not fixed. Refer to the local label for details on 
handling. 

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7 0 of 2 4 1
T he I C C a ge nts will eit her be l ocall y s o urce d b y  t he st u d y site or ce ntrall y s u p plie d b y 
Astra Ze neca a n d will be a d mi nistere d a cc or di n g t o Prescri bi n g I nf or mati o n or treat me nt 
g ui da nce i n ge neral use b y t he i n vesti gati n g site. U n der certai n circ u msta nces w he n l ocal 
s o urci n g b y t he st u d y site is n ot feasi ble, Astra Ze neca will ce ntrall y s u p pl y t he dr u g, w hic h 
will be la belle d wit h lo c al  la n g ua ge tra nslate d te xt i n acc or da nce wit h re g ulat or y g ui deli nes.
6. 3
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g
6. 3. 1
P artici p a nt E nr ol me nt a n d R a n d o miz ati o n
All partici pa nts will be ce ntrall y assig ne d t o ra n d o mize d st u d y  int er ve nt i on usi n g a n I RT.  
Bef ore t he st u d y  is i nitiate d, t he call/l o g -i n directi ons a n d user g ui des f or t he I R T will be 
pr o vi de d t o eac h site. 
If a partici pa nt wit h dra ws fr om t he st u d y, t he n t heir e nr ol me nt c o de ca nn ot be re use d. 
Wit h dra w n partici pa nts will n ot be re place d.
I n vesti gat ors s h o ul d kee p a rec or d (ie, t he partici pa nt scree ni n g l o g) of partici pa nts w h o 
e ntere d scree ni n g.
At  scree ni n g/ baseli ne ( u p t o 2 8 da ys bef ore C 1 D 1), t he i n vesti gat ors ( or s uita bl y traine d 
d el e gate) will:

O btai n si g ne d i nf or me d c o nse nt bef ore a n y st u d y -s pecific pr oce d ures are perf or me d. If 
la b orat or y or i ma gi n g pr oce d ures were perf or me d f or alter nate reas o ns pri or t o si g ni n g 
c o nse nt, t hese ca n be use d f or scree ni n g p ur p oses wit h c o nse nt of  t he partici pa nt. 
H o we ver, all scree ni n g la b orat or y  a n d i ma gi n g res ults must ha ve bee n o btai ne d wit hi n 
2 8 d a y s of ra n d o mizati on e xce pt f or vir us a nt i b o d y test res ults a n d he patitis B vir us 
s urface a nti ge n, w hic h ca n be use d if perf or me d wit hi n 1 2 0 da ys before scree ni n g. 

P arti cipa nts will be i de ntifie d t o t he I R T per c o u ntr y  re g ulat i ons. O btai n a u ni q ue 7 -di gi t 
e nr o l me nt n u m ber ( E-c o de) t hr o u g h t he I R T i n t he f o ll owi n g f or m at: 
 
. T his n u m ber is t he partici pa nt’s u ni q ue i de ntifier a n d is use d 
t o ide nt if y t he partici pa nt o n t he e C R Fs.

Deter mi ne partici pa nt eli gi bilit y (see Sect i ons  5. 1 a n d 5. 2 ).

O btai n si g ne d i nf or me d c o nse nt f or t he o pti o nal Ge n o mics I nit iati ve. Partici pa nts w h o 
deci de n ot t o si g n t he s pecific ge net ic I C F, b ut t he ge neral st u d y I C F, are eli gi ble f or 
st u d y e nr ol me nt a n d all ot her st u d y pr oce d ures.
At  ra n d o mizati on, o nce t he partici pa nt is c o nfir me d t o be eli gi ble, t he i n vesti gat or ( or s uita bl y 
trai ne d dele gate) will:
P P D
P P D

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
Select the ICC treatment (based on the most appropriate option for the participant) that 
the participant would receive if randomized to the ICC group prior to randomization of 
the participant. This must be completed for all participants. The selection will be recorded 
in the IRT system.

Assign a randomized treatment group via the IRT. Randomization codes will be assigned 
strictly sequentially within each stratum and site/country/region as participants become 
eligible for randomization. The system will randomize the eligible participant to one of 
the 2 treatment groups. 
If the participant is ineligible and not randomized, the IRT should be accessed to terminate the 
participant in the system.
Participants will begin treatment on Day 1. Participants must not be randomized and treated 
unless all eligibility criteria have been met.
6.3.2
Procedures for Handling Incorrectly Enrolled or Randomized 
Participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Participants who 
are enrolled but subsequently found not to meet all the eligibility criteria must not be 
randomized or started on study intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the participant 
from treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented and that the potential benefit/risk profile remains positive for the participant.
6.3.3
Methods for Assigning Treatment Groups
The actual treatment given to participants will be determined by the randomization scheme in 
the IRT. The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers. One randomization 
list will be produced for each of the randomization strata. A blocked randomization will be 
generated, and all centers will use the same list in order to minimize any imbalance in the
number of participants randomized to each treatment group.
Randomization codes will be assigned strictly sequentially (refer to the 3 stratification factors 
in Section 4.1), as participants become eligible for randomization. When study intervention is 
provided centrally by AstraZeneca, the IRT will provide the kit identification number to be 
allocated to the participant at the randomization visit and subsequent treatment visits. If 

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medication is provided locally, IRT will not provide kit numbers.
6.3.4
Methods for Ensuring Blinding
This is an open-label study for the personnel at study sites; however, the trial will be 
conducted as “sponsor-blind” and the specific study intervention (Dato-DXd or ICC) to be 
taken by a participant will be assigned using an IRT. To maintain the integrity of the study, 
AstraZeneca personnel directly involved in the study conduct will not undertake or have 
access to efficacy data aggregated by treatment arm prior to final data readout for the primary 
endpoint. Before the first participant is randomized, a Study Integrity Plan document will be 
generated, in which data access levels for relevant AstraZeneca personnel will be pre-
specified.
6.4
Study Intervention Compliance
When participants are dosed at the study site (applicable to Dato-DXd and ICC agents 
gemcitabine, eribulin and vinorelbine), they will have study intervention prepared, dispensed 
and administered by the investigator or designee, under medical supervision. The date, and 
time (if applicable), of the administered study intervention will be recorded in the source 
documents and recorded in the eCRF. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing in accordance with local treatment 
verification practices. Deviation(s) from the prescribed dosage regimen should be recorded in 
the eCRF.
When participants self-administer study intervention(s) at home (as applicable to the ICC 
agent capecitabine), compliance with study intervention will be assessed at each visit. 
Compliance will be assessed by direct questioning and counting returned tablets, as well as by 
the review of participant completed dosing diaries during the site visits and documented in the 
source documents and eCRF. A record of the number of capecitabine tablets dispensed to and 
taken by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention delays 
and/or dose reductions will also be recorded in the eCRF.
The Investigational Product Storage Manager is responsible for managing the study 
intervention from receipt by the study site until the destruction or return of all unused study 
intervention. 
6.5
Concomitant Therapy
Any concomitant treatment, procedure, vaccine, or other medication considered necessary by 
the investigator for the participant’s safety and wellbeing (including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) or other specific categories of 
interest, that the participant is receiving from the time of screening or receives during the 
study, including the 28 (+7) day safety follow-up period following the last dose of study 

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intervention must be recorded in the eCRF along with:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency.
The Study Clinical Lead should be contacted if there are any questions regarding concomitant 
or prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded.
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix I 2.
For participants randomized to receive ICC, refer to the local Prescribing Information with 
regard to warnings, precautions, and contraindications. 
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix I 1.
All concomitant medications administered during the study should be recorded until the end of 
the safety follow-up period. Concomitant medications administered as treatment for drug-
related AESIs should be recorded in eCRF until either event resolution, end of study, trial 
termination, withdrawal of consent, or subject death.
Drug-drug Interactions
Nonclinical PK studies have indicated that MAAA 1181a (payload: deruxtecan) is primarily 
metabolized by CYP3A4 and is a substrate for OATP1B1, OATP1B3, MATE2-K, P-gp, 
BCRP, and MRP1.
No formal drug-drug interaction studies with Dato-DXd have been conducted in humans. 
Since drug-drug interactions are primarily driven by MAAA-1181a, the drug component of 
Dato-DXd, a drug-drug interaction study of trastuzumab deruxtecan, which has the same 
payload, is considered of relevance. Recent results from a clinical drug-drug interaction study 
of trastuzumab deruxtecan (Study NCT03383692) showed that co-administration of a dual 
inhibitor of OATP1B/CYP3A, ritonavir, and a strong CYP3A inhibitor, itraconazole, increased 
MAAA-1181a AUC17d by 22% and 18%, respectively. Therefore, the effect of the 
CYP3A/OATP1B inhibitors on MAAA-1181a is not considered clinically meaningful and as a 

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result, concomitant use of CYP3A/OATP1B inhibitors with Dato-DXd is allowed. However, 
caution must be followed by the investigator in case of concomitant use of Dato-DXd and 
CYP3A inhibitors, or drugs that inhibit OATP1B1, OATP1B3, MATE2-K, P-gp, BCRP, and 
MRP1. Patients must be closely monitored in these cases.
Concomitant use of drugs that inhibit MATE2-K, P-gp, BCRP, and MRP1 is allowed, 
although participants should be closely monitored for adverse reactions. Because the urinary 
excretion of MAAA-1181a is expected to be low, MATE2-K (which is involved in the 
excretion of substrates into urine) is expected to have minimal impact on the exposure of 
MAAA-1181a. In addition, multiple efflux transporters such as P-gp and BCRP are involved 
in the excretion of MAAA-1181a; therefore, the risk of interactions with these inhibitors is 
also expected to be low. Likewise, because the expression of MRP1 in the liver is low, the 
inhibition of MRP1 is expected to have little impact.
Concomitant use of drugs that are substrates of OAT1 and OATP1B1 is allowed. Because the 
exposure of MAAA-1181a is expected to be low with Dato-DXd at doses administered in 
clinical studies, the inhibition of OAT1 and OATP1B1 by MAAA-1181a is expected to have 
little impact on drugs that are substrates of OAT1 and OATP1B1.
There is a hypothetical interaction between Dato-DXd and hydroxychloroquine and/or 
chloroquine, therefore concomitant treatment with hydroxychloroquine or chloroquine is not 
allowed whilst a participant is on Dato-DXd and ≥14 days of washout is required before 
starting Dato-DXd administration. If treatment with chloroquine or hydroxychloroquine 
treatment is absolutely required, study intervention must be interrupted. If chloroquine or 
hydroxychloroquine is administered for any reason, the study intervention must be interrupted, 
and a washout period of ≥14 days is required before restarting study intervention.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix I 1.
6.6
Dose Modification
Dosing modification guidelines and TMGs are included in the Annex document to this CSP. 
Dose delays are permitted for Dato-DXd. Dose reductions are permitted for Dato-DXd. All 
dose reductions and delays (including any missed doses), and the reasons for the 
reductions/delays are to be recorded in the eCRF.
Refer to Section 4.3.1for the justification for dose for Dato-DXd.
6.6.1
Dose Delays
Dose delays are permitted for Dato-DXd treatment and the dosing interval for the next 
Dato-DXd cycle may be shortened, as clinically feasible to gradually align with the schedule 

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of tumor efficacy assessment. Two consecutive doses must be administered at least 19 days 
apart. 
Study treatment dose delay for conditions other than toxicity resolution should be kept as 
short as possible. A dose can be delayed for up to 3 consecutive cycles (63 days) from the 
planned date of administration (ie, 84 days from the last infusion date). If a participant is 
assessed as requiring a dose delay longer than 3 consecutive cycles (ie, > 84 days from last 
infusion date to the planned date of administration on a Q3W schedule), the 
subject/participant must discontinue study treatment (see Figure 3).
Figure 3
Dose Delay Schema for Dato-DXd
Treatment cycles for a participant for whom Dato-DXd dosing is temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last Dato-DXd dose.
In the event of a dose interruption occurring prior to completion of PK/pharmacodynamic 
blood sampling in the study, investigators should contact the study clinical lead for guidance 
regarding scheduling of these procedures.
6.6.2
Dose Delays for Reasons Other Than Treatment-related Toxicity
Study treatment dose delay for conditions other than toxicity resolution should be kept as 
short as possible. If a participant cannot restart study treatment within 84 days from the last 
infusion date for resolution of intercurrent conditions not related to PD or toxicity, the case 
should be discussed with the Study Clinical Lead.

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6.6.3
Dose Reductions
In case a dose reduction is necessary, Dato-DXd will be modified as follows. 
Up to 2 dose reductions will be permitted for participants receiving Dato-DXd (see Table 6 for 
dosing levels). Once the dose of Dato-DXd has been reduced, no dose re-escalation is 
permitted. After the permitted dose reductions, if further toxicity meeting the requirement for 
dose reduction occurs, the participant will be withdrawn from the study intervention. 
In a rare circumstance, one additional dose reduction may be possible on a case-by-case basis 
only after discussion and agreement between the Investigator and Sponsor.
Table 6
Dose Reduction Levels of Dato-DXd
Starting Dose (Dose Level 1)
Dose Level -1
Dose Level -2
6.0 mg/kg IV, Q3W
4.0 mg/kg IV, Q3W
3.0 mg/kg IV, Q3W
Investigators should consider dose reductions or discontinuations of Dato-DXd according to 
the participant’s condition and after discussion with the study clinical lead or designee (see the 
Annex document to this CSP for details of when dose reductions may be required).
Refer to Section 4.3 for the justification of dose for Dato-DXd.
6.6.4
Management of Toxicities
Full TMGs for Dato-DXd are included in the Annex document to this CSP. The most current 
version of the TMGs for Dato-DXd is provided to the investigative site as an Annex document 
to the CSP and is maintained within the Site Master File. Please refer to the Annex document 
to this CSP for the management of drug-induced ILD/pneumonitis.
Specific criteria for interruption, re-initiation, dose reduction and/or discontinuation of 
Dato-DXd are listed in the Annex document to this CSP, which is applicable only to TEAEs 
that are assessed as related to use of Dato-DXd by the investigator(s). For non-drug related 
TEAEs, follow standard clinical practice. Appropriate clinical experts should be consulted as 
deemed necessary.
On improvement of an AE for which Dato-DXd was temporarily interrupted, Dato-DXd may 
be restarted at the same dose at the discretion of the investigator. If a further episode of the 
same AE subsequently requires dose interruption, or if a different AE subsequently requires 
dose interruption, Dato-DXd may be restarted at a 1 dose level reduction on improvement of 
the AE or discontinued if the participant is receiving the lowest protocol-specified dose level.
Appropriate and optimal treatment of the toxicity should be attempted prior to considering 

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dose modifications. Prior to discontinuation of study intervention due to toxicities, please 
consult with the study clinical lead.
If a participant experiences a clinically significant and/or unacceptable toxicity, dosing will be 
interrupted or permanently discontinued in accordance with the TMGs and supportive therapy 
administered as required.
All dose modifications (interruption, reduction, and/or discontinuation) should be based on the 
worst preceding toxicity (CTCAE version 5.0).
For management of toxicities due to ICC, refer to the locally approved Prescribing 
Information or manage in accordance with institutional guidelines.
6.7
Continued Access to Study Intervention After the End of the 
Study
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact. No intervention is planned 
after the end of the study.
After the final DCO for this study, AstraZeneca will continue to supply open-label treatment 
in the continued access phase of this study and after completion of this study to participants 
who received Dato-DXd or centrally supplied ICC while, in the opinion of the investigator, 
the participant is benefiting until PD occurs (as judged by the investigator), or until meeting 
any other discontinuation criteria as defined in Section 7.1. 
Participants should be followed according to the institution’s SoC assessments. No further 
data collection is required, except for reporting of SAEs.
Participants who were randomized to receive other study interventions (ie, locally supplied 
ICC), or who discontinue from the study, should continue appropriate treatment at the 
discretion of the investigator.
Where possible, if commercial supply of Dato-DXd is available in the local market then this 
route should be used. In the event that product development reaches a point where alternative 
product supply options become available, then these alternative product supply options will be 
discussed by AstraZeneca with the investigator. AstraZeneca will work with the investigator to 
transition the participant(s) to alternative supply, where possible.
In the event that a roll-over or safety extension study is available at the time of the final DCO
and database closure, participants currently receiving treatment with Dato-DXd may be 
transitioned to such a study. The roll-over or extension study would ensure treatment 
continuation with visit assessments per its protocol, as applicable. Any participant who would 

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be proposed to move to such a study would be given a new informed consent, as applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for PFS (if the participant has not progressed according to 
RECIST 1.1), PFS2, OS, TFST and TSST. The investigator should instruct the participant to 
contact the site before or at the time if study intervention is stopped. A participant that decides 
to discontinue study intervention will always be asked about the reason(s) and the presence of 
any AEs. The reason for discontinuation should be documented in the source document and 
the appropriate section of the eCRF.
Participants who have permanently discontinued from further receipt of study intervention 
will need to be discontinued from the IRT. All study intervention should be returned by the 
participant at their next on-site study visit or unscheduled visit.
Participants may be discontinued from study intervention in the following situations: 

RECIST 1.1-defined radiological progression (refer to Section 8.1.1 and Appendix F). 

An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing. 

Any AE that meets criteria for discontinuation defined in the TMGs (see the Annex 
document to this CSP), or as defined in the local Prescribing Information for the ICC 
agents.

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. A participant who discontinues treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments (see Section 7.2).

Severe non-compliance with the CSP as judged by the investigator or AstraZeneca.

Pregnancy or intent to become pregnant (refer to Appendix G and Section 8.3.14).

Initiation of subsequent anticancer therapy, including another investigational agent.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
Crossover within the study is not permitted.

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7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention
All participants who discontinue the study intervention will be followed up for safety 
assessments 28 (+7) days after their last dose of study intervention. Additional assessments to 
be performed at the time of the safety follow-up visit are detailed in the SoA (Table 1). For 
ILD/pneumonitis, safety follow-up will continue until the resolution of ILD/pneumonitis.
Participants who have discontinued study intervention prior to objective RECIST 1.1-defined 
radiological progression, regardless of whether or not they have commenced subsequent 
anticancer therapy, will be followed up with tumor and survival assessments as indicated in 
the SoA (Table 1) until one visit after investigator-defined PD according to RECIST 1.1, or 
death regardless of whether or not the participant started a subsequent anticancer therapy, 
unless they have withdrawn all consent to study-related assessments.
See the SoA (Table 1) for data to be collected at the time of intervention discontinuation (ie, 
the end-of-treatment visit) and follow-up and for any further evaluations that need to be 
completed.
7.1.2
Follow-up of Participants to PFS2 
Following objective progression, participants will have their subsequent progression status 
recorded every 3 months (±14 days) per local standard clinical practice to assess PFS2. 
Assessments will be performed according to the local practice, and formal RECIST 1.1 
measurements will not be collected for assessment of PFS2. See Section 8.1.3 for additional 
information.
7.1.3
Follow-up for Survival
Participants will be followed up for survival status as indicated in the SoA (Table 1) until 
death, withdrawal of consent, or the end of the study. Survival information may be obtained 
via telephone contact with the participant or the participant’s family, by contact with the 
participant’s current physician, or local death registries (if allowed by local regulations). 
Additional assessments to be performed at the time of survival follow-up are detailed in the 
SoA (Table 1). The study may continue monitoring participants for OS up to the scheduled 
final analysis, beyond planned interim analyses, to provide more refined estimates of 
treatment effects for survival.
Telephone calls to assess survival will be made at an increased frequency leading up to and 
after the DCO date for the analysis (these contacts will be made until the date of the database 
lock). If participants are confirmed to be alive, or if the death date is after the DCO date, then 
these participants will be censored at the date of DCO.

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7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options to ensure the collection of endpoints and 
safety information, including new AEs and follow-up of any ongoing AEs and 
concomitant medications (eg, telephone contact 28 [+7] days after study intervention is 
discontinued, a contact with a relative or treating physician, or information from medical 
records).

At the time of withdrawal from the study, if possible, an EoT visit and a safety follow-up 
visit should be conducted, as shown in the SoA (Table 1). See SoA for data to be 
collected at the time of study withdrawal and follow-up and for any further evaluations 
that need to be completed.
The participant will discontinue the study intervention and be withdrawn from the study 
at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and no contact has been established by the time the study is completed (see 
Section 4.4), such that there is insufficient information to determine the participant’s status at 
that time.
Participants who decline to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing participants 
throughout the study period. If contact with a missing participant is re-established, the 
participant should not be considered lost to follow-up and evaluations should resume 
according to the protocol.
The following actions must be taken if a participant fails to return to the clinic for a required 

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study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, texts 
or emails and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have been 
lost to follow-up from the study.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant during survival follow-up within legal and ethical boundaries for all 
participants randomized, including those who did not get study intervention. Public 
sources may be searched for vital status information. If vital status is determined as 
deceased this will be documented, and the participant will not be considered lost to 
follow-up. Sponsor personnel will not be involved in any attempts to collect vital status 
information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
In order to support key efficacy endpoints of PFS and OS, the survival status of all 
participants in the ITT population and the Safety Analysis Set should be re-checked; this 
includes those participants who withdrew consent or are classified as “lost to follow-up.”

Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status (the applicable eCRF modules will be updated).

In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1). Data collection 
following study analysis until the end of the study is described below. 

Protocol waivers or exemptions are not allowed.

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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA (Table 
1), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 1).
Data Collection Following Study Analysis until the End of the Study
Following the DCO for the primary PFS efficacy endpoint, assessments for PK will be 
discontinued. Participants will continue with all other assessments as indicated in the SoA 
(Table 1).
For SAE reporting and laboratory assessment collection after final analysis, see 
Section 8.3.12. After the final DCO and database closure, only SAEs will be reported for the 
purposes of this study (see Section 8.3.12).
8.1
Efficacy Assessments
Efficacy assessments of PFS, ORR, DoR, and DCR will be evaluated based on RECIST 1.1 
tumor assessments. 
8.1.1
Imaging Tumor Assessments
Tumor assessments use images from CT (preferred) or MRI, with IV contrast, of the chest, 
abdomen (including the entire liver and both adrenal glands), and pelvis, collected during 
screening/baseline and at regular (follow-up) intervals during study intervention as defined in 
the SoA (Table 1).
An MRI (preferred) or CT of the brain will also be collected for all participants at baseline. 
Follow-up brain scans are subsequently mandatory for all participants randomized with stable 
brain metastases at baseline, whilst participants without brain metastases do not need 
additional brain scans for subsequent tumor assessments, unless clinically indicated. 
All participants should have a baseline whole body bone scan or skeletal survey. For 
participants with no bone lesion, a historical bone scan documenting absence of bone lesions 

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performed no more than 12 weeks before randomization could be provided. For participants 
with documented bone lesion at baseline, the bone scan must be performed no more than 
28 days before randomization. Bone scintigraphy is the preferred modality. If a participant had 
a Choline PET-CT, or Diffusion Weighted MRI as part of the routine clinical management 
performed less than 28 days before randomization, it may be utilized as screening scan to 
document bone disease. Bone lesions identified on bone scan at baseline must be confirmed 
by CT, MRI, or X-ray to be recorded as NTLs and followed by the same method (CT, MRI, or 
X-ray), as indicated in the SoA (Table 1).
Any other areas of disease involvement should be additionally imaged at screening based on 
known metastasis sites or by the signs and symptoms of individual participants.
The imaging modality used for baseline tumor assessment, CT/MRI for chest and abdomen 
and MRI for brain, should be kept the same consistently at each subsequent follow-up 
assessment throughout the study if possible. It is important to follow the tumor assessment 
schedule as closely as possible (refer to the SoA [Table 1]) relative to randomization. 
New lesions may also be identified by fluorodeoxyglucose-PET scans, X-ray, bone 
(scintigraphy) scans. If an unscheduled assessment was performed (eg, to investigate clinical 
signs/symptoms of progression) and the disease has not progressed, every attempt should be 
made to perform the subsequent imaging at the next regularly scheduled visit. Digital copies 
of all scans should be maintained at the site as source documents. 
Screening/baseline imaging should be performed no more than 28 days before randomization 
and ideally should be performed as close as possible to and prior randomization.
Treatment continues until RECIST 1.1-defined radiological progression by Investigator 
assessment (refer to Appendix F). Following disease progression, 1 additional follow-up scan 
should be performed as per imaging schedule (ie, either 6 weeks or 9 weeks later). In the event 
the investigator identified progression does not match with the BICR evaluation, this 
additional scan may identify progression by BICR. 
If an unscheduled assessment is performed (eg, to investigate clinical signs/symptoms of 
progression) and the participant has not progressed, every attempt should be made to perform 
the subsequent assessments at the next scheduled visit. 
The RECIST 1.1 assessments of baseline images identify TLs and NTLs. On-study images are 
evaluated for TLs and NTLs chosen at baseline, and for NLs when they appear. This allows 
determination of follow-up TL response, NTL lesion response, the presence of unequivocal 
NLs, and overall time point responses (CR, PR, SD, PD, or NE).

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8.1.2
Central Reading of Scans 
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed iCRO for quality control, storage, and for BICR. Digital copies of all 
original scans should be stored at the investigator site as source documents. Electronic image 
transfer from the sites to the iCRO is strongly encouraged. A BICR of images will be 
performed at the discretion of AstraZeneca. 
Results of these independent reviews will not be communicated to investigators, and results of 
investigator tumor assessments will not be shared with the central reviewers.
The management of participants will be based upon the results of RECIST 1.1 assessments 
conducted by the Investigator. After the primary PFS analysis, central review of scans will no 
longer be required, and investigators will be advised when to stop sending copies of the scans 
to the iCRO conducting the central review; however, digital copies of all original scans should 
continue to be stored at the investigator site as source documents.
Further details of the BICR will be documented in an Independent Review Charter.
8.1.3
Time to Second Progression or Death
Following objective progression, participants will have their subsequent progression status 
recorded every 3 months (±14 days) per local standard clinical practice to assess PFS2. 
A participant’s PFS2 status is defined according to the local practice and may involve any of: 

objective radiological progression (preferred), 

symptomatic progression, or 

death. 
Scans will be performed according to the local practice and formal RECIST 1.1 measurements 
will not be collected for assessment of PFS2. The second progression event must have 
occurred during or after anticancer treatment with a subsequent treatment after the progression 
event used for the primary variable PFS or death. The date of PFS2 assessment and 
investigator opinion of progression status (progressed or non-progressed) at each assessment 
will be recorded in the source documents and the eCRF.
8.1.4
Overall Survival
Assessments for survival will be conducted every 3 months (±14 days) following objective PD 
or treatment discontinuation until the end of the study. Survival information may be obtained 
via telephone contact with the participant, participant’s family, by contact with the 
participant’s current physician, or local death registries as described in Section 7.2. The study 
may continue monitoring participants for OS up to the scheduled final analysis, beyond 

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planned interim analyses, to provide more refined estimates of treatment effects for survival.
8.1.5
Clinical Outcome Assessments (COA)
A COA is any assessment that may be influenced by human choices, judgment, or motivation 
and may support either direct or indirect evidence of treatment benefit. COAs can be reported 
by a participant (PRO), a clinician (ClinRO), an observer (ObsRO), or through a 
performance-based assessment (FDA-NIH BEST Resource). A COA may be used in clinical 
studies to provide either direct or indirect evidence of treatment benefit. It is important to 
examine the impact of therapy on symptoms, function, and other health-related QoL of the 
participant to aid understanding of the risk-benefit profile.
Patient Reported Outcome (PRO) assessment is one type of COA and is a general term 
referring to all outcomes and symptoms that are directly reported by the participant. Patient 
Reported Outcomes have become important in evaluating the efficacy and tolerability of study 
interventions in clinical studies and will aid in understanding of the benefit/risk evaluation 
(Kluetz et al 2018). 
The following PRO instruments will be administered in this study (see Appendix H):

EORTC QLQ-C30 (see Section 8.1.5.1)

EORTC IL116: selected breast and arm symptom scales from EORTC QLQ-BR45/IL (see 
Section 8.1.5.2)

Selected items from PRO-CTCAE (see Section 8.1.5.3)

EORTC IL117: selected symptomatic AE items from EORTC IL (see Section 8.1.5.4)

PGI-TT (see Section 8.1.5.5)

PGIS (see Section 8.1.5.6)

PGIC (see Section 8.1.5.7)

EQ-5D-5L (see Section 8.1.5.8)
Patient Reported Outcome questionnaires will be administered according to the SoA (Table 1). 
The PRO questionnaires will be completed by participants if a linguistically validated version 
is available in their language for the country in which they live.
8.1.5.1
EORTC QLQ-C30
The EORTC QLQ-C30 was developed by the EORTC QoL Group 1993. It consists of 30 item 
and measures symptoms, functioning, and global health status/QoL (Aaronson et al 1993) for 
all cancer types. Questions are grouped into 5 multi-item functional scales (physical, role, 
emotional, cognitive, and social), 3 multi-item symptom scales (fatigue, pain, and 
nausea/vomiting), a 2-item global QoL scale, 5 single items assessing additional symptoms 

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commonly reported by cancer participants (dyspnea, loss of appetite, insomnia, constipation, 
and diarrhea), and 1 item on the financial impact of the disease. The EORTC QLQ-C30 is a 
valid and reliable PRO instrument in this participant population.
8.1.5.2
EORTC IL116: selected breast and arm symptom scales from EORTC QLQ-
BR45/IL
The EORTC QLQ-BR45 is an updated version of the BR23, a validated breast cancer-specific 
module used in conjunction with the core QLQ-C30 to assess breast cancer-specific HRQoL 
(Bjelic-Radisic et al 2020; Sprangers et al 1996). New breast cancer treatments and 
diagnostics prompted the update of the QLQ-BR23 to include an additional 22 items. Items 
are scored on a 4-point verbal rating scale: “Not at All,” “A Little,” “Quite a Bit,” and “Very 
Much”. Scores are transformed to a 0 to 100 scale, where higher scores for functioning scales 
or items indicate better functioning, whereas higher scores for symptom scales or items 
represent a worse level of symptoms. 
The current study will only include the breast symptoms and arm symptoms scales (7 items) 
from the BR45, ie, EORTC IL116.
8.1.5.3
PRO-CTCAE
The PRO-CTCAE was developed to evaluate symptomatic toxicity in participants in cancer 
trials. The PRO-CTCAE will only be administered in those countries where a linguistically 
validated version is available. PRO-CTCAE is an item library of symptoms experienced by 
participants while undergoing treatment of their cancer. It has been carefully and 
systematically developed based on the NCI-CTCAE to provide participant-reported 
assessment of common adverse effects of cancer treatments, including a library of 124 items, 
representing 78 symptomatic toxicities. The items have previously undergone extensive 
qualitative and quantitative evaluation to support their validity and reliability (Basch et al 
2014, Dueck et al 2015, Hay et al 2014). For each symptomatic AE (eg, headache), there are 
up to three questions related to key symptom attributes, including the symptom frequency, 
severity, and interference with daily activities. Each question uses a 7-day recall with a 5-point 
ordinal response scale. 
The items pre-selected for this study include mouth/throat sores, decreased appetite, nausea, 
vomiting, constipation, diarrhea, abdominal pain, shortness of breath, cough, rash, hair loss, 
hand-foot syndrome, numbness/tingling, and fatigue. These items are based on a review of the 
core symptom set from NCI, expected treatment-related symptoms, and in consideration of 
symptoms that are already captured in the other PRO instruments with a view to minimize 
participant burden. The free text item in the PRO‑CTCAE instrument is not included in the 
study, as the utility of this information and the analysis method have not been established.
8.1.5.4
EORTC IL117: selected symptomatic AE items from EORTC IL
The EORTC IL is an online platform comprised of more than 900 individual items from over 

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60 EORTC questionnaires. As the static questionnaires might not always be sufficient to meet 
the demands of quickly evolving treatment modalities, selecting items from EORTC IL offers 
new opportunities to leverage existing EORTC items for capturing the additional symptoms 
that are relevant to a given study. 
The pre-selected items for this study will include dry eyes, mouth pain, and sore mouth (ie, 
EORTC IL117). These items were selected using the same methodologies as described in 
Section 8.1.5.3 (PRO-CTCAE) to measure additional participant-reported symptomatic AEs 
which are not captured in the PRO-CTCAE. The recall period is during the past week. Items 
are scored on a 4-point verbal rating scale: "Not at all", "A little", "Quite a bit", and "Very 
much".
8.1.5.5
PGI-TT
The PGI-TT item is included to assess how a participant perceives the overall burden of 
treatment-related side effects of cancer treatment over the past 1 week. Participants will be 
asked to choose the response that best describes the level of burden by the side effect of their 
cancer treatment over the past week. The response options are: “not at all”, “a little bit”, 
“somewhat”, “quite a bit”, and “very much”. This item is included to aid in the interpretation 
of other PRO measures and to evaluate the overall impact of treatment-related side effects.
8.1.5.6
PGIS
The PGIS item is included to assess how a participant perceives the overall severity of cancer 
symptoms over the past 1 week. Participants will be asked to choose the response that best 
describes the severity of their overall cancer symptoms over the past week. The response 
options are: “none”, “mild”, “moderate”, and “severe”. This item is included to aid in the 
interpretation of other PRO measures and to evaluate the overall impact of treatment on the 
global severity of cancer symptoms.
8.1.5.7
PGIC
The PGIC item is included to assess how a participant perceives their overall change in health 
status since the start of study treatment. This is single-item questionnaire and participants will 
choose from response options ranging from “Much better” to “Much worse”.
8.1.5.8
EQ-5D-5L
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility.
The EQ-5D-5L, developed by the EuroQoL Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal (EuroQol 2019). The EQ-5D-5L questionnaire comprises 6 questions that cover 
5 dimensions of health (eg, mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Respondents also assess their health today using the EQ-VAS, which 

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ranges from 0 (worst imaginable health) to 100 (best imaginable health) (see Appendix H).
8.1.5.9
Administration of Electronic PRO (ePRO) Questionnaires
Patient Reported Outcome questionnaires will be self-administered electronically at home by 
the participants using an application installed on their personal mobile device, or a handheld 
device (if their personal device is not compatible or preferred) at the time points indicated in 
the SoA (Table 1). Participants should complete the ePROs prior to or at the sites if the 
assessment time point coincides with a scheduled site visit. Participants must be instructed to 
bring their device to all visits.
Each site must allocate the responsibility for the administration of the ePRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent.
A web back-up may be available to answer the questionnaires if there are technical problems 
with the device.
Approximately 10 to 20 minutes is required for participants to complete the questionnaires.
The below instructions should be followed when collecting PRO data:

The research nurse or appointed site staff should explain to participants the value and 
relevance of these data, so they are motivated to comply with questionnaire completion. 
Inform the participant that these questions are being asked to find out, directly from them, 
how they feel.

Participants must not be onboarded onto the ePRO application (ie, must not have their 
account set up or invitation email sent) until the actual day of their C1D1 visit. This is 
required to ensure that the correct C1D1 date is registered in the ePRO system. 

It is vital that the ePRO reporting is initiated prior to dosing or any other study procedure 
on C1D1, as specified in the SoA (Table 1) to capture the effect of the study intervention. 
The ePRO device must be charged and fully functional at the beginning of the baseline 
(ie, C1D1) visit to ensure that the PROs can be completed at the start of the visit.

The participant should bring their device to each site visit so the research nurse or 
appointed site staff can check if there are available PRO questionnaire to be completed 
and that the device is functioning properly.

Patient Reported Outcome questionnaires completed at the sites must be completed prior 
to treatment administration or any other study procedures performed at the site and ideally 
before any discussions of health status (following informed consent), including 
medication treatments, and before discussion of PD to avoid biasing the participant’s 
responses to the questions. As feasible, site staff should also ensure PRO questionnaires 

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are completed prior to other study procedures, such as collection of laboratory samples, to 
further minimize bias.

On completion of the questionnaire at the site, the device should be handed back to the 
research nurse or appointed staff, who should check that all questionnaires were 
completed.

When each instrument is due to be completed, the following order must be observed 
(however although the order will be pre-programmed into the ePRO): 
EORTC QLQ-C30
EORTC IL116
PRO-CTCAE
EORTC IL117
PGI-TT
PGIS
PGIC
EQ-5D-5L

Patient Reported Outcome questionnaires should be completed by the participant in a 
quiet and private location.

The participant should be given sufficient time to complete the PRO questionnaires at 
their own speed.

The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the participant has any medical problems, 
he/she should discuss them with the doctor or research nurse separately from the ePRO 
assessment.

The research nurse or appointed site staff must train the participant on how to use the 
ePRO device/application using the materials and training provided by the ePRO vendor.

The research nurse or appointed site staff must provide guidance on whom to call if there 
are problems with the device when the participant is completing the ePRO at home.

All PRO questionnaires are to be completed using the ePRO application and/or assigned 
device. If technical or other device-related issues prohibit completion on the device, an 
appropriate back-up option may be considered with prior approval from AstraZeneca.

The research nurse or appointed site staff must remind the participant that there are no 
right or wrong answers and avoid introducing bias by not clarifying items.

The participant must not receive help from relatives, friends, or clinic staff deciding on 
answers to the ePRO questionnaires. The responses are the participant's alone.

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
If a participant uses visual aids (eg, glasses or contact lenses) for reading and does not 
have them when he or she attends the site visit, the participant may be exempted from 
completing the PRO questionnaires at that site visit.

Site staff must not read or complete the ePRO questionnaires on behalf of the participant. 
If the participant is unable to read the questionnaire (eg, is blind or illiterate or not fluent 
in the available language), that participant is exempted from completing PRO 
questionnaires but may still participate in the study. If the participant cannot complete the 
PRO questionnaires due to reasons other than being blind, illiterate, or not fluent in an 
available language, the AstraZeneca study team must be contacted to determine if they 
can be exempted. Participants exempted in any regard should be flagged appropriately by 
the site staff in the source documents and in the designated eCRF.

Questions must not be translated from an available language in the device into the 
language for the participant speaks.

Reminders should be provided to participants as needed to ensure compliance with the 
assessment schedules.

The research nurse or appointed site staff must monitor compliance since minimizing 
missing data is a key aspect of the study success.

Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a participant could not 
complete assessments, in the source documents and in the designated eCRF. If the site 
receives an email notification regarding the participant’s compliance, appropriate action 
will be taken (eg, discussion with participant to improve compliance, a check in call from 
the site to ask the participant if they have any difficulties in completing questionnaires on 
schedule, etc). A solution to enhance/resolve compliance should be discussed with the 
participant. Discussion and compliance review should be reflected in source documents.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Physical Examinations
Physical examination, as well as assessment of height and weight, will be performed at the 
timings specified in the SoA (Table 1); investigators should pay special attention to clinical 
signs related to previous serious illnesses, as new or worsening abnormalities may qualify as 
AEs; see Section 8.3.5 for details.
A full physical examination includes assessment of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), oral (mouth), lymph nodes, thyroid, musculoskeletal (including spine and extremities), 
urogenital, dermatological, gastrointestinal, endocrine, hematologic/lymphatic, and 
neurological systems. 

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Targeted physical examinations are to be used by the investigator on the basis of clinical 
observations and symptomatology. A targeted physical examination includes at a minimum, 
assessments of the skin, lungs, oral, cardiovascular system, and abdomen (liver and spleen).
8.2.2
Vital Signs
Vital signs will be performed at timelines as specified in the SoA (Table 1). Temperature, 
pulse rate, respiratory rate, pulse oximetry (SpO2), and blood pressure will be assessed. The 
participant should remain at the site for at least 1-hour post-infusion for close observation for 
possible IRRs (for participants receiving Dato-DXd only).
Blood pressure and pulse measurements will be assessed in a supine, semi-recumbent, or 
seated position with a completely automated device, whenever possible. Manual techniques 
will be used only if an automated device is not available. Blood pressure and pulse 
measurements should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions (eg, television, cell phones).
Vital signs will be evaluated and recorded in eCRF. 
Where applicable, blood pressure and pulse rate should be collected prior to the beginning of 
study intervention infusion (measured once from approximately 30 minutes before up to 
0 minutes [ie, the beginning of the infusion]) and at the end of the infusion. These 
measurements may also be taken more frequently if clinically indicated.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. 
For any AEs of infusion reactions, the vital signs values should be entered into the eCRF.
8.2.3
Electrocardiograms
Triplicate 12-lead ECGs will be performed at screening and at the EoT visit. The 3 individual 
ECG tracings should be obtained in succession, no more than 2 minutes apart. The full set of 
triplicates should be completed within 5 minutes. Subsequent ECGs will only be taken in 
triplicate if abnormalities were noted at screening. 
Electrocardiograms will be performed at timelines as specified in the SoA (Table 1) after the 
participant has been resting supine/semi-recumbent for at least 5 minutes and recorded while 
the participant remains in that position using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTcF intervals, as possible. 
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities detected require triplicate ECG results.

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Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
Whenever ECGs, vital signs, and blood draws are scheduled for the same nominal time, ECG 
assessments should occur first, then vital signs assessments, and then blood draws; the timing 
of the first 2 assessments should be such that it allows the blood draw (eg, PK blood sample) 
to occur at the timepoints indicated in the SoA (Table 1).
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, and 
urinalysis will be taken at the visits indicated in the SoA (Table 1).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. Laboratory assessments for off-schedule study drug 
dosing may be entered in the eCRF as unscheduled visits.
The clinical chemistry, hematology and urinalysis will be performed at a local laboratory at or 
near to the investigator site. Sample tubes and sample volumes may vary depending on 
laboratory method used and routine practice at the site.
Other safety laboratory tests include assessment for pregnancy (serum at screening and urine 
at all other time points), and hepatitis B and C serology, and HIV antibody test. 
Pregnancy tests may be performed at the site using a licensed test. A negative result from a 
serum pregnancy test (which must have a sensitivity of at least 25 mIU/mL) must be available 
at the screening visit. Pregnancy tests should be conducted within 72 hours prior to 
randomization for all female participants of childbearing potential. Repeat pregnancy tests 
(urine beta-human chorionic gonadotropin or serum test per institutional guideline) should be 
performed 72 hours before infusion of each cycle and at the EoT visit. If a positive urine 
pregnancy test result is confirmed using a serum test in a female participant of childbearing 
potential, then the participant should not be treated. 
Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours). 
The laboratory variables to be measured are presented in Table 7.

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Table 7
Laboratory Safety Variables
Hematology/Haemostasis (Whole Blood)
Clinical Chemistry (Serum or Plasma)
Hemoglobin
Creatinine
White blood cell count
Bilirubin, total
Leukocyte differential count (absolute count and/or %; 
neutrophils, lymphocytes, monocytes, eosinophils, 
basophils)
Alkaline phosphatase
AST
Platelet count
ALT
Hematocrit
Albumin
Red blood cell count
Potassium
Urinalysis
Calcium (total) or Calcium (ionized)
Hemoglobin/Erythrocytes/Blood
Sodium
Protein/Albumin
Lactate dehydrogenase
Glucose
Protein, total
Urea nitrogen or blood urea nitrogen or urea
Magnesium
Chloride
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated and recorded on the eCRF. Situations in which laboratory 
safety results should be reported as AEs are described in Section 8.3.5.
All participants with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from study intervention must be followed and have further tests performed 
until the laboratory values have returned to Grade 1 or 2, unless these values are not likely to 
improve because of the underlying disease.
NB. If a participant has an AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, refer to 
Appendix E for further instructions. 
8.2.5
Other Safety Assessments
8.2.5.1
Echocardiogram/Multigated Acquisition Scan 
An echocardiogram or MUGA scan to assess LVEF will be performed at the visits indicated in 
SoA (Table 1). The modality of the cardiac function assessments must be consistent for a 
given participant (ie, if echocardiogram is used for the screening assessment for a given 
participant, then echocardiogram should also be used for subsequent scans for that 
participant). The participants should also be examined using the same machine and operator 
whenever possible, and quantitative measurements should be taken (ie, accurate to 1% and not 

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estimated to 5%).
The EoT echocardiogram/MUGA scan is not required unless clinically indicated. If a 
participant has any clinically significant decrease in LVEF (greater than 10 percentage points 
to below 50%), there should be follow-up within 4 weeks until resolution.
Situations in which echocardiogram or MUGA results should be reported as AEs are described 
in Section 8.3.5.
8.2.5.2
Pulmonary Function Tests
Pulse oximetry (SpO2) should be evaluated by the investigator or the delegate physician at the 
time points outlined in the SoA and as clinically indicated. The SpO2 should be measured at 
the same time as vital signs.
Pulmonary function tests should include basic spirometry at a minimum with optional 
additional components as mentioned in Table 8.
Table 8
Spirometry Component
Required spirometry components
Optional spirometry components
FVC (L)
PEF
FVC % predicted
DLCO
FEV1 (L)
FEV6
FEV1 % predicted
TLC
FEV1/FVC %
RV
Diffusion capacity of the lungs for carbon monoxide will be performed/encouraged if feasible, 
but for participants with prior severe and/or prior clinically significant pulmonary disorders, 
DLCO is a requirement. In event of suspected ILD/pneumonitis, refer to Section 8.2.5.3
additional pulmonary assessments.
8.2.5.3
ILD/Pneumonitis Investigation
For suspected ILD/pneumonitis (ie, if new or worsening pulmonary symptoms [eg, dyspnea, 
cough or fever] or radiological abnormality suggestive of ILD/pneumonitis is observed), 
treatment with Dato-DXd should be delayed and a full investigation is required as described in 
the Dato-DXd TMGs (see the Annex document to this CSP).
Evaluations should include:

Detailed past medical history (including concomitant medications, ocular history, and 
previous use of tobacco, e-cigarettes, and/or vaping, etc.)

Physical examination, including auscultation of lung field

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
Arterial blood gases (if clinically indicated)

Pulmonary function tests (see Section 8.2.5.2) and pulse oximetry (SpO2) 

Bronchoscopy and bronchoalveolar lavage should be considered if clinically indicated 
and feasible.

HRCT of the chest (if feasible, otherwise non-contrast chest CT is acceptable [1 to 2 mm 
slice thickness recommended]). If both a non-contrast chest HRCT scan for assessment of 
ILD/pneumonitis and a diagnostic IV contrast enhanced chest CT scan for tumor response 
assessment (as part of chest-abdomen-pelvis imaging) are to be acquired in the same 
imaging session, HRCT should be performed first.

Pulmonologist consultation (infectious disease consultation as clinically indicated)

Blood culture, complete blood count, and differential white blood cell count; other blood 
tests could be considered as needed.

Troponin measurements will be done to rule out cardiac etiology.

Additional optional blood samples for serum exploratory ILD/pneumonitis biomarker 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed (see Section 8.6.1)

Additional optional blood sample for plasma exploratory ILD/pneumonitis biomarker 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed (see Section 8.6.1).
Other tests may be considered, as needed (eg, COVID-19 test).
The results of the full diagnostic workup (including HRCT, blood and sputum culture, 
hematological parameters, etc) is to be captured in the eCRF. A full diagnostic workup is 
strongly recommended to exclude alternative causes, such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of 
confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a 
diagnosis of ILD/pneumonitis should be considered and the TMGs should be followed (see 
the Annex document to this CSP).
When ILD/pneumonitis is suspected during study treatment, the following markers should be 
collected where possible:

Interstitial lung disease/pneumonitis markers: KL-6, SP-D, and β-D-glucan

Tumor markers: particular tumor markers that are related to disease progression
(carcinoembryonic antigen)

Additional clinical chemistry: C-reactive protein, lactate dehydrogenase
8.2.5.4
ECOG Performance Status
Eastern Cooperative Oncology Group performance status will be assessed at the times 
specified in the SoA (Table 1) based on the following:

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0
Fully active; able to carry out all usual activities without restrictions.
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work).
2
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair.
5
Dead.
Any significant change from baseline or screening must be reported as an AE.
8.2.5.5
Ophthalmologic Assessments
Ophthalmologic assessments by a licensed eye care provider, including but not limited to 
visual acuity testing, fluorescein staining, intraocular pressure, slit-lamp examination, and 
fundoscopy, will be performed as specified in the SoA (Table 1) by an ophthalmologist, or if 
unavailable, another licensed eye care provider. This will be done at screening, and then every 
3 cycles from C1D1 onwards (eg, C4D1, C7D1, C10D1 etc) within 14 days prior to scheduled 
cycle Day 1 visit (but not after scheduled visit), in addition to being done as clinically 
indicated while on trial, and at EoT. A suitable alternative to fluorescein staining of the cornea 
may be used in exceptional circumstances where fluorescein is not available. An 
ophthalmologic assessment should be considered for any ocular symptoms including, but not 
limited to, dry eye, decreased or blurred vision, foreign-body sensation, photophobia, tearing, 
pain, and eye redness. All ophthalmologic assessments should be entered into the eCRF and 
copies of all consultation reports should be filed in source notes. Please refer to the Dato-DXd 
Site Ophthalmologic Assessment Manual for further details.
It should be strongly considered for all participants to avoid the use of contact lenses and to 
use artificial tears 4 times daily as preventative measure and up to 8 times daily as clinically 
needed while participating in the trial, starting at C1D1. The use of other eye medications (eg, 
topical corticosteroids) for prophylaxis should be at the discretion of an ophthalmologist, or if 
unavailable, another licensed eye care provider. Data from the ophthalmologic assessments on 
the first 100 randomized participants (approximately 50 in each arm, Dato-DXd and ICC) will 
be reviewed by a dedicated Ophthalmologic Data Review Committee (Section 9.6.3). The 
proposed data cutoff will be after completion of the last ophthalmologic assessment and a 
minimum of 2 assessments per participant for the first approximately 100 randomized 
participants. Until data collection has been completed and reviewed on the first approximately 
100 participants, ophthalmologic assessments will continue for enrolled participants, and 
participants should continue to be advised to strongly consider using artificial tears and 
avoiding use of contact lenses. Data from these ophthalmologic assessments on the first 

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approximately 100 randomized participants will be reviewed by an Ophthalmologic Data 
Review Committee (Section 9.6.3). Review of the Ophthalmologic Data Review Committee 
findings will further inform the ophthalmologic assessment and monitoring plan. 
The Dato-DXd Site Ophthalmologic Assessment Manual will be supplied by AZ, which 
provides assistance to the licensed eye care provider to assess any ocular surface toxicity.
Any significant change from baseline must be reported as an AE (see Section 8.3.5).
8.2.5.6
Oral Care Plan
A daily Oral Care Protocol (OCP) will be started before study drug initiation for all 
randomized participants (both Dato-DXd and ICC arms), and it must be maintained 
throughout the study as specified in the SoA (Table 1). An oral care kit will be provided at study 
enrolment and monthly thereafter until the safety FU visit, which will include a toothbrush, 
toothpaste, dental floss, and an alcohol-free mouthwash, as well as an oral care plan participant 
information guide will be provided to each randomized participant before study drug initiation. 
Participants should adhere to the following guidance: 

Gently brush their teeth after meals and at bedtime using a soft or ultra-soft toothbrush (or 
swab) and a bland-flavored fluoride-containing toothpaste. 

Floss their teeth every day, if able to do so without pain or causing gingival bleeding.

For participants receiving ICC, daily use of alcohol-free mouthwash is recommended.

For participants receiving Dato-DXd:
Daily use of prophylaxis with a steroid-containing mouthwash (eg, dexamethasone oral 
solution 0.1 mg/mL 10 mL 4 times daily swish for 1 to 2 minutes then spit out; or a 
similar mouthwash regimen using an alternative steroid advocated by institutional/local 
guidelines) is highly recommended.
Note: Participants are allowed to take oral nystatin suspension or other topical 
antifungal agents after the steroid-containing mouthwash according to clinician 
preference based on institutional/local guidelines.

In the absence of a prophylactic steroid-containing mouthwash, daily use of inert, bland
mouth rinses (eg, with a non-alcoholic and/or bicarbonate-containing mouthwash, 4 to 
6 times a day).

Prophylactic cryotherapy (ice chips or ice water held in the mouth throughout the 
infusion) should also be considered.
The algorithm in Figure 4 may be used as a guidance to select an appropriate prophylaxis 
mouthwash:

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Figure 4
Prophylactic Mouthwash Algorithm
As per Investigator judgment, a professional dental evaluation before study drug initiation and 
dental treatment if indicated, may reduce the risk of local and systemic infections from 
odontogenic sources.
For further information, refer to the Dato-DXd TMGs (see the Annex document to this CSP).
8.3
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative). 
Grade ≥ 3 ocular surface toxicity events should be reported in the EDC system within 
24 hours of awareness.
The investigator and any designees are responsible for detecting, documenting, recording, and 
reporting events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs (other than ILD/pneumonitis) will be collected from the time of 
signature of the ICF, throughout the treatment period and including the safety follow-up 

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period (28 [+7] days) after the discontinuation of study intervention). All ILD/pneumonitis 
events regardless of severity should be reported beyond the 28 + 7-day safety follow-up 
period. All AESIs, regardless of severity or seriousness, must be followed until either event 
resolution, end of study, including any post-treatment follow-up, trial termination, withdrawal 
of consent, or participant death. If an event that starts post the defined safety follow-up period 
noted above is considered to be due to a late onset toxicity to study intervention, then it should 
be reported as an AE or SAE as applicable.
Collection and reporting of AEs and SAEs after the final DCO is described in Section 8.3.12.
Pre-existing medical conditions that may have been identified by mandatory screening 
procedures (eg, cataract on baseline ophthalmologic assessment, benign cyst on baseline 
imaging, etc.) should be recorded as medical history in the eCRF. 
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor.
The following should be reported by the investigator in eCRF EDC AE page(s) in the clinical 
study database/paper SAE report form within 24 hours of becoming aware:

SAEs (see Section 8.3.2).

All potential ILD/pneumonitis cases, including both serious and non-serious potential 
ILD/pneumonitis cases (potential ILD/pneumonitis is described by the Event 
Adjudication Site Manual).

Hepatic events (both serious and non-serious) which meet the PHL criteria defined as an 
elevated ALT or AST ≥3 × ULN and an elevated TBL ≥ 2× ULN regardless if it is due to 
disease progression per investigator assessment that may occur either at different time 
points or simultaneously at any time during this study should always be reported to the 
sponsor. These events must be reported in the eCRF, with the investigator’s assessment of 
seriousness, severity, causality, and a detailed narrative. If the participant discontinues 
study intervention due to liver enzyme abnormalities, the participant will have additional 
clinical and laboratory evaluations as described in Appendix E in order to determine the 
nature and severity of the potential liver injury.

Grade ≥ 3 IRR.

Grade ≥ 3 ocular surface toxicity events. 

Grade ≥ 2 keratitis events (includes keratitis, punctate keratitis, and ulcerative keratitis).

Overdose (see Section 8.4). 
Additional relevant information regarding the AESIs, regardless of seriousness, is to be 
collected through targeted questionnaires within the clinical study database (see 

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Section 8.3.11).
8.3.2
Follow-up of AEs and SAEs
Any AE that is unresolved at the participant’s last AE assessment in the study should be 
followed up by the investigator for as long as medically indicated, but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 
participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:

Adverse event (verbatim).

The date when the AE started and stopped.

CTCAE grade/changes in CTCAE grade (report only the maximum CTCAE grade for a 
calendar day).

Whether the AE is serious or not (Appendix B).

Investigator causality rating against the study intervention(s) (yes or no).

Action taken with regard to study intervention(s).

Adverse event caused participant’s withdrawal from study (yes or no).

Administration of treatment for the AE.

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE.

Date investigator became aware of SAE.

Seriousness criteria.

Date of hospitalization.

Date of discharge.

Probable cause of death.

Date of death.

Autopsy performed.

Causality assessment in relation to study procedure(s).

Causality assessment to other medication.
The grading scales found in the NCI-CTCAE Version 5.0 will be utilized for all events with an 
assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 

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CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov). 
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?”
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit/you were 
last asked?”, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
echocardiogram/MUGA scans, ECOG performance status, and ophthalmologic assessments
will be summarized in the CSR. 
Deterioration as compared with baseline in protocol-mandated laboratory values, vital signs, 
ECGs, and ECHO/MUGA scans should therefore only be reported as AEs if they fulfil any of 
the SAE criteria, are the reason for discontinuation of treatment with the study intervention or 
are considered to be clinically relevant as judged by the investigator (which may include but 
not limited to consideration as to whether treatment or non-planned visits were required or 
other action was taken with the study intervention, eg, dose adjustment or study intervention 
interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 

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parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to PD, should not be reported 
as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. A targeted questionnaire in the eCRF needs to be filled out for 
every case that meets these pre-specified laboratory criteria.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new metastases or progression of existing metastasis to the primary cancer 
under study should be considered as PD and not an AE. Events, which are unequivocally due 
to PD, should not be reported as an AE during the study. Death due to disease progression 
should be recorded on the Death eCRF.
8.3.8 Disease Under Study
Symptoms of disease under study are those which might be expected to occur as a direct result 
of breast cancer. Events which are unequivocally due to disease under study should not be 
reported as an AE during the study unless they meet SAE criteria or lead to discontinuation of 
the study intervention.
8.3.9
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study intervention and are identified after the participant’s inclusion in 
this study. They do not include metastases of the original cancer.
8.3.10
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows:

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
Death clearly resulting from PD should be documented in the eCRF in the Statement of 
Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to PD under study, the AE causing the death 
must be reported as an SAE within 24 hours. It should also be documented in the 
Statement of Death page in the eCRF. The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign the main and contributory causes 
of death.

Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study intervention, then it should also 
be reported as an SAE.
8.3.11
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of the Dato-DXd safety profile and require close monitoring and rapid 
communication by investigators to AstraZeneca. An AESI can be serious or non-serious. All 
AESIs will be recorded in the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. Serious AESIs will be recorded and reported as per 
Section 8.3.13.
For the Dato-DXd clinical program, based on the available preclinical data, review of the 
cumulative literature, reported toxicities for drugs with a similar monoclonal antibody and 
payload of Dato-DXd, and biological plausibility, the following are considered AESIs:

ILD/pneumonitis 

IRR

Oral mucositis/stomatitis

Mucosal inflammation other than oral mucositis/stomatitis

Ocular surface toxicity
All AESIs, regardless of severity or seriousness, must be followed until either event 
resolution, end of study, trial termination, withdrawal of consent, or participant death.

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Concomitant medications administered as treatment for drug-related AESIs should be 
recorded until either event resolution, end of study, trial termination, withdrawal of consent, or 
participant death.
ILD/pneumonitis 
Interstitial lung disease/pneumonitis is considered an important identified risk for Dato-DXd 
based on a comprehensive cumulative review of the available safety data from the clinical 
development program as well as the results of potential ILD/pneumonitis cases reviewed by 
the independent ILD Adjudication Committee, available data from recent 
epidemiology/literature, biological plausibility, and safety information from drugs with a 
similar monoclonal antibody and payload as Dato-DXd. Refer to the current IB for a summary 
of preliminary clinical study data.
All potential ILD/pneumonitis cases should be reported within 24 hours, including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD/pneumonitis is 
described in the Event Adjudication Site Manual). A targeted questionnaire is built within the 
eCRF to collect relevant additional information for these potential cases regardless of 
seriousness.
Interstitial lung disease/pneumonitis should be ruled out if a participant develops radiographic 
changes potentially consistent with ILD/pneumonitis or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever. For 
further guidance on the management of suspected ILD/pneumonitis events, refer to 
Section 8.2.5.3 and the Annex document to this CSP.
If the AE is suspected to be ILD/pneumonitis, treatment with study intervention should be 
interrupted pending further evaluations. Evaluations should include those outlined in 
Section 8.2.5.3. If the AE is confirmed to be ILD/pneumonitis, follow the management 
guidance outlined in the TMGs (see the Annex document to this CSP). All events of 
ILD/pneumonitis, regardless of severity or seriousness, will be followed until resolution 
including after Dato-DXd discontinuation. An autopsy in cases of Grade 5 ILD/pneumonitis is 
encouraged. An independent ILD Adjudication Committee for the Dato-DXd program is 
responsible for reviewing all cases of potential ILD/pneumonitis. See Section 9.6.2 for further 
details. 
IRR
Infusion-related reaction is an identified risk for Dato-DXd. A Grade 3 IRR was reported and 
was assessed by an external consultant as anaphylaxis. A targeted questionnaire for ≥ Grade 3 
IRR will be available as an eCRF to collect relevant additional information for these potential 
cases. All grade ≥3 events of IRR, regardless of seriousness, must be reported in EDC within 
24 hours. Refer to the current IB for a summary of preliminary clinical study data.

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Pre-medication is required prior to any dose of Dato-DXd and must include antihistamines 
and acetaminophen with or without glucocorticoids. If there are any signs or symptoms of a 
grade 1 or 2 IRR, the infusion of Dato-DXd must be either slowed down or interrupted based 
on severity of the infusion-related reaction (see Section 6.2.1.2). If the IRR is grade 3 or 4, or 
if there are any signs of anaphylaxis, the infusion of Dato-DXd must be discontinued. Please 
refer to the IRR management guidance outlined in the TMGs (see the Annex document to this 
CSP).
Oral Mucositis/Stomatitis
Oral mucositis/stomatitis AEs are considered as identified risks and AESIs associated with 
Dato-DXd treatment. Oral mucositis/stomatitis is considered as a separate AESI from mucosal 
inflammation other than oral mucositis/stomatitis. Recommendations for preventing and 
treating oral mucositis/stomatitis are outlined in the SoA (Table 1), Section 8.2.5.6, and the 
TMGs (see the Annex document to this CSP). 
Mucosal Inflammation other than Oral Mucositis/Stomatitis
Mucosal inflammation AEs are considered as identified risks associated with Dato-DXd 
treatment and as a separate AESI from oral mucositis/stomatitis.
Ocular Surface Toxicity
Ocular surface toxicity (eg, dry eye, keratitis) is considered an AESI associated with 
Dato-DXd. Dry eye is considered as an identified risk and keratitis as a potential risk within 
this AESI. Participants are advised to use artificial tears daily and to avoid contact lenses. 
Recommendations for preventing and treating ocular surface toxicity are available in the SoA 
(Table 1), Section 8.2.5.5 and the TMGs (see the Annex document to this CSP).
The Dato-DXd Site Ophthalmologic Assessment Manual will be supplied by AstraZeneca to 
provide assistance to the licensed eye care provider to assess any ocular surface toxicity.
8.3.12
Safety Data to be Collected Following the Final Data Cutoff of the 
Study
For participants continuing to receive study intervention after the final DCO, AEs and SAEs 
will be collected, but only SAEs will be reported. In addition, it is recommended that 
investigators monitor all participant’s safety laboratory results periodically during treatment 
with study intervention in order to manage AEs, consistent with the TMGs (see the Annex 
document to this CSP). All data after the final DCO and database closure will be recorded in 
the participant notes but, with the exception of SAEs, will not otherwise be reported for the 
purposes of this study.
All SAEs that occur in participants still receiving study intervention (or within the 
28 [+7] days following the last dose of study intervention) after the final DCO must be 

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reported as detailed in Section 8.3.13. 
8.3.13
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF. For further 
guidance on the definition of an SAE, see Appendix B.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours of when he or she becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone followed by completion of a paper 
SAE form.
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
The reference document for definition of expectedness is the IB for Dato-DXd, and respective 
EU SmPCs for the active comparator products.
8.3.14
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca.
Female participants must not donate, or retrieve for their own use, ova from the time of 
Screening and throughout the study treatment period, and for at least 7 months after the final 
study drug administration.

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8.3.14.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately. The sponsor must be notified of any female participant or female 
partner of a male participant who becomes pregnant while receiving or within 7 months of 
discontinuing Dato-DXd.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs during the course of the study, the investigator or other site personnel 
must inform the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.13) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.3.14.2
Paternal Exposure 
Non-sterilized male participants who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
the duration of the study (from the time of screening) and for 4 months after the last dose of 
study intervention. 
Participants in the ICC (capecitabine, eribulin, vinorelbine or gemcitabine) arm should follow 
the local Prescribing Information relating to contraception, the time limits for such 
precautions, and any additional restrictions for ICC agents.
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) occurring from the date of the first dose of study intervention 
until 7 months after the last dose of study intervention should be followed up and documented 
in the medical record and provided to the AstraZeneca Patient Safety data entry site. Consent 

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from the partner must be obtained before the information is collected and reported to 
AstraZeneca.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRBs/IECs prior to use.
8.3.15
Medication Error, Drug Abuse, and Drug Misuse
8.3.15.1.1 Timelines
If an event of medication error, drug abuse or drug misuse occurs in the course of the study, 
then the investigator or other site personnel informs the appropriate AstraZeneca 
representatives within one calendar day, ie, immediately but no later than 24 hours of when 
he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-threatening or follow-up 
Fatal/Life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.13) and within 30 days for all other 
medication errors.
8.3.15.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP/study intervention or AstraZeneca NIMP that either causes 
harm to the participant or has the potential to cause harm to the participant.
The full definition and examples of a medication error can be found in Appendix B 4.
8.3.15.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
IMP/study intervention or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
8.3.15.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study intervention(s) or AstraZeneca NIMPs, outside 
the intended use as specified in the protocol and includes deliberate administration of the 
product by the wrong route.

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The full definition and examples of drug misuse can be found in Appendix B 4.
8.3.16
Medical Device Deficiencies
This section is not applicable.
8.4
Overdose
The use of Dato-DXd in doses exceeding that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of Dato-DXd, and 
possible symptoms of overdose are not established. An overdose with associated AEs is 
recorded as the AE diagnosis/symptoms on the relevant AE modules in the eCRF and on the 
Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.13) and within 30 days 
for all other overdoses.
For participants receiving ICC (capecitabine, eribulin, vinorelbine or gemcitabine), refer to the 
local Prescribing Information for treatment of cases of overdose. If any overdose is associated 
with an AE or SAE, record the AE/SAE diagnosis or symptoms in the relevant AE modules 
only of the eCRF.
8.5
Human Biological Samples
Instructions for the collection, handling, storage and shipping of biological samples will be 
provided in the study-specific laboratory manual. Samples should be stored in a secure storage 
space with adequate measures to protect confidentiality. 
Samples may be stored for a maximum of 15 years from the end of the study (as defined in the 
Section 4.4) in line with consent and local requirements, after which they will be 
destroyed/repatriated.

PK samples will be disposed of after the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier).

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
Samples may be disposed of or anonymized by pooling. Additional analyses may be 
conducted on the anonymized, pooled samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from 
the CSR.

Samples collected in mainland China will be stored and disposed of according to 
local laws and regulations. PK samples collected in mainland China will be destroyed 
after finalization of Bioanalytical Report or completion of CSR. 

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 5 years from the CSR publication. ADA samples collected in China will be 
disposed of within 1 year of CSR publication. Additional use includes, but is not limited 
to, further characterization of any ADAs, evaluation of novel and emerging biomarkers, 
confirmation and/or requalification of the assay, and/or diagnostic assay development. 
The results from future analysis will not be reported in the CSR.
For further details on Handling of Human Biological Samples, see Appendix C. 
8.5.1
Pharmacokinetics
Whole blood samples will be collected for participants receiving Dato-DXd treatment for 
measurement of plasma concentrations of Dato-DXd, total anti-TROP2 antibody, and 
MAAA-1181a, per the schedule specified in the SoA (Table 1). The actual date and time 
(24-hour clock time) of each sample should be recorded.
Samples may also be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor (eg, for safety reasons). The timing of 
sampling may be altered during the course of the study based on newly available data (eg, to 
obtain data closer to the time of peak or trough matrix concentrations) to ensure appropriate 
monitoring. 
8.5.1.1
Determination of Drug Concentration
Samples for determination of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a 
concentration in plasma will be assayed by bioanalytical test sites operated by or on behalf of 
AstraZeneca, using an appropriately validated bioanalytical method. Full details of the 
analytical method used will be described in a separate Bioanalytical Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Whole blood samples for determination of ADA for Dato-DXd in plasma will be collected 
from participants receiving Dato-DXd per the schedule specified in the SoA (Table 1). The 

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ADA samples may also be further tested for characterization of the ADA response. The ADA 
titer, and the presence of neutralizing ADA will be tested for positive ADA samples.
Samples will be assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, 
using an appropriately validated bioanalytical method. Full details of the methods used will be 
described in a separate report.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Participant consent to the study includes participation in the mandatory biomarker assessment 
components of the study. 
Samples for biomarker assessment are required and will be collected from all participants in 
this study as specified in the SoA (Table 1). In mainland China, tumor sample collection and 
tests will follow local regulatory requirements.
The following mandatory samples will be collected from all randomized participants:
Tumor tissue
Tumor samples are mandatory for all participants in this study and must be available at the 
time of screening. This can be from either the primary disease setting (surgical resection or 
diagnostic sample), or from a metastatic lesion (excluding bone). The mandatory FFPE tumor 
sample submitted for analysis should be obtained as close to the time of diagnosis of 
metastatic or inoperable disease as possible.
If neither an adequate FFPE block nor the minimum of 20 slides are available, a patient may 
still be considered eligible. In this situation, approval by the Global Study Team for patient’s 
entry into the study is required. 
If a block is not available, a minimum of 20 slides of freshly prepared, unstained, 
4 to 5-micron sections from the archival tumor block. As uncontrolled oxidation processes 
affect tumor sections, tumor tissue blocks are preferred. 
Tumor lesions used for fresh biopsies should not be the same lesions used as RECIST 1.1 
target lesions, unless there are no other lesions suitable for biopsy and in this instance only 
core needle (not excisional/incisional) biopsy is allowed. Collection of tumor cells from fluid 
such as ascites or pleural effusion is not permitted. The tumor sample must not be taken from 
a previously irradiated lesion.
In mainland China, tumor sample collection and testing will follow local regulatory approval.
Samples may be tested for biomarkers including (but not limited to) TROP2 protein and gene 

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expression, TROP2-interacting proteins and TOPO-1 expression, and tumor mutational profile 
to evaluate their association with the observed clinical responses to Dato-DXd (including but 
not limited to PFS and OS, as well as key safety endpoints).
Based on availability of tissue, further additional exploratory biomarkers may be evaluated, 
which may include (but are not limited to), cell death and immunological biomarkers such as 
PD-L1 expression and tumor infiltrating lymphocyte, and gene-expression based tumor 
subtyping.
Blood-borne Biomarkers

Blood samples to perform exploratory circulating biomarker, safety or clinical analyses on 
plasma and serum to identify candidate factors that may correlate with drug response, 
likelihood of clinical benefit and tolerability. 
These analyses may include, but are not limited to, cytokines and chemokines, to assess a 
range of oncology, immunological and safety biomarkers, the detection of the presence of 
viruses. Plasma may also be used for the detection/quantification of autoantibodies 
(against tumor-associated antigens).

Blood sample for the isolation of plasma and buffy coat to enable analysis and 
interpretation of ctDNA, to characterize changes in mutational profile (single nucleotide 
variant and copy number alteration) and allele frequency, between baseline and on-
treatment as a predictive marker for clinical outcomes as exploratory endpoints.
The buffy coat layer obtained during the plasma isolation process of the baseline sample 
will be taken, to enable assessment, analysis and interpretation of ctDNA: 

ctDNA samples will be analyzed for predictive biomarkers of response to treatment. 
The sample is requested prior to treatment in order to maximize the probability of 
detecting ctDNA where the tumor burden is relatively high.

ctDNA samples taken during treatment and a final sample taken at disease 
progression will be used for additional exploratory research which may include but is 
not limited to interrogation of changes in genetic alterations, ctDNA levels as well as 
the dynamics changes of the biomarkers on treatment and potential mechanisms of 
resistance to treatment.

Whole blood sample for RNA and DNA to conduct gene expression and mutational 
analyses to understand immunological changes following treatment with Dato-DXd and 
to assess gene signatures that may predict treatment response.
These samples will be taken at multiple timepoints and analyzed for a range of
oncology and immunological biomarkers that may correlate with drug response. These
biomarkers may include but are not limited to T-cell receptor repertoire analysis and analysis 
of gene expression biomarkers associated with immunomodulatory effects.

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Samples may be retained in all regions to allow for potential diagnostic development, while 
mainland China sample usage will still follow local regulatory approval.
Test residual tumor samples collected for TROP2 IHC testing from Chinese participants will 
be destroyed or repatriated within 1 year after CSR completion.
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual.
8.6.2
Collection of Optional Biomarker Samples
Collection of optional samples for biomarker assessment is also part of this study (as specified 
in the SoA; Table 1) and is subject to agreement to optional consent. Collection of some 
optional samples will be mandated at select sites.
Note: Optional biomarker samples will not be collected in mainland China.
Optional tumor tissue samples for exploratory biomarker research

Paired tumor biopsy: A baseline biopsy will be taken (where the participant has provided 
informed consent) before initial dosing of study intervention (at screening or pre-dose on 
C1D1), and a paired (second) biopsy will be taken on-treatment. The paired on-treatment 
biopsy can be collected C2D1 and C2D7. On-treatment sample may also be collected 
outside of this specified timepoint with prior agreement from the Sponsor. Paired pre-
treatment and on-treatment tumor samples must be obtained from the same lesion where 
clinically feasible to maximize the utility for assessment of pharmacodynamic changes. 
These optional paired tumor samples will be mandatory at select sites.

Tumor biopsy on disease progression: An additional tumor biopsy sample should be 
obtained at termination of treatment/documented RECIST 1.1 disease progression in 
participants that have signed the additional optional consent. These samples will be used 
to explore mechanisms of resistance. The on-study provision of tumor tissue is 
encouraged only if clinically appropriate and not considered detrimental to participant 
care.
Biopsies at study entry, on treatment, and progression are optional for the majority of 
participants in this study, and participants will not be excluded from the study if these samples 
are not collected. These optional biopsy samples will be mandatory at select sites.
ILD related samples
Participants will sign an informed consent for optional tissue samples to be taken in the event 
of suspected or diagnosed ILD. 

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Additional optional blood samples (serum and plasma) will be collected for exploratory 
biomarker analysis as soon as ILD/pneumonitis is suspected and/or diagnosed, if feasible (see 
Section 8.2.5.3).
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual.
8.6.3
Other Study Related Biomarker Assessments
Already collected samples may be analyzed on different biomarkers thought to play a role in 
efficacy and safety outcomes including, but not limited to, serum analytes, or tissue 
biomarkers and/or specific candidate genes/genome-wide analysis for RNA, to evaluate their 
association with observed clinical responses to Dato-DXd. The presence of viruses may also 
be investigated.
Additional exploratory analyses may be undertaken on participants’ samples to identify other 
biomarkers of sensitivity and resistance to study interventions and our understanding of 
cancer. These studies would extend the search for other potential biomarkers relevant to the 
effects of Dato-DXd, cancer and/or the response/resistance to the study intervention. This may 
include the development of ways to detect, monitor or treat cancer. These additional 
investigations would be dependent upon clinical outcome, reagent, and sample availability.
Samples collected in China will not be used for additional exploratory biomarker analyses 
beyond initial TROP2 IHC testing.
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for genomics initiative research is also part of this study as 
specified in the SoA (Table 1) and is subject to agreement in the ICF addendum. Samples will 
be collected according to local regulatory approval.
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study.
See Appendix D for information regarding the storage and destruction of Genomics Initiative 
genetic sample. Details on processes for collection, shipment and destruction of these samples 
can be found in the Laboratory Manual. 
Note: These samples will not be collected in mainland China.

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8.8
Medical Resource Utilization and Health Economics
Health care resource use data associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded.
The assessment of health care resource use will increase the understanding regarding the 
relationship between treatment and tumor-related cancer symptoms on resource use. This will 
be captured and analyzed to inform submissions to payers.
The HOSPAD eCRF module will be used to collect information on key health care resource 
use beyond study mandated visits. To investigate the impact of treatment and disease on health 
care resource use and to conduct exploratory economic analyses, the following variables will 
be captured:

Planned and unplanned hospital attendances beyond trial protocol-mandated visits 
(including inpatient or outpatient physician visits, emergency room visits, surgeries, day 
cases and admissions)

Primary sign or symptom the participant presents with

Length of hospital stay

Length of any time spent in an intensive care unit

Number and type of diagnostic and therapeutic tests and procedures

Any other medical encounters and interventions (including physician or emergency room 
visits, tests and procedures, and medications).
9
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by AstraZeneca or its representatives. 
A comprehensive SAP will be prepared prior to 3 months post-FSI, with final amendments 
completed prior to database lock.
9.1
Statistical Hypotheses
The hypotheses of interest with regards to the efficacy for the dual primary endpoints are:

H0: No differences between Dato-DXd and ICC for PFS and OS.

H1: Differences between Dato-DXd and ICC for PFS and/or OS.
The MTP will define which significance levels should be applied to the interpretation of the 
raw p-values for the dual primary endpoints of PFS and OS. Hypotheses will be tested using a 
MTP with an alpha-exhaustive recycling strategy (Burman et al 2009). 

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To strongly control the familywise type I error rate at the 5.0% level (2-sided), an alpha level 
of 1.0% will be allocated to the PFS dual primary analysis and the remaining 4.0% alpha level 
will be allocated to the OS analyses. If the PFS dual primary analysis crosses the efficacy 
threshold, the 1.0% type I error allocated to the PFS endpoint will be reallocated (Burman et 
al 2009) to the OS endpoint for a total 2-sided type I error of 5.0%.
Hypotheses will be tested in the MTP using alpha (test mass) splitting and alpha recycling, 
where the test mass that becomes available to the OS analyses (recycled) if the PFS dual 
primary analysis null hypothesis is rejected. Implementation of this pre-defined ordered 
testing procedure, including recycling, will strongly control type I error at 5.0% (2-sided), 
among all dual primary hypotheses.
To preserve the overall type I error (familywise error rate) in the strong sense, an MTP 
including the dual primary endpoints will be implemented. The MTP will be fully specified in 
the SAP. The MTP for the dual primary endpoints is described in Figure 5.
Figure 5
Multiple Testing Procedure
9.2
Sample Size Determination
Approximately 1000 participants will be enrolled to achieve approximately 700 participants 
randomly assigned to study intervention.
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study 
but are not randomly assigned/assigned in the study, are considered “screen failures”, unless 
otherwise specified by the protocol. 
The study is sized for dual primary endpoints to characterize the PFS and OS benefit of 
Dato-DXd versus ICC in the participants with HR-positive, HER2-negative breast cancer who 

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have been treated with one or two prior lines of systemic chemotherapy in the 
inoperable/metastatic setting. The study will be considered positive (a success) if either the 
PFS analysis results and/or the OS analysis results are statistically significant.
The primary, final analysis of PFS will be performed when approximately 419 PFS BICR 
events occur, approximately 2 months after the last participant is randomized in the study;
419 PFS BICR events from the ITT population across the Dato-DXd and ICC treatment 
groups will represent 60% maturity of data. Assuming the true PFS hazard ratio is 0.55 for 
Dato-DXd versus ICC, the study will have a greater than 99% power to demonstrate statistical 
significance at the 1.0% level (using a 2-sided test). This assumes median PFS times of 
4.7 months and 8.5 months in ICC and Dato-DXd, respectively when the PFS times are 
exponentially distributed. The smallest treatment difference that could be statistically 
significant at the final analysis is a hazard ratio of 0.775. 
The final analysis of OS will be performed when approximately 444 OS events have occurred 
across the Dato-DXd and ICC treatment groups (63% maturity). Assuming the true OS hazard 
ratio is 0.75 for Dato-DXd versus ICC, the study will have 85% power to demonstrate 
statistical significance at the 5.0% level (using a 2-sided test). This assumes the PFS primary 
analysis crosses the efficacy threshold, and allowing 2 interim analyses to be conducted at 
information fractions of approximately 40% and 80% of the target events, respectively (per 
the O’Brien and Fleming approach [Lan and DeMets 1983]). The smallest treatment 
difference that could be statistically significant at the final analysis is a hazard ratio of 0.824. 
If the PFS primary analysis does not cross the efficacy threshold, the OS analysis will have 
83% power to demonstrate statistical significance at the 4.0% level (using a 2-sided test). The 
smallest treatment difference that could be statistically significant at the final analysis is a 
hazard ratio of 0.817. Calculations assume median OS times of 19.0 months and 25.3 months 
in ICC and Dato-DXd, respectively when the survival times are exponentially distributed. The 
study may continue monitoring participants for OS up to the scheduled final analysis, beyond 
planned interim analyses, to provide more refined estimates of treatment effects for survival. 
Further details of the interim analyses are presented in Section 9.5.
A nonuniform accrual of participants (with k = 1.5) is assumed when estimating the analysis 
times. The total proportion of participants randomized at time t [t ≤ 19 months] following the 
start of the study is assumed to be (t/19)k. 
Dual Primary Endpoints

Dato-DXd versus ICC (PFS in the ITT): 
Assuming the true PFS treatment effect under the alternative hypothesis is a hazard ratio 
of 0.55 for Dato-DXd versus ICC, and the median PFS in ICC is 4.7 months, 419 PFS 
events from the ITT population (60% maturity) will provide greater than 99% power to 
demonstrate statistical significance at the 2-sided alpha level of 1.0%. The smallest 

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treatment difference that is statistically significant will be a hazard ratio of 0.775. 
Assuming a recruitment period of 19 months, this analysis is anticipated to be 21 months 
after the first participant has been randomized.

Dato-DXd versus ICC (OS in the ITT):
Assuming the true OS treatment effect under the alternative hypothesis is a hazard ratio of 
0.75 for Dato-DXd versus ICC, and the median OS in ICC is 19.0 months, 444 OS events 
from the ITT population (63% maturity) will provide approximately 83% power to 
demonstrate statistical significance at the 2-sided alpha level of 4.0%. The smallest 
treatment difference that is statistically significant will be a hazard ratio of 0.817. If the 
PFS dual primary analysis crosses the efficacy threshold, OS will be tested at the 2-sided 
alpha level of 5.0% and the analysis will have 85% power to demonstrate statistical 
significance. The smallest treatment difference that is statistically significant will be a 
hazard ratio of 0.824. With a recruitment period of approximately 19 months it is 
anticipated that the primary/final OS analysis will occur approximately 44 months after 
the first participant has been randomized. 
9.3
Populations for Analyses
The populations for analysis are defined in Table 9.
Table 9
Populations for Analysis
Population/Analysis Set
Description
Enrolled
All participants who sign the ICF.
Intent-to-treat (ITT) 
population
All participants who are randomized in the study, excluding participants 
randomized in mainland China after the global cohort last participant 
randomized, if applicable. 
The ITT will be used for all the efficacy analyses (including PROs: EORTC 
QLQ-C30, EORTC IL116, EQ-5D-5L, PGIS, PGIC). Treatment groups will be 
compared on the basis of randomized study intervention, regardless of the 
intervention actually received. Participants who were randomized but did not 
subsequently receive study intervention are included in the analysis in the 
intervention group to which they were randomized.

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Table 9
Populations for Analysis
Population/Analysis Set
Description
Safety Analysis Set 
(SAS)
Participants in the ITT who have received at least 1 dose of study intervention.
Safety data will not be formally analyzed but summarized using the SAS 
according to actual study intervention received (including PROs: PGI-TT, PRO-
CTCAE, EORTC IL117).
Ophthalmologic Analysis 
Set (OAS)
Approximately the first 100 randomized participants (approximately 50 per arm, 
Dato-DXd and ICC) in the ITT. See section 8.2.5.5 for details.
Pharmacokinetic Analysis 
Set (PAS)
All participants in the ITT randomly assigned to study intervention who received 
at least 1 dose of study intervention for whom any post-dose PK data are 
available and who do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses.
The population will be defined by the sponsor Study Physician, 
Pharmacokineticist, and Statistician prior to any analyses being performed.
9.4
Statistical Analyses
The SAP will be finalized prior to 3 months post-FSI of the first randomized participant, and 
will include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints.
9.4.1
General Considerations
More detail will be provided in the SAP.
9.4.2
Efficacy
9.4.2.1
Primary Endpoints
Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Primary Endpoints
Endpoints analyzed
Notes
Progression-free survival
Stratified log-rank test for:
Dual primary analysis using BICR RECIST 1.1 assessments: 

Dato-DXd versus ICC (ITT population)
Secondary analysis using Investigator assessment:

Dato-DXd versus ICC (ITT population)
Sensitivity analysis for the PFS dual primary analysis (ITT population):

Evaluation-time bias

Attrition bias

Ascertainment bias

Subsequent anticancer therapy

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Table 10
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Primary Endpoints
Endpoints analyzed
Notes
Overall survival
Stratified log-rank test for:
Dual primary analysis:

Dato-DXd versus ICC (ITT population) 
9.4.2.1.1
Calculation or Derivation of Tumor Response Variables
Investigator RECIST 1.1-based assessments
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a participant discontinues study intervention or 
receives another anticancer therapy. 
At each visit, participants will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline and 
previous assessments. Baseline will be assessed within the 28 days prior to randomization. 
The tumor response endpoints (PFS, ORR, DoR, and DCR) will then be derived from the scan 
dates and overall visit responses.
BICR
A BICR of radiological scans will be performed on all participants to confirm the robustness 
of the investigator-assessed PFS, ORR, and DoR endpoints. 
All images will be collected centrally, until PFS analysis. Additionally, following 
RECIST 1.1-defined radiological progression by Investigator assessment, 1 additional follow-
up scan should be performed as per imaging schedule (ie, either 6 weeks or 9 weeks later). 
This scan will be used in the PFS dual primary endpoint analysis.
The imaging scans will be reviewed by 2 independent radiologists using RECIST 1.1 and will 
be adjudicated, if required. For each participant, the BICR will define the overall visit 
response data (CR, PR, SD, PD, or NE) and the relevant scan dates for each time point (ie, for 
visits where response or progression is/is not identified). If a participant has had a tumor 
assessment that cannot be evaluated, then the participant will be assigned a visit response of 
NE (unless there is evidence of progression, in which case the response will be assigned as 
PD). Endpoints (PFS, ORR, DoR, and DCR) will then be derived from the scan dates and 
overall visit responses. 
Further details of the BICR will be documented in an Independent Review Charter.
9.4.2.1.2
Progression-Free Survival
Progression-free survival will be defined as the time from the date of randomization until the 

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date of objective PD per RECIST 1.1 (as assessed by BICR) or death (by any cause in the 
absence of progression), (ie, date of event or censoring – date of randomization + 1). The 
comparison will include all randomized participants, as randomized, regardless of whether the 
participant withdraws from randomized therapy, receives another anticancer therapy or 
clinically progresses prior to RECIST 1.1 progression. Participants who have not progressed 
or died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment. However, if the participant progresses or dies 
after 2 or more consecutive missed visits, the participant will be censored at the time of the 
latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. (Note: NE visit is not 
considered as missed visit).
If the participant has no evaluable visits or does not have baseline data, they will be censored 
at the date of randomization, unless they die within 2 scheduled scans of baseline (12 weeks 
[+1 week] allowing for a late assessment within the visit window).
Analysis Methods
The dual primary endpoint of PFS will be based on the BICR assessment of PD by
RECIST 1.1.
Progression-free survival will be analyzed using a log-rank test stratified by number of 
previous lines of chemotherapy, geographic region, and prior use of CDK4/6 inhibitor. The 
hazard ratio together with its 95% CI and p-value will be presented (a hazard ratio less than 1 
will favor the comparator arm). The hazard ratio and CI will be estimated from a stratified 
Cox proportional hazards model (with ties = Efron), and the CI will be calculated using a 
profile likelihood approach. 
The stratification variables will be defined according to data from the IRT. If the number of 
events in an individual stratum are too small for a meaningful analysis, then a method will be 
applied that will remove stratification factors until there are meaningful number of events per 
strata. Details will be presented in the SAP.
Kaplan-Meier plots of PFS will be presented by treatment group. Summaries of the number 
and percentage of participants experiencing a PFS event and the type of event (RECIST 1.1 or 
death) will be provided along with median PFS for each treatment. The primary and final 
analysis of PFS will be performed approximately 2 months after the last participant is 
randomized in the study; approximately 419 PFS BICR events across the Dato-DXd and ICC 
treatment groups (60% maturity) are anticipated at that time.
9.4.2.1.3
PFS Sensitivity Analyses
Details of these analyses will be presented in the SAP.

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Evaluation-time Bias
A sensitivity analysis will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment (using the 
final date of the assessment) will be analyzed using a stratified log-rank test, as described for 
the primary analysis of PFS.
Attrition Bias
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of participants who progressed or died in the absence of 
progression immediately following two, or more, non-evaluable tumor assessments will be 
included. In addition, and within the same sensitivity analysis, participants who take 
subsequent therapy (note that for this analysis radiotherapy is not considered a subsequent 
anticancer therapy) prior to their last evaluable RECIST assessment or progression or death 
will be censored at their last evaluable assessment prior to taking the subsequent therapy. This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring using the PFS data 
from the primary analysis and where the censoring indicator of the PFS analysis is reversed.
Ascertainment bias
Ascertainment bias will be assessed by analyzing the site Investigator data which is a 
secondary efficacy variable (analysis methods presented in Section 9.4.2.2.3). 
If there is an important discrepancy between the primary analysis using the BICR assessments 
and the secondary analysis using investigator assessments, the proportion of participants with 
site but no central confirmation of progression will be summarized; such participants have the 
potential to introduce bias in the central review due to informative censoring. An approach 
that imputes an event at the next visit in the central review analysis may help inform the most 
likely hazard ratio value, but only if an important discrepancy exists.
Subsequent Anticancer Therapy
PFS may be impacted for participants who are treated with a subsequent anticancer therapy. 
Therefore, an analysis will be performed censoring a participant at the last available tumor 
assessment prior to taking subsequent anticancer therapy.
Additional sensitivity analyses may be defined in the SAP.
9.4.2.1.4
Overall Survival
Overall survival is defined as the time from the date of randomization until death due to any 
cause. The comparison will include all randomized participants, as randomized, regardless of 
whether the participant withdraws from randomized therapy or receives another anticancer 

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therapy (ie, date of death or censoring – date of randomization + 1). Any participant not known 
to have died at the time of analysis will be censored based on the last recorded date on which 
the participant was known to be alive. 
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If participants are confirmed to be alive or 
if the death date is after the DCO date, then these participants will be censored at the date of 
DCO. 
Analysis Methods
Overall survival will be analyzed using the same methodology specified for PFS. The effect of 
Dato-DXd versus ICC will be estimated by the hazard ratio together with its corresponding CI 
and p-value. Kaplan-Meier plots will be presented by treatment group. 
The study may continue monitoring participants for OS up to the scheduled final analysis, 
beyond planned interim analyses, to provide more refined estimates of treatment effects for 
survival.
9.4.2.1.5
Subgroup Analysis
Subgroup analyses will be conducted, comparing PFS (per RECIST 1.1 using BICR 
assessments) and OS between Dato-DXd and ICC in the following subgroups of the ITT (but 
not limited to):

Number of previous lines of chemotherapy (1 versus 2)

Geographic region (Region 1 [US, Canada, Europe] versus Region 2 [Rest of World])

Prior use of CDK4/6 inhibitor (Yes versus No)

Prior use of taxanes and/or anthracyclines (taxanes alone, anthracyclines alone, both 
taxanes and anthracyclines, neither taxanes nor anthracyclines)

Age at randomization (< 65 versus ≥65 years of age)

Race (Asian versus non-Asian)

Pre-selected choice of chemotherapy (Capecitabine, Gemcitabine, Eribulin mesylate, or 
Vinorelbine)

Brain metastases (Yes versus No)
Other baseline variables may also be assessed if there is clinical justification, or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors.
A forest plot of the PFS hazard ratios (along with the 95% CIs) will be produced for each level 
of the subgroups listed above.

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The subgroup analyses for the stratification factors will be based on the values entered into the 
IRT; all other factors will be based on values recorded on the eCRF, or from the third-party 
vendor data.
Additional subgroups of interest and analysis methods will be outlined in the SAP.
Unless there is a marked difference between the results of the statistical analyses of the PFS 
from the BICR data and that of the site Investigator tumor data, these subgroup analyses will 
only be performed on the PFS endpoint using the BICR data.
9.4.2.2
Secondary Endpoint(s)
9.4.2.2.1
Objective Response Rate
Objective response rate is defined as the proportion of participants who have a confirmed CR 
or PR, as determined by the BICR/Investigator assessment, per RECIST 1.1.
The analysis will include all randomized participants as randomized, with measurable disease 
at baseline. Data obtained from randomization up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR, 
regardless of whether the participant withdraws from therapy. Participants who go off 
treatment without a response or progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR.
Analysis Methods
The ORR will be compared between the treatment arms using a logistic regression model 
adjusting for the same stratification factors as the PFS as covariates in the model. The results 
of the analysis will be presented in terms of an adjusted odds ratio (OR) together with its 
associated 95% CI and p-value. If there are not enough responses for a meaningful analysis 
using logistic regression, then a CMH test is presented. The CMH test is stratified using the 
same stratification factors as PFS. The results of the analysis are presented in terms of an OR 
together with the 95% CI and p-value. Further details will be presented in the SAP. 
Comparisons between treatment groups will be made using both BICR RECIST 1.1 and 
investigator assessments.
Summaries will be produced that present the number and percentage of participants with a 
tumor response (CR/PR). For each treatment arm, BoR will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE).
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment. It is the best response a participant has had following randomization, but 
prior to starting any subsequent cancer therapy and up to and including RECIST progression 
or the last evaluable assessment in the absence of RECIST progression. Categorization of BoR 
will be based on RECIST using the following response categories: CR, PR, SD, PD, and NE. 

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Best objective response will be determined programmatically based on RECIST from the 
overall visit response using all BICR data up until the first progression event. It will also be 
determined programmatically based on RECIST using all site investigator data up until the 
first progression event. The denominators for each case will be consistent with those used in 
the ORR analysis.
9.4.2.2.2
Duration of Response
Duration of response is defined as the time from the date of first documented confirmed 
response until date of documented progression per RECIST 1.1, as assessed by 
BICR/Investigator assessment or death due to any cause.
The analysis will include all randomized participants as randomized who have a confirmed 
response, regardless of whether the participant withdraws from therapy, receives another 
anticancer therapy or clinically progresses prior to RECIST 1.1 progression.
Analysis Methods
Duration of response will be analyzed by summary statistics and Kaplan-Meier plots. 
Comparisons will be presented for both BICR RECIST 1.1 and investigator assessments. 
9.4.2.2.3
Progression-Free Survival by Investigator assessment
PFS by Investigator assessment will be defined as the time from the date of randomization 
until the date of PD per RECIST 1.1 (by Investigator assessment) or death (by any cause in 
the absence of progression), (ie, date of event or censoring – date of randomization + 1). 
The analysis will include all randomized participants as randomized regardless of whether the 
participant withdraws from therapy, receives another anticancer therapy, or 
clinically progresses prior to RECIST 1.1. However, if the participant progresses or dies 
immediately after two or more consecutive missed visits, the participant will be censored at 
the time of the latest evaluable assessment prior to the two missed visits.
Analysis Methods
This secondary endpoint of PFS based Investigator assessment will be analyzed using the 
same methodology described in Section 9.4.2.1.2.
9.4.2.2.4
Disease control rate
Disease control rate at 12 weeks is defined as the percentage of participants who have a 
confirmed CR or PR or who have SD, per RECIST 1.1, as assessed BICR/per investigator 
assessment and derived from the raw tumor data for at least 11 weeks after randomization. 
The analysis will include all randomized participants as randomized. Data obtained from 
randomization up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of DCR, regardless of whether the participant 
withdraws from therapy. Participants who receive a subsequent therapy prior to week 11 will 

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not be considered to have disease control in the analysis.
Analysis Methods
Disease control rate will be analyzed using the same methodology specified for ORR.
9.4.2.2.5
Time to First Subsequent Therapy (TFST)
Time to first subsequent therapy is defined as the time from randomization until the start date 
of the first subsequent anticancer therapy after discontinuation of randomized treatment, or 
death due to any cause.
The analysis will include all randomized participants as randomized, regardless of progression 
status.
Analysis Methods
Time to first subsequent therapy will be analyzed using the same methodology as that used for 
the analysis of PFS. In addition, medians and a Kaplan-Meier plot of the time to the start of 
subsequent therapy will be presented by treatment arm and the time between progression and 
starting subsequent therapy will be summarized.
9.4.2.2.6
Time to Second Subsequent Therapy (TSST)
Time to second subsequent therapy is defined as the time from randomization to until the start 
date of the second subsequent anticancer therapy after discontinuation of first subsequent 
treatment, or death due to any cause.
The analysis will include all randomized participants as randomized, regardless of progression 
status on study treatment or first subsequent treatment.
Analysis Methods
Time to second subsequent therapy will be analyzed using the same methodology as that used 
for the analysis of TFST.
9.4.2.2.7
Time from randomization to second progression or death (PFS2)
Time to second progression of death will be defined as the time from the randomization to the 
earliest of the progression event (following the initial progression), subsequent to first 
subsequent therapy, or death. The date of second progression will be recorded by the 
Investigator in the eCRF and defined according to local standard clinical practice.
The analysis will include all randomized participants as randomized, regardless of progression 
status on study treatment or first subsequent treatment.
Analysis Methods
Time to second progression or death will be analyzed using identical methods as outlined for 

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PFS.
9.4.2.2.8
Clinical Outcome Assessments
The secondary PRO endpoints include:

TTD in pain as measured by the pain scale from EORTC QLQ-C30 

TTD in physical functioning as measured by the physical functioning scale from EORTC 
QLQ-C30

TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC QLQ-C30.
Time to deterioration (TTD) is defined as time from the date of randomization to the date of 
deterioration. Deterioration is defined as change from baseline that reaches a clinically 
meaningful deterioration threshold. Anchor-based methods using the participant-based 
anchors PGIS and PGIC will be considered to define thresholds for clinically meaningful 
within-participant change used in the TTD endpoints. Other methods including distribution-
based methods, cumulative distribution function, and probability density function curves, and 
methods using other anchors may also be considered.
Clinically meaningful thresholds will be estimated for the following patient-reported 
outcomes:

EORTC QLQ-C30: Global health status/QoL, functioning, and select symptom subscales 
including pain and fatigue

EORTC QLQ IL116: breast symptoms, arm symptoms.
The analysis to define clinically meaningful change thresholds in the TTD PRO endpoints will 
include all randomized participants using the pooled treatment arms data prior to database 
lock. These TTD PRO endpoints will be analyzed using the same time-to-event analysis 
methodology described in Section 9.4.2.1.2.
Details of all statistical analyses, including analyses for other exploratory PRO endpoints, will 
be described in full in the SAP.
9.4.2.2.9
Pharmacokinetics 
Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a PK concentrations will be listed 
and summarized by visit and scheduled time point. Non-compartment PK parameters that can 
be derived with sparse PK sampling, such as peak and trough concentrations, will be reported 
as data allows. Details of those analysis will be described in SAP. Population PK, and 
exploratory exposure response/safety analyses will be performed. A separate modeling 
analysis plan will be written before the database lock. The population PK analysis and 
exploratory exposure response/safety analysis will be presented separately from the main 
CSR. 

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9.4.2.2.10 Immunogenicity 
Immunogenicity results will be listed by participant, and a summary will be provided by the 
number and percentage of participants who develop detectable anti-Dato-DXd antibodies. The 
immunogenicity titer and neutralizing ADA data will be listed for samples confirmed positive 
for the presence of anti-Dato-DXd antibodies. 
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
efficacy, and safety will be evaluated, if the data allow. 
9.4.2.3
Exploratory Endpoints
Details of all statistical analyses for exploratory endpoints (including biomarkers, PRO, and 
medical resource utilization) will be described in full in the SAP.
9.4.2.3.1
Biomarkers
Biomarker status will be assessed for participants in each treatment group according to 
pre-specified criteria that may be detailed in the SAP. The relationship of biomarker 
expression and, if applicable, of exploratory biomarkers to clinical outcomes (including but 
not restricted to) of PFS, ORR, and OS may be presented. Biomarker exploratory analyses 
may be described in a separate analysis plan and may be reported outside the CSR in a 
separate report. The results of this biomarker assessment will be reported either in the CSR 
itself or as an addendum, or separately in a scientific report or publication. 
The results of this biomarker assessment may be pooled with biomarker data from other 
studies with the study intervention to generate hypotheses to be tested in future research.
9.4.2.3.2
Medical Resource Utilization and Health Economics
To investigate the impact of treatment and disease on health care resource use, the following 
variables will be captured:

Planned and unplanned hospital attendances beyond protocol-mandated visits (including 
physician visits, emergency room visits, day cases, and admissions)

Primary sign or symptom the participant presents with

Length of hospital stay, per stay

Length of any time spent in an intensive care unit

Procedures and tests
Where admitted overnight, the length of hospital stay will be calculated as the difference 
between the date of hospital discharge (or death date) and the start date of hospitalization or 
start of study intervention if the start of study intervention is after start date of hospitalization 
(length of hospital stay = end date of hospitalization – start date of hospitalization + 1). 
Participants with missing discharge dates will be calculated as the difference between the last 
day with available data and the start date of hospitalization. The length of intensive care unit 

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stay will be calculated using the same method.
Analysis Methods
The potential impact of the disease and treatment on health care resource use will be analyzed 
for the purposes of submissions to payers. Descriptive statistics (as appropriate, including 
means, median, ranges or frequencies, and percentages) will be provided for each treatment 
group on the different types of hospital admissions, the length of stay for participants admitted 
to hospital for at least 1 overnight stay, and the length of stay for participants admitted to 
intensive care/high dependency units, as well as the primary sign or symptom the participant 
presents with.
9.4.3
Safety
Safety summaries will be provided using the SAS. Safety data will be presented using 
descriptive statistics unless otherwise specified. Summary statistics for continuous variables 
will include number of participants, mean, standard deviation, minimum, median, and 
maximum. Frequency tables and shift tables will include number and percentage of 
participants in the respective category. Unless otherwise stated, percentages will be calculated 
out of the population total.
Baseline
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of study intervention. Details are described in the SAP.
Adverse events
Adverse events will be coded using the most recent version of MedDRA that will be released 
for execution at AstraZeneca, and graded using NCI-CTCAE v5.0.
The following adverse events are considered treatment emergent:

Adverse events with an onset date on or after first dose of study intervention and within 
28 (+7) days after last dose of study intervention or up to the day prior to start of 
subsequent therapy, whichever comes first.

Worsening of pre-existing events on or after first dose of study intervention and within 
28 (+7) days after last dose of study intervention or up to the day prior to start of 
subsequent therapy, whichever comes first.
Adverse events will be presented for each treatment group by System Organ Class, HLT 
and/or PT covering number and percentage of participants reporting at least one event and 
number of events where appropriate. 
An overview of AEs will present for each treatment group the number and percentage of 

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participants with any AE, AEs with outcome of death, serious AEs, and AEs leading to 
discontinuation of study intervention, as well as AEs leading to study intervention dose 
interruptions, AEs leading to study intervention dose reduction and AEs leading to withdrawal 
from study as well as the number of individual occurrences in those categories.
Treatment emergent adverse events will be presented for each treatment group by System 
Organ class and/or PT covering number and percentage of participants reporting at least one 
event and number of events where appropriate. 
Separate AE tables will be provided taken into consideration relationship as assessed by the 
investigator, maximum CTCAE grading, seriousness, death and events leading to 
discontinuation of study intervention, as well as other action taken related to study 
intervention, and AESIs.
Key participant information will be presented for participants with AEs with outcome of 
death, SAEs, and AEs leading to discontinuation of study intervention.
An AE listing for the safety analysis set will cover details for each individual AE.
Full details of AE analyses will be provided in the SAP.
Vital signs
Vital sign parameters will be presented for each treatment group. 
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline. 
Details of vital sign analyses will be provided in the SAP. 
Laboratory parameters
Laboratory parameters will be presented for each treatment group. 
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
hematology parameters will be presented for observed values and change from baseline. 
Elevation in liver parameters for assessment of Hy’s Law will be reported appropriately. 
A shift table for urinalysis will be presented with baseline assessment against the maximum on 
treatment category. 
Supportive laboratory listings will cover observed values and changes from baseline for each 
individual participant as well as abnormalities.

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Details of laboratory analyses will be provided in the SAP.
Other safety endpoint analyses
Details of analyses of urinalysis, ECGs, and ECHOs/MUGAs will be specified in the SAP.
9.4.4
Other Analyses
9.4.4.1
Optional Exploratory Genetic Sample
Data will be reported outside the CSR (please see Appendix D).
9.4.4.2
Ophthalmologic Analysis
See Section 8.2.5.5. Details will be specified in the SAP.
9.5
Interim Analyses 
Two interim analyses for OS are planned. The first OS interim will occur at the primary PFS 
analysis (approximately 40% of target OS events) and the second when approximately 80% of 
the target OS events have occurred. The Lan DeMets approach (Lan and DeMets 1983) that 
approximates the O’Brien and Fleming spending function will be used to maintain an overall 
2-sided type I error across the three planned analyses of OS. If the PFS dual primary analysis 
crosses the efficacy threshold, the 1.0% type I error allocated to the PFS endpoint will be 
reallocated to the OS endpoint for a total 2-sided type I error of 5.0%. Details of the planned 
timing of the two interim and final analyses are provided in Table 11. Note that the actual 
allocation of alpha across the three analysis times will be driven by the actual information 
fraction associated with the analysis.
The interim analyses will be performed by an IDMC. It is expected that recruitment will have 
completed prior to the results of the interim analyses being available. For the interim analyses, 
the IDMC will review unblinded interim data and inform the sponsor whether the interim 
boundaries specified in Table 11 are met. 
Table 11
Summary of planned timings of the interim and final OS analyses
Interim Analysis 1
Interim Analysis 2
Primary Analysis
Projected Timing
21 Months b
34 Months
44 Months
Number of Deaths a
178
355
444
Information Fraction
40%
80%
100%
Maturity
25%
51%
63%
Recommendation
Continue
Reject 
Null 
Hypothesis
Continue
Reject 
Null 
Hypothesis
Do Not 
Reject Null 
Hypothesis
Reject 
Null 
Hypothesis
At 4.0% 2-sided alpha c
   2-sided nominal p-value
≥ 0.0005
< 0.0005
≥ 0.0184
< 0.0184
≥ 0.0345
< 0.0345

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Table 11
Summary of planned timings of the interim and final OS analyses
Interim Analysis 1
Interim Analysis 2
Primary Analysis
   Estimated hazard ratio
≥ 0.591
< 0.591
≥ 0.777
< 0.777
≥ 0.817
< 0.817
At 5.0% 2-sided alpha c
   2-sided nominal p-value
≥ 0.0008
< 0.0008
≥ 0.0241
< 0.0241
≥ 0.0427
< 0.0427
   Estimated hazard ratio
≥ 0.604
< 0.604
≥ 0.786
< 0.786
≥ 0.824
< 0.824
a Estimates based on exponential survival where the median OS is 19.0 months for ICC and 25.3 months for 
Dato-DXd. The total proportion of participants randomized at time t [t ≤ 19 months] following the start of the 
study is assumed to be (t/19)1.5.
b Timing of first IA based on PFS. Number of deaths is an estimate.
c Alpha allocated to OS endpoint (4.0% or 5.0%) dependent on statistical significance of PFS.
The study may continue monitoring participants for OS up to the scheduled final analysis, 
beyond planned interim analyses, to provide more refined estimates of treatment effects for 
survival.
The first IA for OS will occur at the time of the PFS analysis. If 40% of the target OS events 
(178/444) are available at the time of the first OS IA, then the largest (nominal) 2-sided 
p-value that will cross the efficacy threshold is 0.0008. If the first interim results do not meet 
the criterion for rejecting the null hypothesis in the ITT population, then follow-up will 
continue until at the criteria are met for the second OS IA. The second OS IA is planned when 
approximately 80% of target OS events (355/444) are available. The largest (nominal) 2-sided 
p-value that will cross the efficacy threshold is 0.0241 based on the expected timing of the 
second IA. If the interim results do not meet the criterion for rejecting the null hypothesis in 
the ITT population, then follow-up will continue until the criteria is met for the for OS 
primary analysis. The OS primary analysis will be performed when 444 OS events are 
observed, and the nominal 2-sided p-value will be 0.0427 based on the expected timing of the 
second IA. Note that the p-value boundaries reported in this paragraph presume that 5.0% 
type I error is available for the OS analysis.
If the PFS primary analysis does not cross the efficacy threshold, the total 2-sided type I error 
allocated to the OS analyses will be 4.0%. For the 2 interim and primary analyses of OS, 
based on the expected number of events at each analysis, the nominal 2-sided p-values 
associated with the three analyses times are 0.0005, 0.0184, and 0.0345, respectively.
The SAP will describe the planned interim analyses in greater detail.
9.6
Data Monitoring Committees
9.6.1
Independent Data Monitoring Committee
An IDMC comprised of independent experts will convene and will meet approximately 
6 months after the study has started. The IDMC will review unblinded safety data and make 

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recommendations on whether the study should continue, be amended, or stopped based on 
safety findings. In addition, the IDMC may be requested to review efficacy data. For the 
interim analyses, the IDMC will review unblinded interim data and inform the Sponsor 
whether the interim boundaries specified in Section 9.5 are crossed.
Full details of the IDMC communications, procedures, processes, and interim analyses will be 
presented in the IDMC Charter.
9.6.2
ILD Adjudication Committee
An independent ILD Adjudication Committee for the Dato-DXd program is responsible for 
reviewing all cases of potential ILD/pneumonitis. To ensure adequate and relevant 
independent evaluation, systematic additional data collection will be conducted for all cases 
that will be brought for adjudication. These additional data collections will cover a more 
in-depth relevant medical history (eg, smoking, radiation, COPD and other chronic lung 
conditions), diagnostic evaluation, treatment and outcome of the event. This data collection 
will be triggered based on a pre-defined list of PTs eligible for adjudication as described in the 
Event Adjudication Site Manual. Further details can be found in the ILD Adjudication Charter.
9.6.3
Ophthalmologic Data Review Committee
An independent Ophthalmologic Data Review Committee is responsible for reviewing the 
data from baseline, periodic and end of therapy ophthalmologic assessments. This data 
collection will be triggered based on a pre-defined list of PTs eligible for review. Further 
details will be available in the Ophthalmologic Data Review Committee Charter.
9.7
Mainland China Cohort
The global cohort will enrol approximately 1000 participants to randomize approximately 700 
participants. The mainland China cohort will consist of approximately an additional 20 
randomized participants in mainland China. The global cohort will consist of participants 
recruited by the documented date of the last participants randomized of the global cohort. 
Participants randomized in the mainland China cohort prior to the last participants randomized 
of the global cohort enrolment will be included in both the ITT and the mainland China ITT. 
Participants randomized in the mainland China cohort after the last participants randomized of 
the global cohort enrolment will be included only in the mainland China ITT. The mainland 
China ITT will include all participants randomized in the mainland China cohort including 
those who were recruited prior to the closure of the global cohort and are therefore included in 
the analyses of efficacy and safety for the main study. The mainland China safety analysis set 
will consist of all participants included in the mainland China ITT who received at least 1 
dose of study treatment.
Per NMPA guidance, in addition to the evaluation of the global cohort data for primary, 
secondary and safety objectives, evaluation of consistency in efficacy and safety in Chinese 

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populations is required to facilitate the benefit-risk assessment for mainland Chinese 
participants. Hence, the safety and efficacy data in the mainland China cohort will be analyzed 
separately where the same endpoint definitions and the same analysis methods are applied.
Details of the mainland China cohort analyses will be specified in the SAP.

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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines
Applicable ICH GCP Guidelines
Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organization but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21CFR 312.120, ICH guidelines, the IRB/IEC, 
and the European Regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 

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and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
A “serious breach” means a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU CT Regulation 536/2014 applies, AstraZeneca is required to enter details of 
serious breaches into the European Medicines Agency CTIS. It is important to note 
that redacted versions of serious breach reports will be available to the public via 
CTIS.

The investigator should have a process in place to ensure that:
The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.
A (potential)_serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 

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during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF. The ICF will contain a 
separate section that addresses and documents the collection and use of any mandatory and/or 
optional human biological samples. The investigator or authorized designee will explain to 
each participant the objectives of the analysis to be done on the samples and any potential 
future use. Participants will be told that they are free to refuse to participate in any optional 
samples or the future use and may withdraw their consent at any time and for any reason 
during the retention period.
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Unless previously specified, the biomarker data will have unknown clinical significance and 
AstraZeneca will not provide biomarker assessment results to participants, their family 
members, any insurance company, any employer, a clinical study investigator, a general 
physician, or any other third party, unless required to do so by law; however, AstraZeneca may 
share data and biosamples with research partners, for example Daiichi Sankyo.
The participant’s samples will not be used for any purpose other than those described in the 

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study protocol.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
For additional details see Section 9.6.1.
A 6
Dissemination of Clinical Study Data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant.
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com, http://www.clinicaltrials.gov, and 
https://www.clinicaltrialsregister.eu as will the summary of the main study results when they 
are available. The clinical study and/or summary of main study results may also be available 
on other websites according to the regulations of the countries in which the main study is 
conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on the CRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents.

The sponsor or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including clinical reviews of 
study data from a medical perspective, and handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan.

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
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca GRAD Schedule. No records 
may be destroyed during the retention period without the written approval of 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies).
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 

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and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence (other than progression of the
malignancy under evaluation) in a participant or clinical study participant administered a 
study intervention and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the study 
intervention. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:

Results in death.

Is immediately life-threatening.

Requires in-participant hospitalization or prolongation of existing hospitalization. 

Results in persistent or significant disability or incapacity. 

Is a congenital anomaly or birth defect.

Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
AEs for malignant tumors reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the “Important Medical Event” criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumor under study). Malignant tumors that – as part 
of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of B 
cell chronic lymphocytic leukemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumor.
Life-threatening
“Life-threatening” means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
participant’s death. “Life-threatening” does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important medical event or medical treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse

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Intensity rating scale:
The grading scales found in the revised National Cancer Institute CTCAE version 5.0 will be 
utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a “reasonable possibility” that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

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
Is there a known mechanism?
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as “not related”.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, and Drug Misuse
Medication Error 
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error: 

Occurred.

Was identified and intercepted before the participant received the drug.

Did not occur, but circumstances were recognized that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant.

Drug not administered as indicated, eg, wrong route, dose (error greater than +/- 10%), or 
wrong site of administration.

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet.

Drug not stored as instructed eg, kept in the refrigerator when it should be at room 
temperature. 

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
Wrong participant received the medication (excluding IRT errors).

Wrong drug administered to participant (excluding IRT errors).
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error. 

Participant accidentally missed drug dose(s) eg, forgot to take medication.

Accidental overdose (will be captured as an overdose).

Participant failed to return unused medication or empty packaging.
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP/study intervention or AstraZeneca NIMP for a perceived 
reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site using the Drug Abuse Report Form. This form should be used both if the 
drug abuse happened in a study participant or if the drug abuse regards a person not enrolled 
in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant or a 
person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of getting 
high.
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study interventions or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol, and includes deliberate administration of the product 
by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site using the Drug Misuse Report Form. This form should be used both if the 

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drug misuse happened in a study participant or if the drug misuse regards a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes 

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that they were feeling 
better when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. If required, AstraZeneca will ensure that remaining 
biological samples are returned to the site according to local regulations or at the end of the 
retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analyzed, AstraZeneca is not obliged to destroy the results of this 
research. The participant will be presented with the option to opt out of the subsequent use of 
the donated samples during the withdrawal process. If the participant decides to opt out, then 
the donated samples will be disposed of. If the participant withdraws consent without opting 
out for the subsequent use of the donated samples, then the samples will be used as per 
protocol.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

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
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented, and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
IATA (https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx ) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt:
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.
Category A pathogens are, for example, Ebola, Lassa fever virus. Infectious substances 
meeting these criteria which cause disease in humans or both in humans and animals must be 
assigned to UN 2814. Infectious substances which cause disease only in animals must be 
assigned to UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations.

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging. 
(https://www.iata.org/contentassets/b08040a138dc4442a4f066e6fb99fe2a/dgr-62-en-
pi650.pdf).

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
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content.

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Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant’s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained while research on Dato-DXd continues but no longer than 
15 years from the end of the study (as defined in the protocol) or other period as per local 
requirements.
D 2
Genetic Research Plan and Procedures
Selection of genetic research population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and provide informed consent for the Genomics 
Initiative sampling and analyses.
Exclusion criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:
Previous allogeneic bone marrow transplant.
Transfusion of non-leukocyte depleted blood or blood component within 120 days of
genetic sample collection.

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Withdrawal of consent for genetic research
Participants may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.2 of the main 
CSP.
Collection of samples for genetic research
The blood sample for this genetic research will be obtained from the participants pre-dose at 
the first dosing visit. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an AE. If for any 
reason the sample is not drawn at the first dosing visit, it may be taken at any visit until the 
last study visit. Only one sample should be collected per participant for genetics during the 
study.
Coding and storage of DNA samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples may be stored for a maximum 
of 15 years from the end of the study (as defined in the protocol), after which they will be 
destroyed. DNA is a finite resource that is used up during analyses. Samples will be 
stored and used until no further analyses are possible or the maximum storage time has 
been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA).

The link between the participant enrolment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.

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Informed consent
The genetic component of this study is optional, and the participant may participate in other 
components of the main study without participating in this genetic component. To participate 
in the genetic component of the study the participant must sign and date both the consent form 
for the main study and the addendum for the Genomics Initiative component of the study. 
Copies of both signed and dated consent forms must be given to the participant and the 
original filed at the study center. The principal investigator(s) is responsible for ensuring that 
consent is given freely and that the participant understands that they may freely withdrawal 
from the genetic aspect of the study at any time.
Participant data protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician, or any other third party 
unless required to do so by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.

AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organizations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.
Statistical methods
The number of participants that will agree to participate in the genetic research is unknown. It 
is therefore not possible to establish whether sufficient data will be collected to allow a formal 

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statistical evaluation or whether only descriptive statistics will be generated. An SAP may be 
prepared where appropriate.

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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
Specific guidance on managing liver abnormalities can be found in the TMGs (see the Annex 
document to this CSP).
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point during the study 
following the start of study intervention irrespective of an increase in alkaline phosphatase. 
Hy’s Law (HL)
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated alkaline 

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phosphatase indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN.

AST ≥3 × ULN.

TBL ≥2 × ULN.
Local laboratories being used
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:

Notify the AstraZeneca representative.

Determine whether the participant meets PHL criteria (see Section E 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory eCRF.
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
E 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team. 

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
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criterion “Important medical event” and causality assessment “yes/related” 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition. 

The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participant’s follow-up (including any further laboratory testing) 
and the continuous review of data.

Subsequent to this contact the investigator will:
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the study physician. 
Complete the 3 Liver eCRF Modules as information becomes available. 
#A “significant” change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study intervention, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria were met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 

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whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.

If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention:

Send updated SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes. 
The “Medically Important” serious criterion should be used if no other serious criteria 
apply.
As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned.
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of PHL, (report term now 
“Hy’s Law case”) ensuring causality assessment is related to study intervention and 
seriousness criterion is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review, and 
amend the reported term if an alternative explanation for the liver biochemistry elevations 
is determined.
E 6
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention 
This section is applicable to participants with liver metastases who meet PHL criteria on study 
intervention, having previously met PHL criteria at a study visit prior to starting study 
intervention.
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participant’s condition compared with 

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the last visit where PHL criteria were met.

If there is no significant change no action is required.

If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2.
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study eg, chronic or progressing malignant disease, severe infection or liver 
disease, or did the participant meet PHL criteria prior to starting study intervention and at their 
first on-study intervention visit as described in Section E 6 of this Appendix?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’s condition 
compared with when PHL criteria were previously met.

If there is no significant change no action is required.

If there is a significant change follow the process described in Section E 4.2 for reporting 
PHL as an SAE.
E 8
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests that are 
recommended but not mandatory to further evaluate increases in liver biochemistry and Hy’s 
Law. This list may be modified according to clinical judgment. Any test result must be 
recorded.

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Tests to Further Evaluate Increases in Liver Biochemistry and Hy’s Law
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA a
IgM and IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate-deficient transferrin b
Autoimmune hepatitis
Antinuclear antibody
Anti-liver/kidney microsomal antibody
Anti-smooth muscle antibody
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = gamma glutamyl transferase; 
HAV = hepatitis A virus; HBc = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HEV = hepatitis E virus; HSV = herpes simplex virus; IgG = immuno-globulin G; 
IgM = immuno-globulin M; INR = international normalized ratio; LDH = lactate dehydrogenase; RNA = ribonucleic acid.
a
HCV RNA/HBV DNA are only tested when anti-HCV IgG/anti-HBc IgM or IgG are positive or inconclusive.
b
Carbohydrate-deficient transferrin and transferrin are not available in mainland China.
E 9
References
Aithal et al 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 
2011;89(6):806-15.
FDA Guidance 2009
Food and Drug Administration. Guidance for industry: Drug-induced liver injury: 

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premarketing clinical evaluation. July 2009. Available from: URL: 
https://www.fda.gov/downloads/guidances/UCM174090.pdf. Accessed 08 October 2019.

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Appendix F
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors)
Introduction
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix.
Additional special guidance is provided for evaluation of scans collected after a 
RECIST 1.1-defined radiological progression.
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumor assessment of TLs, NTLs 
and NLs is provided in Table 12.
Table 12
Summary of Imaging Modalities for Tumor Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
18F-fluoro-deoxyglucose-PET
CT = computed tomography; PET/CT = positron emission tomography/CT; MRI = magnetic resonance imaging.
Computed Tomography and Magnetic Resonance Imaging 
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumor 
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), and 
method of tumor assessment (eg, RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumor assessment schedule as closely 
as possible (refer to the SoA; Table 1), and this on-study imaging schedule MUST be followed 
regardless of any delays in dosing or missed imaging visits. If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the participant has 
not progressed, every attempt should be made to perform the subsequent scan acquisitions at 
the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 

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scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen-pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
PD, careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumor 
measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA (Table 1). Examples include the following:

IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis).

Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis).

IV contrast-enhanced CT or MRI of the head and neck.

IV contrast-enhanced MRI (preferred) or CT of the brain.
For chest-abdomen-pelvis imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to IV contrast or have compromised renal function:
6
Chest-abdomen-pelvis CT with IV CT contrast (most preferred).
7
Chest CT without IV contrast + abdomen-pelvis MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study.

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8
Chest-abdomen-pelvis CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function.
9
Chest-abdomen-pelvis MRI with IV MRI contrast, if CT cannot be performed at any time 
during the study.
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5 mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 

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equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a PD assessment at 
that time point.
18F-Fluoro-deoxyglucose-PET/CT
18F-fluoro-deoxyglucose positron emission tomography(PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive 18F-Fluoro-deoxyglucose uptake1 not present on baseline or prior 
18F-fluoro-deoxyglucose-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the 18F-fluoro-deoxyglucose-PET scan. The PET portion of 
the PET/CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed. Therefore, if there is no baseline or prior 18F-fluoro-deoxyglucose-PET 
scan available for comparison, and no evidence of NLs on companion CT/MRI scans, then 
follow-up CT/MRI assessments should continue as per the regular imaging schedule to verify 
the unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated 
diagnostic contrast-enhanced CT scans for tumor measurements by RECIST 1.1. In 
exceptional situations, if a site can document that the CT performed, as part of a PET/CT 
examination, is of identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT 
scan, then the CT portion of the PET/CT can be used for RECIST 1.1 tumor assessments. 
Caution that this is not recommended because the PET portion of the CT introduces additional 
(PET) data that may bias an investigator if it is not routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
Other tumor assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
                                               
1
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed.

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not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment.
Histology and cytology
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1.
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically.
Measurability of tumor lesions at baseline
RECIST 1.1 measurable lesions at baseline
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis1 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please 
see additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline

Truly non-measurable lesions include the following:
Bone lesions (see exception below for soft tissue component).
Leptomeningeal disease.
Ascites, pleural effusion, or pericardial effusion.
Inflammatory breast disease.
Lymphangitic involvement of skin or lung.
                                               
1
The short axis is defined as the longest in-plane axis perpendicular to the long axis.

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
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 mm to < 15 mm short axis diameter at baseline).1

Previously irradiated lesions.2

Brain metastasis.
Special considerations regarding lesion measurability at baseline

Bone lesions:
Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques to 
measure bone lesions; however, these techniques can be used to confirm the presence 
or disappearance of bone lesions.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.
Blastic lesions are considered non-measurable.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs.
RECIST 1.1 TL selection at baseline
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
                                               
1
Lymph nodes with < 10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.
2
Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment.

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organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline

For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.

When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter.

Tumor lesions selected for newly acquired screening biopsy should not be selected as 
TLs, unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing.

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL.
RECIST 1.1 NTL selection at baseline
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumor response and progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimeters. The sum of the diameters for all TLs at each follow-up visit will be 
compared with the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression).

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Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.

If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter.

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion. 

When a TL has had any intervention (eg, definitive radiotherapy, embolization, surgery, 
transarterial chemoembolization, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 CRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm.
Table 13
RECIST 1.1 Evaluation of Target Lesions
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to < 10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference 
the baseline sum of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the 
smallest previous sum of diameters (nadir). This includes the baseline sum if 
that is the smallest on study. In addition to the relative increase of 20%, the 
sum must demonstrate an absolute increase of at least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, 
missing anatomy) or had a lesion intervention at this visit. Note: If the sum of 
diameters meets the PD criteria, PD overrides NE as a TL response.
Not applicable
Only relevant if no TLs present at baseline.
CR = complete response; NE = not evaluable; PD = progression of disease; PR = partial response; SD = stable disease; 
TL = target lesion.

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RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs. 
A modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PD of target disease will therefore be 
extremely rare.
Table 14
RECIST 1.1 Evaluation of Non-Target Lesions
CR
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (< 10 mm short axis).
Non-CR/non-PD
Persistence of 1 or more NTLs.
PD
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in 1 lesion only or in several lesions. In all cases, the 
progression MUST be clinically significant for the physician to consider 
changing (or stopping) therapy.
NE
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met.
Not applicable
Only relevant if no NTLs present at baseline.
CR = complete response; NE = not evaluable; NTL = non-target lesion; PD = progression of disease; TL = target lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the CRF. The presence of 1 or more NLs is assessed as progression. The 
finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. If a NL is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared.

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A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD.
RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 15.
Table 15
RECIST 1.1 Overall Visit Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
CR
CR
No
CR
CR
NA
No
CR
CR
Non-CR/Non-PD
No
PR
CR
NE
No
PR
PR
Non-PD or NE or NA
No
PR
SD
Non-PD or NE or NA
No
SD
NE
Non-PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; NE = not evaluable; NTL = non-target lesion; PD = progression of disease; PR = partial 
response; SD = stable disease; TL = target lesion.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:

For participants with TLs (at baseline): CR, PR, SD, PD, or NE.
Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organization (iCRO) for quality control, 
storage, and for BICR. Digital copies of all original scans should be stored at the investigator 
site as source documents. Electronic image transfer from the sites to the iCRO is strongly 
encouraged. A BICR of images will be performed at the discretion of AstraZeneca. Results of 
these independent reviews will not be communicated to investigators, and results of 
investigator tumor assessments will not be shared with the central reviewers.
The management of participants will be based in part upon the results of the tumor 
assessments conducted by the investigator. Further details of the BICR will be documented in 
an Independent Review Charter.

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F 1
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

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Appendix G
Contraception Requirements
Contraception requirements for this study are as follows.
G 1
Female Participants
Women not of childbearing potential are defined as those who are surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply:

Women < 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution, or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy).

Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses > 1 year ago, or had 
chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 16). They should have been stable on their chosen 
method of birth control starting at a minimum of 3 months before C1D1 and continue to use it 
throughout the total duration of the drug treatment and the drug washout period (7 months 
after the last dose of study intervention). 
Non-sterilized male partners of a woman of childbearing potential must use a male condom 
plus spermicide (condom alone in countries where spermicides are not approved) throughout 
this period. Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Total sexual abstinence is an acceptable method 
provided it is the usual lifestyle of the participant. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial. Female participants should refrain 
from breastfeeding throughout this period. Women must not donate, or retrieve for their own 
use, ova from the time of screening and throughout the study treatment period, and for at least 
7 months after the final study drug administration. Preservation of ova should be considered 
prior to enrolment in this study.

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G 2
Male Participants with a Female Partner of Childbearing 
Potential
Non-sterilized male participants (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from the time of screening throughout the total duration of the study and the drug washout 
period (ie, at least 4 months after the last dose of study intervention) to prevent pregnancy in a 
partner. 
Not engaging in sexual activity for the duration of the study and drug washout period is an 
acceptable practice. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. Male participants should refrain from sperm donation or banking throughout 
the drug washout period. Preservation of sperm should be considered prior to enrolment in this 
study.
Vasectomized (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study.
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide (where approved), as indicated above during the clinical study, if there is a concern 
about damaging the developing fetus from drug in ejaculate.
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 16).
G 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 16. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper-containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).

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For participants in the ICC (eribulin, capecitabine, vinorelbine, or gemcitabine) group: 
Follow the local Prescribing Information relating to contraception, the time limits for such 
precautions, and any additional restrictions required for the specific ICC agent.
Table 16
Highly Effective Methods of Contraception (< 1% Failure Rate)
Non-Hormonal Methods
Hormonal Methodsb
•
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant)
•
Vasectomized sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia)
•
Tubal occlusion
•
Intrauterine device (provided coils are 
copper-banded)
•
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®) a
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a
•
Progesterone T intrauterine device
•
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®)
•
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®) 
•
Combined pill: Normal and low dose combined 
oral contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®)
•
Mini pill: Progesterone-based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill
a
Hormonal methods not prone to drug-drug interactions.
b
Hormonal methods of contraception must not be used by female patients participating in this study; this 
information is meant for female partners of male participants.

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Appendix H
Patient-reported Outcomes
H 1
EORTC QLQ-C30

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H 2
EORTC IL116

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H 3
PRO-CTCAE

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H 4
EORTC IL117

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H 5
PGI-TT

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H 6
PGIS

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H 7
PGIC

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H 8
EQ-5D-5L

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Appendix J
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
participant’s safety. If in doubt, please contact the AstraZeneca Study Physician.
J 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in the sections below. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
J 2
Rescreening of Participants to Reconfirm Study Eligibility
An extended rescreening period will be allowed for participants that are affected by study 
disruptions, that have already screen failed and entered rescreening. The investigator should 
confirm this with the designated study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Table 1, the participant 
will be allowed to remain in screening until reconfirmation of eligibility before commencing 
study procedures. The procedures detailed in Table 1 must be undertaken to confirm eligibility 
using the same E-code as initially assigned to the participant.

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J 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service will visit the participants home or other 
remote location as per local Standard Operating Procedures, as applicable. Supplies will be 
provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the clinical study protocol (CSP). 
J 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication, and targeted physical 
examination to be reported and documented. Site personnel to also ensure that ePROs are 
being completed by participant as per SoA. 
J 5
Data Capture During Telemedicine Visits (where applicable)
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP (or site delegate) from the study site or TPV service in the source documents.

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Appendix K
Protocol Version History
The Summary of Changes Table for the current revision is located directly before the TOC.
Amendment 3 (10 October 2022)
Overall Rationale for the Amendment:
The overall rationale for the amendment is to provide flexible language for the inclusion of a 
mainland China-specific recruitment tail, if required, for regulatory submission purposes, as 
well as alignment with the latest Dato-DXd program standards.
Other important administrative and operational clarifications have also been made.
The rationale for each of these changes is provided in the table below:
Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 1.1, Synopsis, 
Number of 
Participants, 
Statistical Methods
Section 4.1, Overall 
Design
Updated to include possibility of a 
mainland China cohort.
If required for regulatory 
submission purposes, the 
recruitment of participants in 
mainland China may continue 
beyond the close of the global 
cohort.
Non-Substantial
Section 1.2, Schema
Clarified requirement for patient 
to have progressed on and not be 
suitable for endocrine therapy, in 
accordance with existing 
eligibility criteria.
Typographical correction.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Section 8.2.5.1, 
Echocardiogram/Mult
igated Acquisition 
Scan
Removed requirement to do an 
ECHO or MUGA scan to assess 
LVEF at EoT visit. Updated 
footnote “i” to clarify that an 
ECHO or MUGA may be done at 
EoT visit, if clinically indicated.
To align with AstraZeneca 
Dato-DXd program standards, 
the ECHO/MUGA scan is not 
required at EoT visit unless 
clinically indicated.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Section 8.2.4, Table 7
Removed requirement to do 
coagulation tests at screening.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Added optional bronchoalveolar 
lavage and lung biopsy sample on 
diagnosis of suspected 
ILD/Pneumonitis into SoA.
Administrative clarification, as 
collection of this sample was 
previously omitted from the 
SoA.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Updated footnote “a” to ensure 
the safety follow-up visit is 
performed 28 (+7) days after the 
last study intervention 
administration regardless of 
participant starting new anticancer 
treatment.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Updated footnote “q” to specify 
prior HIV serology, HBV 
serology, and HCV serology test 
results can still be used if 
performed within 120 days of 
enrolment.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Updated footnote “r” to specify 
that participants must be tested for 
HIV if applicable by local 
regulations or an IRB/EC.
Administrative clarification.
Non-substantial
Section 5.2, 
Exclusion Criteria #5
Updated text to clarify 
circumstances where patients may 
still be eligible with respect to 
hepatitis B or C.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 5.2, 
Exclusion Criteria #6
Updated definition of well 
controlled HIV infection. 
Clarified recommendation to 
monitor viral RNA load and 
CD4+ count, and that participants 
must be tested for HIV if 
acceptable by local regulations or 
an IRB/EC.
To align with AstraZeneca 
Dato-DXd program standards.
Substantial
Section 6.5, 
Concomitant Therapy
Added requirement for all 
concomitant medications 
administered during the study to 
be recorded until the end of the 
safety follow up period and those 
administered for drug-related 
AESIs to be recorded in the eCRF 
as required.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 6.6, Dose 
Modification
Clarified dose delay allowance. 
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 8.2.4, 
Clinical Safety 
Laboratory 
Assessments
Section 8.3.6, Hy’s 
Law
E2 Definitions, E3
Identification of 
Potential Hy’s Law 
Cases
Corrected typo in Hy’s Law 
criteria from TBL > 2 ULN to 
TBL ≥ 2 ULN.
Typographical correction.
Non-substantial
Section 8.3.1, Time 
Period and Frequency 
for Collecting AE and 
SAE Information
Added Grade ≥ 2 keratitis events 
to list of AEs to be reported by 
the investigator in eCRF within 
24 hours of awareness.
To align with AstraZeneca 
Dato-DXd program standards.
Substantial
Section 8.3.6, Hy’s 
Law
Removed reference to Section 
8.3.11 as Hy’s Law event is no 
longer considered an AESI.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 8.3.11, 
Adverse Events of 
Special Interest
Clarified that all AESIs must be 
followed until either event 
resolution, end of study, trial 
termination, withdrawal of 
consent, or participant death.
Administrative clarification.
Non-substantial
Section 9.3, Table 9, 
Population for 
Analysis
Updated table to specify that 
participants in the mainland China 
cohort will be excluded from ITT 
population. Additional changes to 
clarify SAS, OAS, and PAS will 
be comprised of participants in 
the ITT population.
Included as part of flexible 
language to allow for 
mainland China tail, if 
required.
Non-substantial
Section 9.4.2.2.9, 
Pharmacokinetics
Corrected substrate name from 
MAAA-1191a to MAAA-1181a.
Typographical correction.
Non-substantial
Section 9.7, Mainland 
China Cohort
Summarized details of mainland 
China cohort.
If required for regulatory 
submission purposes, the 
recruitment of participants in 
mainland China may continue 
beyond the close of the global 
cohort.
Non-substantial
Appendix I, Table 19, 
Supportive 
Medications/therapies
Clarified recommendation for 
usage of prophylactic anti-emetic 
agents.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Throughout CSP
Clarified that ‘China’ refers to
mainland China.
To align with China R&D 
preferred terminology.
Non-substantial

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Amendment 2 (19 April 2022)
Overall Rationale for the Amendment:
The overall rationale for the amendment is to provide additional guidance for investigators 
after the annual update of the Dato-DXd Investigator’s Brochure v6.0. The Toxicity 
Management Guidelines includes further details on management of ocular surface toxicities, 
and are now located in an Annex document. Adverse Events of Special Interest no longer 
include “combined elevations of aminotransferase and bilirubin”, and stomatitis/mucosal 
inflammation have been separated into “oral mucositis/stomatitis” and “mucosal inflammation 
other than oral mucositis/stomatitis.”
Other administrative and operational clarifications have also been made.
The rationale for each of these changes is provided in the table below:
Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 1.1, Synopsis, 
Participant 
Population
Section 5.1, Inclusion 
Criteria #1
Removed requirement for 
participants in Japan to be 
≥20 years.
Update to the civil code for 
age of adulthood in Japan.
Substantial
Section 1.1, Synopsis, 
Intervention Groups 
and Duration
Section 4.1, Overall 
Design
Section 9.4.2.1.5, 
Subgroup Analysis
Added Canada as a Region 1 
country.
Administrative clarification.
Non-Substantial
Section 1.1, Synopsis, 
Follow-up of 
Participants Post 
Discontinuation of 
Study Intervention
Added that the EoT assessments 
can function as the Safety Follow-
up visit if the date of 
discontinuation is over 35 days 
from the last administration of 
study intervention.
Administrative clarification.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Added ePRO training and set up.
Administrative clarification.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Updated footnote “d” so that 
safety assessments do not have to 
be repeated if they have been 
performed within 72 hours prior 
to the day of dosing.
To allow flexibility in patient
management without 
compromising safety.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Section 5.1, Inclusion 
Criteria #14
Updated footnote “p” and added 
clarification that a serum 
pregnancy test should be negative 
at screening and.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Section 6.3, 
Participant Enrolment 
and Randomization
Updated footnote “q” and 
Section 6.3.1 to be consistent with 
Exclusion Criterion #5.
Administrative clarification.
Non-substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Section 8.1.1, 
Imaging Tumor 
Assessments
Updated footnote “x” and added 
clarification of abdomen imaging.
To align with AstraZeneca 
program standards.
Non-substantial
Section 1.3, Schedule 
of Assessments
Table 2 added detailing the 
assessments to be performed in 
the event of suspected 
ILD/pneumonitis.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 2.2.1, 
HR-positive, 
HER2-negative, 
inoperable/metastatic 
breast cancer
Added baseline 
characteristics/factors which 
could be relevant to the target 
study population.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 2.2.2.1, 
TROPION-
PanTumor01 study
Section 2.3.3, Overall 
Benefit: Risk 
Conclusion
Updated safety and efficacy data 
from the DS1062-A-J101 study.
To align with latest Dato-DXd 
Investigator Brochure.
Non-substantial
Section 2.3.1.1, 
Dato-DXd, Table 3
Section 8.3.11, 
Adverse Events of 
Special Interest
Labeled “stomatitis/oral 
mucositis” as an identified 
risk/AESI and established 
“mucosal inflammation other than 
oral mucositis/stomatitis” as a 
separate identified risk/AESI.
Removed anaphylaxis in relation 
to IRR.
To align with latest Dato-DXd 
safety profile information.
Substantial
Section 4.3.1, 
Dato-DXd
Updated to include latest available 
data.
To align with latest Dato-DXd 
Investigator Brochure.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 5.1, Inclusion 
Criteria #8
Limit of AST/ALT criteria 
extended to assess adequate organ 
and bone marrow function.
Removed INR or PT, and either 
PTT or aPTT criteria.
To allow flexibility in patient 
enrolment without 
compromising safety.
Substantial
Section 5.1, Inclusion 
Criteria #10
Added definition for washout 
period of immunotherapy.
Administrative clarification.
Non-substantial
Section 5.1, Inclusion 
Criteria #15
Appendix G1, Female 
Participants
Removed references to HRT in 
relation to female participant 
contraception.
HRT is contraindicated for 
HR-positive disease.
Substantial
Updated contraceptive 
requirement to 3 months before 
C1D1.
Administrative clarification.
Substantial
Section 5.1, Inclusion 
Criteria #16
Added that female partners of 
male participants are allowed to 
use HRT for contraception.
Updated that male participants 
should use a highly effective 
method of contraception.
Clarification following the 
change to Inclusion Criteria 
#15.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 5.2, 
Exclusion Criteria #3
Removed allowance of study 
physician judgment and added 
examples of permitted toxicities 
related to previous anticancer 
therapy.
To provide operational 
flexibility without 
compromising safety.
Substantial
Section 5.2, 
Exclusion Criteria 
#16
Clarified to allow concurrent use 
of hormones for non-cancer 
related conditions (eg, insulin for 
diabetes).
To align with CSP permitted 
medications.
Non-substantial
Section 5.2, 
Exclusion Criteria 
#19
Removed exclusion criteria to 
allow for the enrolment of 
participants using chronic 
systemic corticosteroids.
To align with AstraZeneca 
Dato-DXd program standards.
Substantial
Section 5.3, Lifestyle 
Considerations
Added recommendation regarding 
consideration to preserve ova 
prior to enrolment.
Compliance with AstraZeneca 
program standards.
Non-substantial
Section 6.2.1.2, 
Administration of 
Dato-DXd
Added clarification regarding 
mandated pre-medications.
Added that the IV line will be 
flushed following infusion.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 6.2.1.3, 
Monitoring of Dato-
DXd Administration
Section to include Dato-DXd 
monitoring added.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 6.5, 
Concomitant Therapy
Added information regarding 
concomitant use of Dato-DXd and 
CYP3A inhibitors and drugs that 
inhibit OATP1B1, OATP1B3, 
MATE2-K, P-gp, BCRP, and 
MRP1.
Added information regarding 
concomitant use of Dato-DXd and 
hydroxychloroquine and/or 
chloroquine.
To align with AstraZeneca and 
Dato-DXd program standards.
Non-substantial
Section 6.6, Dose 
Modification
Added information regarding dose 
delays, interruptions, and 
modifications.
Consequent to change in 
Section 6.1.1, and to align 
with AstraZeneca Dato-DXd 
program standards.
Non-substantial
Section 6.6.4, 
Dato-DXd Dose 
Modification/ 
Toxicity Management 
Guidelines
Removed Toxicity Management 
Guidelines (TMG) from the body 
of the CSP (including 
Appendix L) and included as an 
Annex.
To provide operational 
flexibility, as the TMG may be 
updated without CSP 
amendment.
Non-substantial
Section 6.7, 
Intervention after the 
End of the Study
Added text regarding continuation 
of open-label treatment and 
alternative supply options should 
they become available.
To align with AstraZeneca 
program standards.
Substantial
Section 8.1.1 Imaging 
Tumor Assessments
Added that for participants with 
documented bone lesion at 
baseline, the bone scan must have 
been performed no more than 
28 days before randomization.
To align with AstraZeneca and 
Dato-DXd program standards.
Non-substantial
Section 8.1.1 Imaging 
Tumor Assessments
Added clarification that CT/MRI 
are to be collected for all 
participants at baseline.
Removed the text regarding 
treatment continuation regardless 
of study intervention 
discontinuation or start of 
subsequent anticancer therapy.
Administrative clarification.
Non-substantial
Section 8.1.5.9, 
Administration of 
Electronic PRO 
(ePRO) 
Questionnaires
Added timing of onboarding 
participant onto the ePRO 
application.
To ensure the correct C1D1 
date is registered in the ePRO 
system.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 8.2.2, Vital 
signs
Added seated assessment 
position.
To allow flexibility in patient 
management without 
compromising safety.
Non-substantial
Section 8.2.3, 
Electrocardiograms
Amended the requirement of 
timing of ECGs and ECG 
machine capabilities.
To provide operational 
flexibility for both timing and 
the ECG machine capabilities; 
without compromising safety.
Non-substantial
Section 8.2.4, 
Clinical Safety 
Laboratory 
Assessments
Added urea and calcium (ionized) 
to the laboratory safety variables.
To align with AstraZeneca 
Dato-DXd program standards
and allow for operational 
flexibility without 
compromising safety.
Non-substantial
Section 8.2.5.3, 
ILD/Pneumonitis 
Investigation
Added troponin assessment to the 
ILD/pneumonitis investigations.
Clarified that bronchoscopy and 
bronchoalveolar lavage are 
options and added optional lung 
biopsy to the ILD/pneumonitis 
investigations.
To align with AstraZeneca 
Dato-DXd program standards 
to rule out cardiac etiology.
Substantial
Section 8.2.5.3, 
ILD/Pneumonitis 
Investigation
Section 8.5.1, 
Pharmacokinetics
Removed the requirement for a 
blood sample for PK in the case 
of suspected ILD/pneumonitis.
No longer within the scope of 
the study.
Non-substantial
Section 8.2.5.5, 
Ophthalmologic 
Assessments
Section 8.3.11, 
Adverse Events of 
Special Interest
Added that the assessments are to 
be performed by an 
ophthalmologist, or if unavailable, 
another licensed eye care 
provider.
To align with AstraZeneca 
Dato-DXd program standards.
Substantial
Section 8.2.5.5, 
Ophthalmologic 
Assessments
Added alternative to fluorescein 
staining, ocular symptoms to be 
considered during assessment, 
reporting of assessment results 
and use of additional eye 
medications.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 8.2.5.6, Oral 
Care Plan
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 18
Added details of use of 
prophylactic mouthwash and 
cryotherapy.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Section 8.3, Adverse 
Events and Serious 
Adverse Events
Added requirements for reporting 
Grade ≥ 3 ocular surface toxicity 
events.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 8.3.1, Time 
Period and Frequency 
for Collecting AE and 
SAE Information
Added specific AEs that should 
be reported within 24 hours of the 
investigator becoming aware.
To align with AstraZeneca
program standards.
Substantial
Section 8.3.5, 
Adverse Events 
Based on 
Examinations and 
Tests
Added that ECOG performance 
status and ophthalmologic 
assessments will be summarized 
in the CSR.
To align with AstraZeneca 
program standards.
Non-substantial
Section 8.3.11, 
Adverse Events of 
Special Interest
Removed combined elevations of 
aminotransferases and bilirubin.
Added the actions to be taken for 
ILD/pneumonitis cases.
Clarified dry eye is an identified 
risk and keratitis is a potential risk 
within the ocular surface toxicity 
AESI.
To align with AstraZeneca 
Dato-DXd program standards.
Substantial
Section 8.3.14.1, 
Maternal Exposure
Added that AstraZeneca must be 
notified of any female participant 
or partner of a male participant 
who becomes pregnant while 
receiving or within 7 months of 
discontinuing Dato-DXd.
To align with AstraZeneca 
Dato-DXd program standards.
Substantial
Section 8.6.3, Other 
Study Related 
Biomarker 
Assessments
Added reasons for additional 
exploratory analyses.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Section 8.8, Medical 
Resource Utilization 
and Health 
Economics
Added variables to be captured in 
the HOSPAD eCRF module.
To align with AstraZeneca 
program standards.
Non-substantial
Appendix A7, Data 
Quality Assurance
Increased the record and 
document retention time to 25 
years.
To align with updated 
AstraZeneca Global 
Retention and Destruction 
standards.
Substantial
Appendix A7, Data 
Quality Assurance
Added medical oversight 
responsibility.
To align with AstraZeneca 
program standards.
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / Non-
substantial
Appendix I2, Guidance 
Regarding Potential 
Interactions with 
Concomitant 
Medications
Added information regarding 
concomitant use of Dato-DXd and 
CYP3A inhibitors and drugs that 
inhibit OATP1B1, OATP1B3, 
MATE2-K, P-gp, BCRP, and 
MRP1.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 17
Added palliative radiotherapy.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 18
Added other investigational 
therapeutic agents.
To align with AstraZeneca 
Dato-DXd program standards.
Non-substantial
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 19
Added additional supportive 
medications/therapies.
To align with AstraZeneca 
program standards.
Non-substantial
Appendix J, 
Instructions Related 
to COVID-19
Added requirement if PCR testing 
is not available.
To align with AstraZeneca 
program standards.
Non-substantial
Appendix K2, 
Rescreening of 
Participants to 
Reconfirm Study 
Eligibility
Rescreening period extended for 
those participants who have 
entered rescreening.
Updated to allow for participants 
to remain in screening until 
reconfirmation of eligibility.
To accommodate enrolment of 
participants during periods of 
study disruption, in alignment 
with established study 
processes already in place.
Substantial
Throughout
Minor changes to protocol 
wording, tables and figures, and 
editorial and document formatting 
revisions.
To align with project standard 
or to provide clarification.
Non-substantial

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Amendment 1 (27 August 2021)
Overall Rationale for the Amendment:
The overall rationale for the amendment is to provide additional guidance for investigators on 
the monitoring and management of ocular surface toxicities potentially associated with 
Dato-DXd, the management of Grade 3 non-hematologic toxicities, as well as clarifying the 
Oral Care Protocol (OCP) to be used on this study. Furthermore, the schedule of assessments 
and inclusion/exclusion criteria were updated.
The rationale for each of these changes is provided in the table below:
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Title Page
Added EudraCT number.
Added EudraCT number as it 
has become available.
Non-substantial
Section 1.1, Synopsis, 
Overall Design
Section 9.2, Sample 
Size Determination
Updated number of participants to 
be enrolled from 900 to 1000.
Updated number of participants 
enrolled based on available 
feasibility recruitment data. The 
number of participants to be 
randomized remains 
unchanged.
Non-substantial
1.2 Schema
Removed PARP inhibitors from 
being considered a prior line of 
chemotherapy.
To ensure that enrolled 
participants have received at 
least one prior line of 
chemotherapy.
Substantial
Section 1.3, Schedule 
of Assessments, 
Table 1
Section 8.2.5.5, 
Ophthalmologic 
Assessments
Ophthalmological Assessment:
Updated SoA for ophthalmologic 
assessments to occur every 3 cycles 
from C1D1(within 14 days prior to 
scheduled cycle Day 1 visit), in 
addition to as clinically indicated; 
updated footnote “l” to provide 
additional clarifications around the 
ophthalmologic assessments.
Section 8.2.5.5 has additional 
details around ophthalmologic 
assessments and care.
To help prevent ocular surface 
toxicities, and to monitor and 
treat these events should they 
arise.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Section 1.3, Schedule 
of Assessments, Table 
1
Section 8.2.5.6, Oral 
Care Plan
Oral Care Plan:
Oral Care Plan added to SoA; 
updated footnote “m” and created 
section 8.2.5.6 to provide 
additional details and guidance 
around daily oral care.
The Oral Care Plan is designed 
to mitigate the risk of oral 
mucositis/stomatitis. This was 
previously listed in section 
6.6.1, Table 5, but has been 
moved to SoA and new section
created (8.2.5.6) to ensure 
introduction of this plan for 
participants at the appropriate 
time.
Substantial
Section 2.3.1.1, Risk 
Assessment – Dato-
DXd
Section 8.3.11, 
Adverse Events of 
Special Interest
Ocular surface toxicity was added 
to the list of AESIs, and 
mitigations were added.
For participant safety, as ocular 
surface toxicity has been noted 
in some participants treated 
with Dato-DXd. Associated 
monitoring by ophthalmologic 
assessments and a dedicated 
safety review will be 
performed.
Substantial
Section 5.1, Inclusion
Criteria #3
Removed PARP inhibitors from 
being considered a prior line of 
chemotherapy.
To ensure that enrolled 
participants have received at 
least one prior line of 
chemotherapy.
Substantial
Section 5.1, Inclusion 
Criteria #8
Hemoglobin level unit of 
measurement corrected to g/dL.
Correction of incorrect unit of 
measurement listed in initial 
version of CSP. 
Non-substantial
Section 5.2, Exclusion 
Criteria #9
Additional note added to Exclusion 
Criteria #9 regarding ineligibility 
of participants found to have 
ILD/pneumonitis on baseline 
screening chest CT.
To ensure participants enrolled 
do not have active ILD.
Substantial
Section 6.2.1.2, 
Administration of 
Dato-DXd
Updated total cumulative time 
from dilution start time until end of 
infusion for Dato-DXd.
To align with updated handling 
instructions.
Non-substantial
Section 6.2.1.2, 
Administration of 
Dato-DXd
Added guidance around dose re-
calculation if participant’s weight 
changes during the study.
Original wording is lacking 
information important for 
correct dose re-calculation.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Section 6.6.1, Table 5: 
Dose Modifications 
for Non-hematologic 
and Hematologic 
Toxicity Related to 
Dato-DXd
Amended dose reduction 
thresholds and added guidance 
around optimizing use of 
prophylactic and supportive 
medications.
For participant safety, emphasis 
has been placed on providing 
prophylactic/supportive 
medications (when 
appropriate); in addition, dose 
reductions for Grade 3 
toxicities (regardless of time of 
resolution) have been added for 
most non-hematologic 
toxicities.
Substantial
Section 7.1.3, Follow-
up for Survival
Specified that local death registries 
may be used to obtain survival 
status information.
To clarify options for gathering 
survival data, in line with AZ 
standards.
Non-substantial
Section 8.2.4, Table 7
Updated list of acceptable values 
for leukocyte differential count to 
now include percentages.
To accommodate sites only 
able to provide a percentage 
value, as absolute count is not 
key.
Non-substantial
Section 9.3, 
Populations for 
Analysis
Added Ophthalmologic Analysis 
Set (OAS).
Added analysis for potential 
risk of ocular surface toxicity, 
and terminology clarification.
Substantial
Section 9.4.2.1, 
Efficacy, Primary 
Endpoints, Table 10
Added ‘subsequent anticancer
therapy’ to list of sensitivity 
analyses.
Additional sensitivity analysis 
to assess robustness of PFS 
dual primary analysis.
Substantial
Section 9.4.2.1.3, PFS 
Sensitivity Analyses
Added language regarding 
subsequent anticancer therapy.
Additional sensitivity analysis 
to assess robustness of PFS 
dual primary analysis.
Substantial
Section 9.4.2.1.5, 
Subgroup Analysis
Added two additional subgroups: 
prior use of taxanes and/or 
anthracyclines, and pre-selected 
choice of chemotherapy.
Clarified that forest plot of the PFS 
hazard ratios will be produced for 
each level of the subgroups.
More detailed subgroup
analysis to provide additional 
data, and terminology 
clarification.
Substantial
Section 9.4.2.2.8, 
Clinical Outcome 
Assessments
Updated analysis language.
To clarify that clinically 
meaningful change thresholds 
will be based on pooled data, 
not the actual TTD endpoint 
analyses.
Non-substantial
Section 9.6.3, 
Ophthalmologic Data 
Review Committee
Added details around the 
independent Ophthalmologic Data 
Review Committee.
Data review of participant 
safety with regard to 
ophthalmologic assessments.
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Appendix I, Table 19, 
Supportive 
Medications/Therapies
Updated details around 
prophylactic/supportive 
stomatitis/oral mucositis agents.
To mitigate risk of stomatitis 
for participant safety.
Non-substantial
Throughout
Minor changes to protocol 
wording, tables and figures.
To align with project standard 
or to provide clarification.
Non-substantial
Throughout
Minor editorial and document 
formatting revisions.
To further clarify.
Non-substantial

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Appendix L
Country-Specific Addendums to the Protocol
L 1
Country-specific Requirements for Brazil
Table L20
Country-specific Requirements for Brazil (Effective 15 September 2022)
Section # and Name
Description of Change with Reason
Table 1: Informed consent: genetic sample and 
analysis (optional)
Item 5.1 – Inclusion Criteria #16: “Provision of 
signed and dated written Optional Genetic Research 
Information informed consent prior to collection of 
sample for optional genetic research that supports 
Genomic Initiative”
Item 6.3.1 – Participant Enrolment (“Obtain 
signed informed consent for the optional Genomics 
Initiative”)
Item 8.7 – Optional Genomics Initiative Sample
Item 9.4.4.1 - Optional Exploratory Genetic 
Sample
Appendix D – Optional Genomics Initiative 
Sample
AZ clarifies that the information related to the 
Optional Genetic Research described in the 
items/appendix is not applicable for the Brazilian 
Research Participants since Brazil will not take part 
in the Optional Genetic Research (Genomic 
Initiative).

Item 5.1 – Inclusion Criteria - #13: “ 
(…) Contraceptive use by men or women 
should be consistent with local regulations 
(…)”.

Item 5.1 – Inclusion Criteria – #15: “(…) 
Female participants must be post-menopausal 
for at least 1 year, surgically sterile, or using one 
highly effective form of birth control (…)” 

Item 5.1 – Inclusion Criteria – #16: “Male 
participants who intend to be sexually active 
with a female partner of childbearing potential 
must be surgically sterile or using an acceptable 
method of contraception (…)”

Item 
5.3 
–
Lifestyle 
Considerations: 
“Participants must follow the contraception 
requirements outlined in Appendix G.”
AZ clarifies that the research participant will receive 
the contraceptive method chosen in common 
agreement with the Study Doctor, with no costs for 
her/his health insurance and public health system.
Additionally, AZ clarifies that, according to Brazilian 
Resolution 466/12, item III.2.t, if the research 
participant has sexual relationship only with 
partner(s) with the same gender, there is no need to 
use contraceptive methods to participate in this study.

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Section # and Name
Description of Change with Reason

Appendix G- Contraception Requirements

Item 5.2 - Exclusion Criteria - #21: 
“Participation in another clinical study with a 
study intervention or investigational medicinal 
device administered in the last 4 weeks prior to 
first dosing (…)”
AZ clarifies that, according to Brazilian Resolution 
CNS/MS 251/97, item III.2.j, the study doctor should 
recommend that no individual be selected as research 
participant before a year has passed from her 
participation in another research, unless that 
individual were to directly benefit from it.

Item 1.1 – Synopsis - Intervention Groups 
and Duration: “Continued treatment with the 
same study drug post-progression may be 
allowed, based on prior discussion with study 
physician on case-by-case basis”

Item 4.1 – Overall Design

Item 6.1.1.1 – Duration of Treatment
AZ clarifies that after the end of the research 
participant participation in the study, in accordance
with the Resolutions of Health National Council, 
AstraZeneca is committed to guarantee the free and 
indefinite access to the study medication, if it has 
been shown effective (for example, until disease 
progression – worsening of your cancer – or toxicity) 
and indicated by the Doctor.

Item 8.5 – Human Biological Samples – This 
item states the following:
“Samples may be stored for a maximum of 15 
years from the end of the study (as defined in 
Section 4.4) in line with consent and local 
requirements, 
after 
which 
they 
will 
be 
destroyed/repatriated.
        PK and ADA samples will be disposed of after 
the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report 
(whichever is earlier), unless consented for 
future analyses. Samples may be disposed of or 
anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled 
samples to further evaluate and validate the 
analytical method. Any results from such 
analyses may be reported separately from the 
CSR.
        Remaining sample aliquots will be retained at 
AstraZeneca or its designee for a maximum of 
15 years from the end of the study (as defined in 
Section 4.4). Additional use includes, but is not 
limited to, further characterization of any ADAs, 
evaluation of novel and emerging biomarkers, 
confirmation and/or requalification of the assay, 
AZ clarifies that the information described on these 
items are not applicable for the samples collected 
from Brazilian research participants. For Brazil, the 
biological samples (tumor and blood) will be used as 
stated in the attached document “Sample Receipt and 
Storage Process”. We confirm that there will be no 
future additional analysis different from those 
detailed on this document. After processing the 
biological samples and receiving the results, the 
remaining biological samples will be stored only 
during the execution of this specific project for 
repetition and/or confirmation of the tests previously 
performed when needed and, after that, discarded. 
AZ also clarifies that from CSP v2.0 and CSP v3.0 
implementation, Brazil will no longer participate in 
the exploratory analyses. The samples collected 
under CSP v1.0 will be analyzed and destroyed after 
the end of the study. 
For tumor samples (biopsies), the remaining samples 
will be repatriated (sent back to the hospital 
department who provided it) immediately after all 
study analysis has been completed.

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Section # and Name
Description of Change with Reason
and/or diagnostic assay development. The results 
from future analysis will not be reported in the 
CSR.”

Item 8.6 -
Human Biological Sample 
Biomarkers: “(…) Samples may be retained in 
all regions to allow for potential diagnostic 
development (…)”
Appendix A – Item A3 - Informed consent 
process: “(…) The investigator or authorized 
designee will explain to each participant the 
objectives of the analysis to be done on the samples 
and any potential future use. (..)”
Appendix C – Item C1 – Chain of custody of 
biological samples (“Samples retained for further 
use will be stored in the AstraZeneca-assigned 
biobanks or other sample archive facilities and will 
be tracked by the appropriate AstraZeneca Team 
during for the remainder of the sample life cycle”).

Appendix J - Instructions Related to SARS-
COV-2 (COVID-19) - If the participant 
consents, the remaining serum samples will 
also be stored for future analysis.
Item 8.5 – Human Biological Samples;
Items 8.5.1 – Pharmacokinetics; 
Item 8.5.2 – Immunogenicity Assessments; 
Item 
8.6 
–
Human 
Biological 
Sample 
Biomarkers;
Item 8.6.1 – Collection of Mandatory Samples 
for Biomarker analysis; 
Item 8.6.2 – Collection of Optional Biomarker 
Samples;
Item 8.6.3 – Other Study-related Biomarker 
Assessments
Related to the tests described on these items, AZ 
clarifies that all tests which may be done with 
biological samples during the study (tumor and 
blood) are listed on the attached document “Sample 
Receipt and Storage Process”. No additional tests 
will be performed with the samples provided by 
Brazilian research participants.
AZ clarifies that from CSP v2.0 and CSP v3.0 
implementation, the information related to 
Exploratory Analysis described in the items/appendix 
listed are also not applicable for the Brazilian 
Research Participants since Brazil will no longer 
participate in the any exploratory analysis (biomarker 
and genetic). The samples collected under CSP v1.0 
will be analyzed and destroyed after the end of the 
study. 
Appendix A – Item A3 - Informed consent 
process
This item points that a copy of the signed ICF is 
given to each patient or his/her legal representative. 
We clarify that, according to the Brazilian Resolution 

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Section # and Name
Description of Change with Reason
CNS/MS 466/12, item IV.3.f, the principal 
investigator must ensure that another original of the 
signed ICF is given to each research participant.
Moreover, the FDA has mandated that for additional study participant safety, dose reductions by 1 level for Grade 
3 toxicities (regardless of time to resolution) be added for most non-hematologic toxicities.
Section # and Name
Description of Change with Reason
Section 6.6.1, Table 5:
Dose 
Modifications for Non-hematologic 
and Hematologic Toxicity Related 
to Dato-DXd
The following sections do not specify dose reduction by 1 level for 
Grade 3 toxicities:
The text should read as follows:

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L 2
Country-specific Requirements for Canada
Table L21
Country-specific Requirements for Canada (Effective 13 December 2022)
Section # and Name
Description of Change with Reason
A7 – Data Quality 
Assurance
Prior text:
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the end of the study 
(as defined in the protocol) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the 
sponsor.
Modified text:
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years from the end of the study 
(as defined in the protocol) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the 
sponsor.
Rationale: Health Canada reduced the retention period for clinical trial records 
for drugs and natural health products from 25 years to 15 years under the Food 
and Drug Regulations and Natural Health Products Regulations.

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L 3
Country-specific Requirements for France
Table L22
Country-specific Requirements for France (Effective 10 November 2022)
Section # and 
Name
Description of Change with Reason
Section 1.3, 
Schedule of 
Activities: 
Table 1
Change:
Addition of Footnote ‘cc’ to clarify that Clinical Outcome Assessments are not 
applicable to date to participants in France.
Reason:
Electronic Patient Reported Outcomes (ePROs) will not be collected from participants 
in France at this time until further notice. This is due to ePRO vendor (Medable) non-
compliance to date with French CNIL regulations which require processing of directly 
identifying data and health data by the same vendor to remain excluded.
Section 8.1.5, 
Clinical 
Outcome 
Assessments 
(COA)
Change:
Addition of note to clarify that PROs will not be collected to date from participants in 
France.

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Reason:
Electronic Patient Reported Outcomes (ePROs) will not be collected from participants 
in France at this time until further notice. This is due to ePRO vendor (Medable) non-
compliance with French CNIL regulations which require processing of directly 
identifying data and health data by the same vendor to remain excluded.

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Table L23
Country-specific Requirements for France (Effective 21 January 2022)
Section # and Name
Description of Change with Reason
Section 5.1, Inclusion 
Criteria: Criterion #3
Change:
Progressed on or not suitable for endocrine therapy per investigator 
assessment, and treated with 1 to 2 lines of prior standard of care 
chemotherapy in the inoperable/metastatic setting. Participant must have 
documented progression on their most recent line of chemotherapy.
Note:

If a chemotherapy drug is changed within 28 days of use to another 
drug in the same class (ie, antimetabolite to antimetabolite) for any 
reason, the first drug is not counted as a line (Flatiron 2019). 
Targeted agents (such as mTOR inhibitors, PD-1/PD-L1 inhibitors, 
PARP inhibitors), endocrine therapies, and CDK4/6 inhibitors on 
their own do not contribute to the count of prior lines of 
chemotherapy; however, regimens with such agents in 
combination with metastatic chemotherapy should be classified as 
one line of chemotherapy.

Patients must have been treated with (neo)adjuvant 
anthracycline and/or taxane, if they received systemic 
treatment in the (neo)adjuvant setting, unless anthracycline 
and/or taxane was contraindicated or not considered the best 
treatment option for the subject in the opinion of the treating 
physician.
Reason:
The French Regulatory Authority (ANSM) request to precise the standard 
of care chemotherapy that patients should have received prior to 
ennrolment. According to the ESMO guidelines, in the absence of 
medical contraindications or patient concerns, anthracycline- or taxane-
based regimens, preferably as single agents, would usually be considered 
as first-line chemotherapy for HER2-negative advanced breast cancer in 
those patients who have not received these regimens as (neo)adjuvant 
treatment. Moreover, capecitabine, vinorelbine or eribulin (and 
gemcitabine as additional choice) are recommended for patients pre-
treated with an anthracycline and a taxane. Thus, the sponsor should 
ensure that patients have had the opportunity to receive taxanes and 
anthracyclines (if not contraindicated) along the course of their disease. 
This request is in line with the EMA scientific advice 
EMA/SA/0000060979 (22/07/2021). 
Section: 6.6.1, Dato-
Change:

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DXd Dose 
Modification/Toxicity 
Management 
Guidelines: Table 5
Anemia 
Grade 3 
(Hemoglobin < 8.0 g/dL; 
transfusion indicated)
Delay dose until resolved to 
≤Grade 2, then maintain dose.
Grade 4 
Life-threatening consequences; 
urgent intervention indicated
Delay dose until resolved to ≤ 
Grade 2, then reduce dose by 1 
level.
Permanently discontinue Dato-
DXd, if recurrent grade 4/life-
threatening anemia occurs after 
dose reduction by 1 level.
Reason:
The French Regulatory Authority (ANSM) request to modify the protocol 
so as to permanently discontinue Dato-DXd in case of recurrent life-
threatening Grade 4 anemia after one level dose reduction.
Section 6.4, 
Concomitant Therapy
Change:
Any concomitant treatment, procedure, vaccine, or other medication 
considered necessary by the investigator for the participant’s safety and 
wellbeing (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) or other specific categories of 
interest, that the participant is receiving from the time of screening or 
receives during the study, including the 28 (+7) day safety follow-up 
period following the last dose of study intervention must be recorded in 
the eCRF along with:
Reason for use.
Dates of administration including start and end dates.
Dosage information including dose and frequency.
The Study Clinical Lead should be contacted if there are any questions 
regarding concomitant or prior therapy.
If any concomitant therapy is administered due to new or unresolved AE, 
it should be recorded.
Participants must be instructed not to take any medications, including 
over-the-counter products, without first consulting with the investigator.

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Restricted, prohibited, and permitted concomitant medications/therapies 
are described in more detail in Appendix I2.
For participants randomized to receive ICC, refer to the local Prescribing 
Information with regard to warnings, precautions, and contraindications. 
Guidance regarding potential interactions with concomitant medications 
is provided in Appendix I1.
For management of patients receiving capecitabine, gemcitabine, 
eribulin mesylate and vinorelbine, investigators must refer to local 
prescribing information and to the SmPC website (https://base-
donnees-publique.medicaments.gouv.fr/), especially for information 
concerning contraindications, special warnings and precautions, 
posology adaptation in case of toxicity, monitoring, as well as 
medications that are contraindicated or that must be used with 
caution.
Reason:
The French Regulatory Authority (ANSM) request to modify the protocol 
in order to inform the investigators that they must refer to the SmPC of 
capecitabine, gemcitabine, eribulin mesylate and vinorelbine for the 
management of patients, especially concerning contraindications, special 
warnings and precautions, posology adaptation in case of toxicity, 
monitoring, as well as medications that are contraindicated or that must 
be used with caution, and, enclose the SmPC or refer to the website: 
http://base-donnees-publique.medicaments.gouv.fr which presents the 
updated version of the SmPCs of medications.
Section 1.3, Schedule 
of Activities: Table 1, 
Footnote ‘P’
Change:
Within 72 hours before randomization for all female subjects of 
childbearing potential; a positive urine pregnancy test result must 
immediately be confirmed using a serum test. Perform repeat pregnancy 
tests (urine or serum test per institutional guideline) within 72 hours 
before each cycle of study intervention and at end of treatment.
Pregnancy testing is to be repeated monthly during 7 months after 
treatment discontinuation.
Reason:
The French Regulatory Authority (ANSM) request to modify the Table 1 
Schedule of Activities and correspondent sections so as to extend the 
duration for monthly pregnancy testing to 7 months after treatment 

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discontinuation, in order to align with post-treatment contraception 
duration.
Section 8.2.4, Clinical 
Safety Laboratory 
Assessments
Change:
A negative result from a serum pregnancy test (which must have a 
sensitivity of at least 25 mIU/mL) must be available at the screening visit. 
Pregnancy tests should be conducted within 72 hours prior to 
randomization for all female participants of childbearing potential. 
Repeat pregnancy tests (urine beta-human chorionic gonadotropin or 
serum test per institutional guideline) should be performed 72 hours 
before infusion of each cycle and at the EoT visit. Pregnancy testing is 
to be repeated monthly during 7 months after treatment 
discontinuation. If a positive urine pregnancy test result is confirmed 
using a serum test in a female participant of childbearing potential, then 
the participant should not be treated.
Reason:
The French Regulatory Authority (ANSM) request to modify the Table 1 
Schedule of Activities and correspondent sections so as to extend the 
duration for monthly pregnancy testing to 7 months after treatment 
discontinuation, in order to align with post-treatment contraception 
duration.

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L 4
Country-specific Requirements for Germany
Table L24
Country-specific 
Requirements 
for 
Germany 
(Effective 
15 November 2022)
Section # and Name
Description of Change with Reason
N/A
Editorial change: adaption of the referenced CSP version 
N/A
According to AstraZeneca’s procedures the Clinical Study Protocol (CSP)
version 4.0 from 10 October 2022 was signed by the sponsor electronically 
only.
This Addendum to the CSP contains the signature of the National Coordinating 
Investigator as requested by local regulatory authority.
The protocol version 4.0 has no further impact on the German addendum and 
therefore no additional changes were made.
N/A
According to AstraZeneca’s procedures the Clinical Study Protocol (CSP) 
version 3.0 from 19 April 2022 was signed by the sponsor electronically only.
Overall study conduct, 
tumor sampling
2.3.2 Benefit assessment
8.6.2 Collection of 
Optional Biomarker 
Samples
No invasive sampling for fresh tumor specimen for the purpose of testing with 
companion diagnostics will be done for study participants. Therefore, no fresh 
biopsies will be taken during the study and only archived residual tumor 
material will be used at Screening. No optional paired tumor biopsy and no 
optional fresh tumor biopsy at progression will be conducted. Study participants 
will be informed in ICF accordingly.
“Additionally, at the time of disease progression, participants will be offered an 
optional tumor biopsy, which will provide real-time next-generation sequencing 
results from the FoundationOne®CDx, that may help guide next treatment 
options.”
Is deleted from section 2.3.2
“Optional tumor tissue samples for exploratory biomarker research

Paired tumor biopsy: A baseline biopsy will be taken (where the 
participant has provided informed consent) before initial dosing of study 
intervention (at screening or pre-dose on C1D1), and a paired (second) 
biopsy will be taken on-treatment. The paired on-treatment biopsy can be 
collected C2D1 and C2D7. On-treatment sample may also be collected 
outside of this specified timepoint with prior agreement from the Sponsor. 
Paired preclinical treatment and on-treatment tumor samples must be 
obtained from the same lesion where clinically feasible to maximize the 
utility for assessment of pharmacodynamic changes.
These optional paired tumor samples will be mandatory at select sites.

Tumor biopsy on disease progression: An additional tumor biopsy sample 
should be obtained at termination of treatment/documented RECIST 1.1 
disease progression in participants that have signed the additional optional 

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Section # and Name
Description of Change with Reason
Table 1
consent. These samples will be used to explore mechanisms of resistance. 
The on-study provision of tumor tissue is encouraged only if clinically 
appropriate and not considered detrimental to participant care.
Biopsies at study entry, on treatment, and progression are optional for the 
majority of participants in this study, and participants will not be excluded from 
the study if these samples are not collected. These optional biopsy samples will 
be mandatory at select sites.”
Is deleted from Section 8.6.2
“Optional tumor biopsy (FFPE/FF) at Progression” and “Optional paired tumor 
biopsy (FFPE/FF)” is deleted from Table 1
Section 7.1 
Discontinuation of Study 
Intervention
The wording in this section is changed from 
Participants may be discontinued from study intervention in the following 
situations: 
to
Participants must be discontinued from study intervention in the following 
situations: 

RECIST 1.1-defined radiological progression (refer to Section 8.1.1 and 
Appendix F). 

An AE that, in the opinion of the investigator or AstraZeneca, 
contraindicates further dosing. 

Any AE that meets criteria for discontinuation defined in the TMGs (see 
the Annex document to this CSP), or as defined in the local Prescribing 
Information for the ICC agents.

Participant decision. The participant is at any time free to discontinue 
treatment, without prejudice to further treatment. A participant who 
discontinues treatment is normally expected to continue to participate in 
the study (eg, for safety and survival follow-up) unless they specifically 
withdraw their consent to all further participation in any study procedures 
and assessments (see Section 7.2).

Severe non-compliance with the CSP as judged by the investigator or 
AstraZeneca.

Pregnancy or intent to become pregnant (refer to Appendix G and Section 
8.3.14).

Initiation of subsequent anticancer therapy, including another 
investigational agent.
Note that discontinuation from study intervention is NOT the same thing as a 
withdrawal from the study.
Crossover within the study is not permitted.
Appendix G Contraception 
Requirements
Women of childbearing potential who are not totally sexually abstinent (ie, 
refraining from heterosexual intercourse during the entire period of risk 

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Section # and Name
Description of Change with Reason
G1 Female participants
associated with study interventions) and intend to be sexually active with a non-
sterilized male partner must use at least 1 highly effective method of 
contraception (Table 16).
Is changed to:
Women of childbearing potential who are not totally sexually abstinent (ie, 
refraining from heterosexual intercourse during the entire period of risk 
associated with study interventions) and intend to be sexually active with a non-
sterilized male partner must use at least 1 highly effective non-hormonal 
method of contraception (Table 16). Hormonal methods of contraception must 
not be used by female patients participating in this study. 

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L 5
Country-specific Requirements for India
Table L25
Country-specific Requirements for India (Effective 02 November 2021)
Section # and Name
Description of Change with Reason
Section 6.6.1, Table 5:
Dose Modifications for 
Non-hematologic and
Hematologic Toxicity
Related to Dato-DXd
The following sections do not specify dose reduction by 1 level for Grade 3 
toxicities:
The text should read as follows:
The global clinical study protocol and its amendments (as applicable) for the study is to 
be read as follows:
Section # and Name
Description of Change with Reason
8.3.5 Adverse Events
Based on Examinations
andTests
Previous Text:
The results from the CSP-mandated laboratory tests, vital signs, physical 
examinations, ECGs, and echocardiogram/MUGA scans will be summarized in 
the CSR. 
Deterioration as compared with baseline in protocol-mandated laboratory values, 
vital signs, ECGs, and ECHO/MUGA scans should therefore only be reported as 
AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of 
treatment with the study intervention or are considered to be clinically relevant as 
judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, e.g., dose adjustment or study intervention 
interruption). 
If deterioration in a laboratory value/vital sign is associated with clinical signs 
and symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information. Wherever 
possible the reporting investigator uses the clinical, rather than the laboratory 
term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs 

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Section # and Name
Description of Change with Reason
or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to PD, should not 
be reported as an AE/SAE. Any new or aggravated clinically relevant abnormal 
medical finding at a physical examination as compared with the baseline 
assessment will be reported as an AE unless unequivocally related to the disease 
under study.
Revised Text:
The results from the CSP-mandated laboratory tests, vital signs, physical 
examinations, ECGs, and echocardiogram/MUGA scans will be summarized in 
the CSR. 
Deterioration as compared with baseline in protocol-mandated laboratory values, 
vital signs, ECGs, and ECHO/MUGA scans should therefore only be reported as 
AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of 
treatment with the study intervention or are considered to be clinically relevant as 
judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, e.g., dose adjustment or study intervention
interruption). 
If deterioration in a laboratory value/vital sign is associated with clinical signs 
and symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information. Wherever 
possible the reporting investigator uses the clinical, rather than the laboratory 
term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs 
or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to PD, should not 
be reported as an AE/SAE. Any new or aggravated clinically relevant abnormal 
medical finding at a physical examination as compared with the baseline 
assessment will be reported as an AE unless unequivocally related to the disease 
under study.
However, all the events occurring at the Indian sites (the reason whatsoever) that 
meet the criteria for seriousness (SAEs) from the time of signing the ICF, 
throughout the treatment period, including the safety follow up period (28 [+7] 
days after the discontinuation of study intervention) and if an event that starts 
after the defined safety follow-up period noted above and is considered to be due 
to a late onset toxicity to the study intervention, should be reported as an SAE per 
local regulatory requirements to the Sponsor (appropriate AstraZeneca 
representatives), Indian regulatory authority and the concerned Ethics 
Committees in accordance with New Drugs and Clinical Trials Rules, 2019.

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Section # and Name
Description of Change with Reason
Reason for change:
Per Indian regulatory requirements, all the events that meet criteria for 
seriousness have to be reported expeditiously to the Sponsor, Indian regulatory 
authority and the concerned Ethics Committees.
8.3.7 Disease
Progression
Previous Text:
Disease progression can be considered as a worsening of a participant’s condition 
attributable to the disease for which the study intervention is being studied. It may 
be an increase in the severity of the disease under study and/or increases in the 
symptoms of the disease. The development of new metastases or progression of 
existing metastasis to the primary cancer under study should be considered as PD 
and not an AE. Events, which are unequivocally due to PD, should not be 
reported as an AE during the study. Death due to disease progression should be 
recorded on the Death eCRF.
Revised Text:
Disease progression can be considered as a worsening of a participant’s condition 
attributable to the disease for which the study intervention is being studied. It may 
be an increase in the severity of the disease under study and/or increases in the 
symptoms of the disease. The development of new metastases or progression of 
existing metastasis to the primary cancer under study should be considered as PD 
and not an AE. Events, which are unequivocally due to PD, should not be 
reported as an AE during the study. Death due to disease progression should be 
recorded on the Death eCRF.
However, all the events occurring at the Indian sites (the reason whatsoever) that 
meet the criteria for seriousness (SAEs) from the time of signing the ICF, 
throughout the treatment period, including the safety follow up period (28 [+7] 
days after the discontinuation of study intervention) and if an event that starts 
after the defined safety follow-up period noted above and is considered to be due 
to a late onset toxicity to the study intervention, should be reported as an SAE per 
local regulatory requirements to the Sponsor (appropriate AstraZeneca 
representatives), Indian regulatory authority and the concerned Ethics 
Committees in accordance with New Drugs and Clinical Trials Rules, 2019.
Reason for change:
Per Indian regulatory requirements, all the events that meet criteria for 
seriousness have to be reported expeditiously to the Sponsor, Indian regulatory 
authority and the concerned Ethics Committees.
8.3.10 Deaths
Previous Texts:
All deaths that occur during the study intervention period, or within the protocol-
defined follow-up period after the administration of the last dose of study 
intervention, must be reported as follows:

Death clearly resulting from PD should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE.

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Section # and Name
Description of Change with Reason

Where death is not due (or not clearly due) to PD under study, the AE 
causing the death must be reported as an SAE within 24 hours. It should 
also be documented in the Statement of Death page in the eCRF. The 
report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign the main and contributory causes of 
death.

Deaths with an unknown cause should always be reported as an SAE and 
documented in the Statement of Death page in the eCRF, but every effort 
should be made to determine a cause of death. A post-mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy 
of the post-mortem results should be forwarded to AstraZeneca Patient 
Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the 
administration of the last dose of study intervention should be documented in the 
Statement of Death page. If the death occurred as a result of an event that started 
after the defined follow-up period and the event is considered to be due to a late-
onset toxicity to study intervention, then it should also be reported as an SAE.
Revised Text:
All deaths that occur during the study intervention period, or within the protocol-
defined follow-up period after the administration of the last dose of study 
intervention, must be reported as follows:

Death clearly resulting from PD should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to PD under study, the AE 
causing the death must be reported as an SAE within 24 hours. It should 
also be documented in the Statement of Death page in the eCRF. The 
report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign the main and contributory causes of 
death.

Deaths with an unknown cause should always be reported as an SAE and 
documented in the Statement of Death page in the eCRF, but every effort 
should be made to determine a cause of death. A post-mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy 
of the post-mortem results should be forwarded to AstraZeneca Patient 
Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the 
administration of the last dose of study intervention should be documented in the 
Statement of Death page. If the death occurred as a result of an event that started 
after the defined follow-up period and the event is considered to be due to a late-
onset toxicity to study intervention, then it should also be reported as an SAE.
However, all the events occurring at the Indian sites (the reason whatsoever) that 
meet the criteria for seriousness (SAEs) from the time of signing the ICF, 
throughout the treatment period, including the safety follow up period (28 [+7] 
days after the discontinuation of study intervention) and if an event that starts 

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Section # and Name
Description of Change with Reason
after the defined safety follow-up period noted above and is considered to be due 
to a late onset toxicity to the study intervention, should be reported as an SAE per 
local regulatory requirements to the Sponsor (appropriate AstraZeneca 
representatives), Indian regulatory authority and the concerned Ethics 
Committees in accordance with New Drugs and Clinical Trials Rules, 2019.
Reason for change:
Per Indian regulatory requirements, all the events that meet criteria for 
seriousness have to be reported expeditiously to the Sponsor, Indian regulatory 
authority and the concerned Ethics Committees.
Study sites affected by this addendum:
This Clinical Study Protocol - Addendum affects all the study sites in India and will prevail
if in conflict with any other section in the Clinical Study Protocol (CSP) (including its
appendices).

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L 6
Country-specific Requirements for United Kingdom
Table L26
Country-specific 
Requirements 
for 
United 
Kingdom 
(Effective 
19 May 2022)
Section # and Name
Description of Change with Reason
Section 5.1 Inclusion
Criteria #16
Inclusion #16 states - “Male participants who intend to be sexually active 
with a female partner of childbearing potential must be surgically sterile or 
using an acceptable method of contraception (see Appendix G) from the 
time of screening throughout the total duration of the study and the drug 
washout period (at least 4 months after the last dose of study intervention) 
to prevent pregnancy in a partner. Male participants must not donate or 
bank sperm during this same time period. Not engaging in heterosexual 
activity (sexual abstinence) for the duration of the study and drug washout 
period is an acceptable practice if this is the preferred usual lifestyle of the 
participant; however, periodic or occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of 
contraception.”
To clarify for the UK: If administered with either Gemcitabine or 
Vinorelbine, non-sterilized male participants must use an acceptable 
method of contraception and refrain from donating or banking sperm from 
the time of screening throughout the total duration of the study and the 
drug washout period (i.e., at least 6 months after the last dose of study 
intervention).
Section 8.3.14.2 
Paternal
Exposure
To clarify specifically for non-sterilized male participants administered 
either Gemcitabine or Vinorelbine who intend to be sexually active with a 
female partner of childbearing potential, that they must use an acceptable 
method of contraception and refrain from donating or banking sperm from 
the time of screening throughout the duration of the study and the drug 
washout period (i.e., at least 6 months after the last dose of study 
intervention).
Appendix G, G2 
Male Participants 
with a Female 
Partner of 
Childbearing
Potential
To clarify specifically for non-sterilized male participants administered 
either Gemcitabine or Vinorelbine who intend to be sexually active with a 
female partner of childbearing potential, that they must use an acceptable 
method of contraception and refrain from donating or banking sperm from 
the time of screening throughout the duration of the study and the drug 
washout period (i.e., at least 6 months after the last dose of study 
intervention).

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11
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VERSION HISTORY 
DOCUMENT HISTORY 
Document 
Date 
Local Amendment 1, European Union (Version 
1.0 European Union) 
22 April 2024 
Amendment 3 (Version 4.0) 
10 October 2022 
Amendment 2 (Version 3.0) 
19 April 2022 
Amendment 1 (Version 2.0) 
27 August 2021 
Original Protocol (Version 1.0) 
01 July 2021 
 
Local Amendment 1, European Union (22 April 2024) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the EU and in 
the EU CT Regulation Article 2, 2 (13). 
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to update the protocol for EU CTR requirements 
and to align with the latest Dato-DXd program standards. 
Other important administrative and operational clarifications have also been made. 
The rationale for each of these changes is provided in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
Title page 
EU CT number added 
To meet EU CTR 
requirements. 
Non-substantial 
Synopsis 
Regulatory Agency Identifiers added 
For completeness of the 
Synopsis and to meet EU 
CTR requirements. 
Non-substantial 
1.3 Schedule of 
Activities Table 1 and 
Table 2, 
8.2.5.3 ILD/Pneumonitis 
Investigation, 
8.6.2 Collection of 
Optional Biomarker 
Samples 
Optional lung biopsy specimen 
removed 
To reflect that lung 
biopsy is no longer an 
optional biomarker 
sample. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
1.3 Schedule of 
Activities Table 1 
Reference to the Dato-DXd Site 
Ophthalmologic Assessment Manual 
was added. 
To clarify that the 
Ophthalmologic 
Assessment form is now 
included in the Dato-
DXd Site 
Ophthalmologic 
Assessment Manual. 
Non-substantial 
1.3 Schedule of 
Activities Table 1 
Oral care plan row, arrow from Cycle 
1 through Safety FU assessment was 
replaced with wording “Daily before 
dosing, throughout treatment, and up 
to the first follow-up visit”. 
To ensure clarity of the 
oral care protocol and 
avoid footnote details 
being missed. 
Non-substantial 
1.3 Schedule of 
Activities Table 1, 8.6.2 
Collection of Optional 
Biomarker Samples 
Optional bronchoalveolar lavage and 
lung biopsy sample on suspected 
ILD/diagnosis of ILD row was 
deleted. 
The lung biopsy will not 
be collected. The lavage 
sample will not be 
collected centrally 
anymore and is specified 
in Table 2. 
Non-substantial 
1.3 Schedule of 
Activities Table 2 
Table for assessments to be 
performed if ILD/pneumonitis 
suspected during the intervention 
period was updated to match the 
corresponding Section 8.2.5.3 for 
clarity and consistency eg, physical 
examination including auscultation of 
lung field, arterial blood gases if 
clinically indicated were added to 
Table 2. 
To clarify assessments in 
case of suspected and/or 
confirmed 
ILD/pneumonitis and 
ensure consistency 
across protocol sections.  
Non-substantial 
2.3.1.1 Dato-DXd 
Table 3 Risk 
Assessment, 
2.3.3 Overall Benefit: 
Risk Conclusion 
IRR was downgraded from important 
identified risk to the identified risk 
category. A sentence was added to 
clarify that Dato-DXd has not been 
studied in participants with renal or 
hepatic impairment. The Summary of 
Data/Rationale for Risk was updated 
with the latest safety data from the 
IB. The Mitigation Strategy was 
updated to list out the AESIs. 
To reflect clinical data 
for Dato-DXd in 
alignment with Dato-
DXd IB Edition 7.0. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
2.3.3 Overall Benefit: 
Risk Conclusion, 
6.5 Concomitant 
Therapy, 6.6 Dose 
Modification, 8.3 
Adverse Events and 
Serious Adverse Events, 
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis, 
8.6.3 Other Study 
Related Biomarker 
Assessments, 9.4.1 
General Considerations, 
Appendix I2 (Table 18), 
Appendix J 
COVID-19 specific text was deleted 
throughout the protocol. 
No specific safety 
concerns have been 
identified in patients with 
COVID-19 who have 
been treated with Dato-
DXd. 
Non-substantial 
4.1 Overall Design, 
5 Study Population 
A reference for country-specific 
study requirements provided in 
Appendix L was added.  
Country-specific 
addendums were added 
to the appendices to 
create one global 
protocol for EU CTR 
submission. 
Non-substantial 
4.4 End of Study 
Definition 
The end of study definition was 
updated to distinguish between end of 
study (EU definition) and study 
completion (FDA definition). 
To provide a clear 
definition of end of the 
study for results 
disclosure purposes. 
Non-substantial 
6.1.1 Investigational 
Products 
In Table 5, AxMP was added to the 
IMP and NIMP row. For the unit 
dose strength row, ‘vial’ was deleted 
from ‘100 mg vial’. Reference to 
GMP Annex 13 was removed from 
labelling information. 
To ensure all 
interventions are 
designated as an 
investigational medicinal 
product or a non-
investigational medicinal 
product/auxiliary 
medicinal product. To 
omit repetition of 
packaging details in dose 
unit dose strength 
information. To ensure 
country-specific labelling 
requirements are 
followed. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
6.2.1 Dato-DXd 
Density of Dato-DXd was added. 
Reference to the Pharmacy Manual 
was moved to Section 6.2.1.1 and 
corrected. 
To ensure the latest 
available information is 
reflected in the protocol 
and to align with the 
Pharmacy Manual. 
Non-substantial 
6.2.1.1 Preparation of 
Dato-DXd 
Guidance for preparation of Dato-
DXd has been updated with 
additional details. A reference to the 
Pharmacy Manual for administration 
details provided separately was 
added. 
To ensure the latest 
available information is 
reflected in the protocol 
and to align with the 
Pharmacy Manual. 
Non-substantial 
6.2.1.2 Administration of 
Dato-DXd 
Guidance for administration of Dato-
DXd has been updated additional 
details. 
To ensure the latest 
available information is 
reflected in the protocol 
and to align with the 
Pharmacy Manual. 
Non-substantial 
6.6 Dose Modification 
Subheadings were added: 6.6.1 Dose 
Delays, 6.6.2 Dose Delays for 
Reasons Other than Treatment-
related Toxicity, 6.6.3 Dose 
Reductions and the text restructured 
accordingly.  
Clarification was added around doses 
delayed for up to 3 consecutive 
cycles (63 days) from the planned 
date of administration (ie, 84 days 
from the last infusion date). 
Figure 3 Dose Delay Schema for 
Dato-DXd was added.  
Section 6.6.2 Dose Delays for 
Reasons Other Than 
Treatment-related Toxicity guidance 
as included. 
To clarify dose 
modification guidance. 
Non-substantial 
6.7 Intervention after the 
End of the Study 
Section heading was updated to 
Continued Access to Study 
Intervention after the End of the 
Study. Language was added to 
describe methods of providing 
participants with access to treatment 
after data collection in the study has 
ended. 
To clarify intervention 
available to participants 
after the end of the study. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
8.2.2 Vital Signs 
End of infusion vital signs collection 
window restriction of ±5 minutes was 
removed.  
To avoid unnecessary 
protocol deviations since 
vital signs measurements 
timing can be more 
flexible.  
Non-substantial 
8.2.5.3 ILD/Pneumonitis 
Investigation 
ILD/pneumonitis investigation 
paragraph was updated for clarity. 
Signs and symptoms entry was 
deleted from the list of evaluations. 
Optional bronchoscopy and 
bronchoalveolar lavage if clinically 
indicated text was updated for clarity. 
Acceptable CT scan was clarified to 
include non-contrast chest CT with 1 
to 2 mm slice thickness 
recommended. Differential white 
blood cell count was specified with 
blood tests for clarification. 
The additional blood sample for 
exploratory biomarker analysis was 
clarified as an optional serum sample 
when ILD/pneumonitis is suspected 
and/or diagnosed. 
An example of other tests that may be 
needed was added.  
Text was updated to match the 
corresponding Section 8.2.5.3 for 
clarity and consistency. 
To clarify 
ILD/pneumonitis 
investigations. Signs and 
symptoms are not 
assessments and covered 
under adverse events 
reporting.  
To clarify what 
constitutes an acceptable 
CT and biomarker 
sample requirements. 
 
Non-substantial 
8.2.5.5 Ophthalmologic 
Assessments, 8.3.11 
Adverse Events of 
Special Interest 
A reference to the Dato-DXd 
Ophthalmologic Assessment Manual 
was added. The frequency of use of 
artificial tears was specified as 4 
times daily as preventative measures 
and up to 8 times daily as clinically 
needed. 
To clarify the frequency 
of use of artificial tears. 
Non-substantial 
8.2.5.6 Oral Care Plan 
Oral care guidance for participants 
was updated to state participants 
receiving ICC are recommended 
daily use of alcohol-free mouthwash 
while participants receiving Dato-
DXd are recommended to use a 
steroid-containing mouthwash. A 
reference to the Dato-DXd TMGs 
was added. 
To specify the 
recommended 
mouthwash for oral care 
with study treatments. To 
direct reader to TMGs 
should oral mucosal 
toxicity arise despite 
prophylaxis measures. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
8.3 Adverse Events and 
Serious Adverse Events 
The section title was updated to 
Adverse Events, Serious Adverse 
Events, and Other Safety Reporting. 
To clarify that other 
safety reporting is also 
captured in this section.  
Non-substantial 
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information 
The reporting period for 
ILD/pneumonitis events was clarified 
to extend beyond the 28 + 7 day 
safety follow-up period. The 
reporting period for all AESIs was 
clarified. Reporting instructions for 
pre-existing medical conditions was 
included. Clarification was provided 
for reporting details of hepatic events. 
To ensure appropriate 
data collection on 
ILD/pneumonitis events 
and all other AEs and 
SAEs. 
Non-substantial 
8.3.11 Adverse Events of 
Special Interest 
Reporting requirements for 
concomitant medication administered 
as treatment for drug-related AESIs 
was specified. 
IRR was changed from important 
identified risk to identified risk. 
To ensure that 
concomitant medications 
for drug-related AESIs 
are appropriately 
recorded. 
Non-substantial 
8.3.15 Medication Error 
Section heading was updated to 
Medication Error, Drug Abuse, and 
Drug Misuse. Subsections including 
relevant definitions were added for 
Medication Error, Drug Abuse, Drug 
Misuse. A reference to Appendix B4 
was added.  
To clarify what 
constitutes a medication 
error, drug abuse, and 
drug misuse in the study. 
Non-substantial 
8.5 Human Biological 
Samples 
For PK and ADA samples retention, 
the wording “unless consented for 
future analysis” was deleted. 
It was clarified that remaining ADA 
sample aliquots will be retained for a 
maximum of 5 years after CSR 
publication. Wording was added to 
clarify ADA samples collected in 
China will be disposed of 1 year after 
CSR publication. 
The samples will be used 
for study analysis only. 
To clarify sample 
retention periods. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis, 
1.3 Schedule of 
Activities Table 1 
Additional blood samples for 
exploratory biomarker analysis to be 
collected as soon as ILD/pneumonitis 
is suspected, if feasible was moved to 
Section 8.6.2 since these are optional 
samples. In Table 1, It was clarified 
that the additional exploratory 
biomarker blood samples are 
optional. 
The retention time for residual tumor 
samples collected for TROP2 IHC 
testing from Chinese participants was 
corrected to state samples will be 
destroyed or repatriated within 1 year 
after CSR completion. 
To clarify that the 
additional exploratory 
biomarker samples are 
optional. To correct 
residual tumor sample 
retention for Chinese 
participants. 
Non-substantial 
9.3 Populations for 
Analyses Table 9 
ITT and Safety Analysis Set 
descriptions were updated to specify 
clinical outcomes assessments 
included in each set.  
To clarify the 
populations definitions 
and align with objectives 
and endpoints. 
Non-substantial 
Appendix A1 Regulatory 
and Ethical 
Considerations 
Investigator oversight of the conduct 
of the study and adherence to 
regulatory requirements was clarified. 
A subsection for Regulatory 
Reporting Requirements of Serious 
Breaches was added. 
To clarify investigator 
responsibilities and 
include guidance on 
reporting serious 
breaches during study 
conduct. 
Non-substantial 
Appendix A6 
Dissemination of 
Clinical Study Data 
The timeframe for submitting results 
summaries to EU CTIS was included. 
The AstraZeneca website for a 
description of the study was updated. 
To clarify study result 
submission timelines and 
include the current 
AstraZeneca website. 
Non-substantial 
Appendix A7 Data 
Quality Assurance 
It was clarified that clinical reviews 
of data from a medical perspective 
form part of the monitoring strategy. 
The record and document retention 
period was clarified. 
To clarify the monitoring 
process and record 
retention policy. 
Non-substantial 
Appendix B4 Medication 
Error 
Section heading was updated to 
Medication Error, Drug Abuse, and 
Drug Misuse. Subheading for 
Medication Error as well as a range 
for dose error was added. Subsections 
for Drug Abuse and Drug Misuse 
were added. 
To clarify what 
constitutes a medication 
error, drug abuse, and 
drug misuse in the study. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
Appendix I2 Restricted, 
Prohibited, and 
Permitted Concomitant 
Medications/Therapies 
In Table 17 was updated to include 
instructions regarding Dato-DXd 
therapy when palliative radiotherapy 
is given. It was clarified that curative 
radiotherapy prohibited. 
To clarify Dato-DXd 
therapy delays in the 
case of palliative 
radiotherapy. 
Non-substantial 
Appendix I2 Supportive 
Medications/Therapies 
Table 19: ‘Antihistamines and 
acetaminophen’ was re-labeled as 
‘pre-medications for prevention of 
IRR or as supportive treatment of 
Dato-DXd’. Examples of 
prophylactic anti-emetic agents was 
deleted from text in the supportive 
medication column. 
Text was updated to 
mention examples in the 
Usage column instead of 
in the medications/class 
of drug/therapy column. 
Non-substantial 
Appendix K Protocol 
Version History 
Previous protocol amendments were 
moved to Appendix K. 
To focus protocol text on 
current information with 
additional information 
provided in appendices. 
Non-substantial 
Appendix L 
Country-specific addendums to the 
protocol were added in Appendix L.  
Country-specific 
addendums were added 
to the appendices to 
create one global 
protocol for EU CTR 
submission. 
Non-substantial 
Throughout 
Minor editorial and formatting 
revisions. 
To further clarify. 
Non-substantial 
 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ......................................................................................................... 11 
LIST OF FIGURES ................................................................................................................. 14 
LIST OF TABLES ................................................................................................................... 15 
1 
PROTOCOL SUMMARY .................................................................................... 17 
1.1 
Synopsis ................................................................................................................ 17 
1.2 
Schema .................................................................................................................. 24 
1.3 
Schedule of Activities ........................................................................................... 26 
2 
INTRODUCTION ................................................................................................ 34 
2.1 
Study Rationale ..................................................................................................... 35 
2.2 
Background ........................................................................................................... 36 
2.2.1 
HR-positive, HER2-negative, inoperable/metastatic breast cancer ...................... 36 
2.2.1.1 
Unmet medical need ............................................................................................. 37 
2.2.2 
Dato-DXd ............................................................................................................. 38 
2.2.2.1 
TROPION-PanTumor01 study ............................................................................. 38 
2.3 
Benefit/Risk Assessment ...................................................................................... 39 
2.3.1 
Risk Assessment ................................................................................................... 39 
2.3.1.1 
Dato-DXd ............................................................................................................. 39 
2.3.2 
Benefit Assessment ............................................................................................... 40 
2.3.3 
Overall Benefit: Risk Conclusion ......................................................................... 41 
3 
OBJECTIVES AND ENDPOINTS ...................................................................... 43 
4 
STUDY DESIGN ................................................................................................. 48 
4.1 
Overall Design ...................................................................................................... 48 
4.1.1 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 51 
4.2 
Scientific Rationale for Study Design .................................................................. 51 
4.2.1 
Rationale for Study Design ................................................................................... 51 
4.2.2 
Rationale for Choice of Comparator Treatments .................................................. 52 
4.2.3 
Rationale for Stratification Factors ....................................................................... 53 
4.2.3.1 
Stratification based on previous lines of chemotherapy ....................................... 53 
4.2.3.2 
Stratification based on prior CDK4/6 inhibitor use .............................................. 53 
4.2.3.3 
Stratification based on geographical region ......................................................... 53 
4.2.4 
Rationale for Primary Efficacy Endpoints ............................................................ 53 
4.2.5 
Rationale for Other Study Endpoints .................................................................... 54 
4.3 
Justification for Dose ............................................................................................ 55 
4.3.1 
Dato-DXd ............................................................................................................. 55 
4.3.2 
Investigator Choice of Chemotherapy (ICC) ........................................................ 55 
4.4 
End of Study Definition ........................................................................................ 56 
5 
STUDY POPULATION ....................................................................................... 56 

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5.1 
Inclusion Criteria .................................................................................................. 57 
5.2 
Exclusion Criteria ................................................................................................. 60 
5.3 
Lifestyle Considerations ....................................................................................... 64 
5.4 
Screen Failures...................................................................................................... 64 
6 
STUDY INTERVENTION ................................................................................... 65 
6.1 
Study Intervention(s) Administered ...................................................................... 65 
6.1.1 
Investigational Products........................................................................................ 65 
6.1.1.1 
Duration of Treatment........................................................................................... 66 
6.1.2 
Medical Devices ................................................................................................... 66 
6.2 
Preparation, Handling, Storage, Accountability of Interventions ......................... 66 
6.2.1 
Dato-DXd ............................................................................................................. 67 
6.2.1.1 
Preparation of Dato-DXd ...................................................................................... 67 
6.2.1.2 
Administration of Dato-DXd ................................................................................ 68 
6.2.1.3 
Monitoring of Dato-DXd Administration ............................................................. 69 
6.2.1.4 
Storage of Dato-DXd ............................................................................................ 69 
6.2.2 
Investigator’s Choice of Chemotherapy ............................................................... 69 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 70 
6.3.1 
Participant Enrolment and Randomization ........................................................... 70 
6.3.2 
Procedures for Handling Incorrectly Enrolled or Randomized Participants ........ 71 
6.3.3 
Methods for Assigning Treatment Groups ............................................................ 71 
6.3.4 
Methods for Ensuring Blinding ............................................................................ 72 
6.4 
Study Intervention Compliance ............................................................................ 72 
6.5 
Concomitant Therapy ........................................................................................... 72 
6.6 
Dose Modification ................................................................................................ 74 
6.6.1 
Dose Delays .......................................................................................................... 74 
6.6.2 
Dose Delays for Reasons Other Than Treatment-related Toxicity ....................... 75 
6.6.3 
Dose Reductions ................................................................................................... 76 
6.6.4 
Management of Toxicities .................................................................................... 76 
6.7 
Continued Access to Study Intervention After the End of the Study ................... 77 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................. 78 
7.1 
Discontinuation of Study Intervention ................................................................. 78 
7.1.1 
Follow-up of Participants Post Discontinuation of Study Intervention ................ 79 
7.1.2 
Follow-up of Participants to PFS2 ........................................................................ 79 
7.1.3 
Follow-up for Survival ......................................................................................... 79 
7.2 
Participant Withdrawal from the Study ................................................................ 80 
7.3 
Lost to Follow-up ................................................................................................. 80 
8 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 81 
8.1 
Efficacy Assessments ............................................................................................ 82 
8.1.1 
Imaging Tumor Assessments ................................................................................ 82 
8.1.2 
Central Reading of Scans...................................................................................... 84 
8.1.3 
Time to Second Progression or Death .................................................................. 84 

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8.1.4 
Overall Survival .................................................................................................... 84 
8.1.5 
Clinical Outcome Assessments (COA) ................................................................. 85 
8.1.5.1 
EORTC QLQ-C30 ................................................................................................ 85 
8.1.5.2 
EORTC IL116: selected breast and arm symptom scales from EORTC QLQ-
BR45/IL ................................................................................................................ 86 
8.1.5.3 
PRO-CTCAE ........................................................................................................ 86 
8.1.5.4 
EORTC IL117: selected symptomatic AE items from EORTC IL ....................... 86 
8.1.5.5 
PGI-TT .................................................................................................................. 87 
8.1.5.6 
PGIS ...................................................................................................................... 87 
8.1.5.7 
PGIC ..................................................................................................................... 87 
8.1.5.8 
EQ-5D-5L ............................................................................................................. 87 
8.1.5.9 
Administration of Electronic PRO (ePRO) Questionnaires ................................. 88 
8.2 
Safety Assessments ............................................................................................... 90 
8.2.1 
Physical Examinations .......................................................................................... 90 
8.2.2 
Vital Signs ............................................................................................................. 91 
8.2.3 
Electrocardiograms ............................................................................................... 91 
8.2.4 
Clinical Safety Laboratory Assessments .............................................................. 92 
8.2.5 
Other Safety Assessments ..................................................................................... 93 
8.2.5.1 
Echocardiogram/Multigated Acquisition Scan ..................................................... 93 
8.2.5.2 
Pulmonary Function Tests .................................................................................... 94 
8.2.5.3 
ILD/Pneumonitis Investigation ............................................................................. 94 
8.2.5.4 
ECOG Performance Status ................................................................................... 95 
8.2.5.5 
Ophthalmologic Assessments ............................................................................... 96 
8.2.5.6 
Oral Care Plan....................................................................................................... 97 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety Reporting ............... 98 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 98 
8.3.2 
Follow-up of AEs and SAEs ............................................................................... 100 
8.3.3 
Causality Collection............................................................................................ 101 
8.3.4 
Adverse Events Based on Signs and Symptoms ................................................ 101 
8.3.5 
Adverse Events Based on Examinations and Tests ............................................ 101 
8.3.6 
Hy’s Law ............................................................................................................. 102 
8.3.7 
Disease Progression ............................................................................................ 102 
8.3.8 
Disease Under Study........................................................................................... 102 
8.3.9 
New Cancers ....................................................................................................... 102 
8.3.10 
Deaths ................................................................................................................. 102 
8.3.11 
Adverse Events of Special Interest ..................................................................... 103 
8.3.12 
Safety Data to be Collected Following the Final Data Cutoff of the Study ....... 105 
8.3.13 
Reporting of Serious Adverse Events ................................................................. 106 
8.3.14 
Pregnancy ........................................................................................................... 106 
8.3.14.1 
Maternal Exposure .............................................................................................. 107 
8.3.14.2 
Paternal Exposure ............................................................................................... 107 
8.3.15 
Medication Error, Drug Abuse, and Drug Misuse .............................................. 108 
8.3.15.2 
Medication Error ................................................................................................. 108 
8.3.15.3 
Drug Abuse ......................................................................................................... 108 
8.3.15.4 
Drug Misuse........................................................................................................ 108 
8.3.16 
Medical Device Deficiencies .............................................................................. 109 

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8.4 
Overdose ............................................................................................................. 109 
8.5 
Human Biological Samples ................................................................................ 109 
8.5.1 
Pharmacokinetics ................................................................................................ 110 
8.5.1.1 
Determination of Drug Concentration ................................................................ 110 
8.5.2 
Immunogenicity Assessments ............................................................................. 110 
8.6 
Human Biological Sample Biomarkers .............................................................. 111 
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis ................................ 111 
8.6.2 
Collection of Optional Biomarker Samples ........................................................ 113 
8.6.3 
Other Study Related Biomarker Assessments .................................................... 114 
8.7 
Optional Genomics Initiative Sample ................................................................. 114 
8.8 
Medical Resource Utilization and Health Economics ........................................ 115 
9 
STATISTICAL CONSIDERATIONS ................................................................. 115 
9.1 
Statistical Hypotheses ......................................................................................... 115 
9.2 
Sample Size Determination ................................................................................ 116 
9.3 
Populations for Analyses .................................................................................... 118 
9.4 
Statistical Analyses ............................................................................................. 119 
9.4.1 
General Considerations ....................................................................................... 119 
9.4.2 
Efficacy ............................................................................................................... 119 
9.4.2.1 
Primary Endpoints .............................................................................................. 119 
9.4.2.2 
Secondary Endpoint(s)........................................................................................ 124 
9.4.2.3 
Exploratory Endpoints ........................................................................................ 128 
9.4.3 
Safety .................................................................................................................. 129 
9.4.4 
Other Analyses .................................................................................................... 131 
9.4.4.1 
Optional Exploratory Genetic Sample ................................................................ 131 
9.4.4.2 
Ophthalmologic Analysis.................................................................................... 131 
9.5 
Interim Analyses ................................................................................................. 131 
9.6 
Data Monitoring Committees ............................................................................. 132 
9.6.1 
Independent Data Monitoring Committee .......................................................... 132 
9.6.2 
ILD Adjudication Committee ............................................................................. 133 
9.6.3 
Ophthalmologic Data Review Committee .......................................................... 133 
9.7 
Mainland China Cohort ...................................................................................... 133 
10 
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL 
CONSIDERATIONS .......................................................................................... 135 
Amendment 3 (10 October 2022) .......................................................................................... 194 
Amendment 2 (19 April 2022) .............................................................................................. 197 
Amendment 1 (27 August 2021) ........................................................................................... 204 
11 
REFERENCES ................................................................................................... 234 
 
LIST OF FIGURES  
Figure 1 
Study Design ............................................................................................... 25 

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Figure 2 
Study Flow Chart ........................................................................................ 50 
Figure 3 
Dose Delay Schema for Dato-DXd ............................................................. 75 
Figure 4 
Prophylactic Mouthwash Algorithm ........................................................... 98 
Figure 5 
Multiple Testing Procedure ....................................................................... 116 
LIST OF TABLES  
Table 1 
Schedule of Activities ................................................................................. 27 
Table 2 
Assessments if ILD/Pneumonitis is Suspected during the Intervention 
Period .......................................................................................................... 34 
Table 3 
Risk Assessment .......................................................................................... 39 
Table 4 
Objectives and Endpoints ............................................................................ 43 
Table 5 
Investigational Products .............................................................................. 65 
Table 6 
Dose Reduction Levels of Dato-DXd ......................................................... 76 
Table 7 
Laboratory Safety Variables ....................................................................... 93 
Table 8 
Spirometry Component ............................................................................... 94 
Table 9 
Populations for Analysis ........................................................................... 118 
Table 10 
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Primary Endpoints ..................................................................................... 119 
Table 11 
Summary of planned timings of the interim and final OS analyses .......... 131 
Table 12 
Summary of Imaging Modalities for Tumor Assessment ......................... 162 
Table 13 
RECIST 1.1 Evaluation of Target Lesions ............................................... 169 
Table 14 
RECIST 1.1 Evaluation of Non-Target Lesions ....................................... 170 
Table 15 
RECIST 1.1 Overall Visit Response ......................................................... 171 
Table 16 
Highly Effective Methods of Contraception (< 1% Failure Rate) ............ 175 
Table 17 
Restricted medications/therapies ............................................................... 189 
Table 18 
Prohibited medications/therapies .............................................................. 190 
Table 19 
Supportive medications/therapies ............................................................. 191 
Table L20 
Country-specific Requirements for Brazil (Effective 15 September 2022)208 
Table L21 
Country-specific Requirements for Canada (Effective 13 December 
2022) ......................................................................................................... 212 
Table L22 
Country-specific Requirements for France (Effective 10 November 
2022) ......................................................................................................... 213 
Table L23 
Country-specific Requirements for France (Effective 21 January 2022) . 215 
Table L24 
Country-specific Requirements for Germany (Effective 
15 November 2022) ................................................................................... 219 

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Table L25 
Country-specific Requirements for India (Effective 02 November 2021) 222 
Table L26 
Country-specific Requirements for United Kingdom (Effective 
19 May 2022) ............................................................................................ 227 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations ........................ 136 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................... 142 
Appendix C 
Handling of Human Biological Samples ................................................... 148 
Appendix D 
Optional Genomics Initiative Sample ....................................................... 151 
Appendix E 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 155 
Appendix F 
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors) ................... 162 
Appendix G 
Contraception Requirements ..................................................................... 173 
Appendix H 
Patient-reported Outcomes ........................................................................ 176 
Appendix I 
Concomitant Medications ......................................................................... 189 
Appendix J 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 192 
Appendix K 
Protocol Version History ........................................................................... 194 
Appendix L 
Country-Specific Addendums to the Protocol .......................................... 208 
Appendix M 
Abbreviations ............................................................................................ 228 
 

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1 
PROTOCOL SUMMARY  
1.1 
Synopsis  
Protocol Title:  A Phase 3, Open-label, Randomized Study of Dato-DXd Versus 
Investigator’s Choice of Chemotherapy in Participants With Inoperable or Metastatic 
Hormone Receptor-Positive, HER2-Negative Breast Cancer Who Have Been Treated With 
One or Two Prior Lines of Systemic Chemotherapy (TROPION-Breast01). 
Short Title: A Study of Dato-DXd Versus Investigator's Choice Chemotherapy in Inoperable 
or Metastatic Hormone Receptor-positive, HER2-negative Breast Cancer. 
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2020-005620-12; IND Number: 155696; EU CT number: 2023-509631-37 
Rationale:  
Single agent chemotherapy remains the cornerstone of therapy for patients with HR-positive, 
HER2-negative metastatic breast cancer who have exhausted endocrine therapy options. 
However, patient prognosis is poor, and durable antineoplastic therapy options are necessary 
to improve outcomes in this patient population. 
Dato-DXd is a TROP2 antibody-drug conjugate (administered via IV infusion, Q3W). Within 
the Dato-DXd clinical development program, preliminary data supporting the use of 
Dato-DXd in participants with HR-positive, HER2-negative breast cancer are available from 
an ongoing phase 1 first-in-human study, TROPION-PanTumor01 (NCT03401385), which is 
evaluating Dato-DXd in participants with advanced non-small cell lung cancer and triple-
negative breast cancer, relapsed or refractory to standard-of-care therapy. These data have 
demonstrated highly encouraging efficacy across dose groups, with tumor responses observed 
at doses of 4, 6, and 8 mg/kg and an acceptable and manageable toxicity profile.  
Given these encouraging preliminary safety and efficacy data, the current study is designed to 
provide a robust and detailed understanding of the efficacy and safety of Dato-DXd when 
compared with Investigator’s choice of standard-of-care single-agent chemotherapy (eribulin, 
capecitabine, vinorelbine, or gemcitabine; henceforth referred to as ICC) in participants with 
inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated 
with one or two prior lines of systemic chemotherapy, for which an unmet medical need 
remains. 

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Objectives and Endpoints 
Objectives 
Endpoints 
Dual Primary 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR. 
• PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by BICR, or 
death due to any cause.  
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinically progresses prior to RECIST 1.1.  
The measure of interest is the hazard ratio of PFS. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of OS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• OS is defined as time from randomization until the date of 
death due to any cause.  
The comparison will include all randomized participants as 
randomized, regardless of whether the participant withdraws 
from therapy or receives another anticancer therapy. 
The measure of interest is the hazard ratio of OS. 
Secondary 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of ORR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment. 
• ORR is defined as the proportion of participants who have a 
confirmed CR or PR, as determined by the 
BICR/Investigator assessment, per RECIST 1.1. 
The analysis will include all randomized participants as 
randomized.  
Data obtained from randomization up until  
progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR, 
regardless of whether the participant withdraws from therapy. 
Participants who go off treatment without a response or 
progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR. 
The measure of interest is the odds ratio of the ORR. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DoR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• DoR is defined as the time from the date of first documented 
confirmed response until date of documented progression 
per RECIST 1.1, as assessed by BICR/Investigator 
assessment or death due to any cause. 
The analysis will include all randomized participants as 
randomized who have a confirmed response, regardless of 
whether the participant withdraws from therapy, receives 
another anticancer therapy or clinically progresses prior to 
RECIST 1.1 progression. 
The measure of interest is the median of DoR. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per investigator assessment. 
• PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by investigator 
assessment, or death due to any cause.  
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinically progresses prior to RECIST 1.1. 
The measure of interest is the hazard ratio of PFS. 

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Objectives 
Endpoints 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DCR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment. 
• DCR at 12 weeks is defined as the percentage of 
participants who have a confirmed CR or PR or who have 
SD, per RECIST 1.1, as assessed BICR/per investigator 
assessment and derived from the raw tumor data for at least 
11 weeks after randomization.  
Data obtained from randomization up until progression, or the 
last evaluable assessment in the absence of progression, will 
be included in the assessment of DCR, regardless of whether 
the participant withdraws from therapy. Participants who 
receive a subsequent therapy prior to week 11 will not be 
considered to have disease control in the analysis. 
The analysis will include all randomized participants as 
randomized. 
The measure of interest is the odds ratio of the DCR. 
To assess pain in participants treated with 
Dato-DXd compared to ICC. 
• TTD in pain as measured by the pain scale from EORTC 
QLQ-C30 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants.  
The measure of interest is the hazard ratio of TTD in pain.  
To assess physical functioning in 
participants treated with Dato-DXd 
compared to ICC. 
• TTD in physical functioning as measured by the physical 
functioning scale from EORTC QLQ-C30 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants.  
The measure of interest is the hazard ratio of TTD in physical 
functioning.  
To assess global health status/quality of life 
(GHS/QoL) in participants treated with 
Dato-DXd compared to ICC. 
• TTD in GHS/QoL as measured by the GHS/QoL scale from 
EORTC QLQ-C30 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants.  
The measure of interest is the hazard ratio of TTD in 
GHS/QoL. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TFST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• TFST is defined as the time from randomization until the 
start date of the first subsequent anticancer therapy after 
discontinuation of randomized treatment, or death due to 
any cause. 
The analysis will include all randomized participants as 
randomized, regardless of progression status. 
The measure of interest is the hazard ratio of TFST. 

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Objectives 
Endpoints 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TSST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• TSST is defined as the time from randomization to until the 
start date of the second subsequent anticancer therapy after 
discontinuation of first subsequent treatment, or death due to 
any cause. 
The analysis will include all randomized participants as 
randomized, regardless of progression status on study 
treatment or first subsequent treatment. 
The measure of interest is the hazard ratio of TSST.  
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS2 in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• PFS2 will be defined as the time from the randomization to 
the earliest of the progression event (following the initial 
progression), subsequent to first subsequent therapy, or 
death. The date of second progression will be recorded by 
the Investigator in the eCRF and defined according to local 
standard clinical practice. 
The comparison will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from subsequent therapy and regardless of missed visits. 
The measure of interest is the hazard ratio of PFS2. 
To assess the PK of Dato-DXd 6mg/kg IV 
Q3W. 
• Plasma concentrations of Dato-DXd, total anti-TROP2 
antibody, and MAAA-1181a (payload).  
To investigate the immunogenicity of 
Dato-DXd 6mg/kg IV Q3W. 
• Presence of ADA. 
Safety 
To assess the safety and tolerability profile 
of Dato-DXd compared to ICC. 
Safety and tolerability will be evaluated in terms of adverse 
events (graded by CTCAE version 5.0), and also in terms of: 
• ECOG PS 
• Vital signs, body weight, physical examination  
• Clinical chemistry, hematology, and urinalysis assessments 
• ECG, ECHO/MUGA and Ophthalmologic assessments 
 
For exploratory objectives and endpoints, see Section 3 of the protocol. 
Overall Design 
Disclosure Statement: This is a Phase 3, randomized, open-label, 2 arm, multicenter, 
international study assessing the efficacy and safety of Dato-DXd compared with ICC in 
participants with inoperable or metastatic HR-positive, HER2-negative breast cancer who 
have been treated with one or two prior lines of systemic chemotherapy in the inoperable or 
metastatic setting. 
Participant Population: The target population of interest in this study is male or female adult 
(≥ 18 years participants with inoperable or metastatic HR-positive, HER2 negative breast 
cancer (per ASCO/CAP guidelines, on local laboratory results) who have progressed on and 
are not suitable for endocrine therapy per investigator assessment, and have been treated with 
1 to 2 lines of prior chemotherapy in the inoperable/metastatic setting. Participants must have 
documented progression on their most recent line of chemotherapy, and be eligible for one of 

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the chemotherapy options listed as ICC (eribulin, capecitabine, vinorelbine, gemcitabine), per 
investigator assessment. 
To be eligible for randomization, availability of a FFPE tumor sample (block preferred, or a 
minimum of 20 freshly cut slides) is required, at the time of screening. This sample can be 
from either the primary disease setting (surgical resection or diagnostic sample), or from a 
metastatic lesion (excluding bone). If neither an adequate FFPE block nor the minimum of 
20 slides are available, a patient may still be considered eligible. In this situation, approval by 
the Study Team for patient’s entry into the study is required. If there is no written 
confirmation of the availability of an appropriate tumor sample prior to enrolment, the 
participant will not be eligible for the study. At the time of enrolment all participants must 
have an ECOG PS of 0 or 1, and have at least 1 measurable lesion not previously irradiated 
that qualifies as a RECIST 1.1 target lesion. Participants with clinically inactive brain 
metastases may be included in the study. 
Number of Participants: Approximately 1000 participants will be enrolled to achieve 
approximately 700 randomly assigned participants to study intervention. If required for 
regulatory submission purposes, the recruitment of participants in mainland China may 
continue beyond the close of the global cohort, to include approximately an additional 20 
randomized participants in the mainland China cohort. The mainland China cohort is defined 
as all participants from sites in mainland China randomized into the study. A participant 
randomized in the mainland China cohort prior to the last participant randomized in the global 
cohort will be included in both the global and mainland China cohorts. A participant 
randomized in mainland China after the last participant was randomized in the global cohort 
will be included only in the mainland China cohort. 
Note: "Enrolled" means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
but are not randomly assigned in the study, are considered “screen failures”, unless otherwise 
specified by the protocol.  
Intervention Groups and Duration: Participants will be randomized in a 1:1 ratio to one of 
the following intervention groups: 
• 
Arm 1: Dato-DXd (6 mg/kg IV on Day 1, Q3W) 
• 
Arm 2: ICC: 
− Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W); choice between 
the 2 doses will be determined by standard institutional practice. 
− Gemcitabine (1000 mg/m2 IV on Day 1 and Day 8, Q3W) 

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− Eribulin mesylate (1.4 mg/m2 IV on Days 1 and 8, Q3W) 
− Vinorelbine (25 mg/m2 IV on Days 1 and 8, Q3W) 
Randomization will be stratified by the following prognostic and/or predictive factors: 
• 
Number of previous lines of chemotherapy (1 versus 2) 
• 
Geographic region (Region 1 [US, Canada, Europe] versus Region 2 [Rest of World]) 
• 
Prior use of CDK4/6 inhibitor (Yes versus No) 
A 50% cap will be applied to participants who have had 2 prior lines of chemotherapy in the 
inoperable/metastatic setting, while a 49% cap will be applied to participants who have not 
received prior CDK4/6 inhibitor therapy. 
All participants will receive study intervention until Investigator-defined disease progression 
according to RECIST 1.1, or until unacceptable toxicity, withdrawal of consent, or another 
criterion for discontinuation is met. Continued treatment with the same study drug post-
progression may be allowed, based on prior discussion with study physician on case-by-case 
basis. No crossover between study treatment arms will be allowed.  
Follow-up of participants post discontinuation of study intervention 
After study intervention discontinuation, all participants will undergo an end-of-treatment visit 
(to be conducted +7 days of the decision to discontinue treatment) and will be followed up for 
safety assessments 28 (+7) days after their last dose of study intervention (ie, the safety 
follow-up visit). If the date of discontinuation is over 35 days from last study intervention 
administration, then the EoT assessments can also function as the Safety Follow-up visit. 
Participants who have discontinued study intervention in the absence of RECIST 1.1-defined 
radiological progression (by investigator assessment) will be followed up with tumor 
assessments according to the Schedule of Activities (SoA) until RECIST 1.1-defined PD (as 
assessed by the Investigator) or death regardless of whether or not the participant started a 
subsequent anticancer therapy, unless they have withdrawn all consent to study related 
assessments. Following disease progression, 1 additional follow-up scan should also be 
performed as per imaging schedule (ie, either 6 weeks or 9 weeks later). In the event the 
investigator identified progression does not match with the BICR evaluation, this additional 
scan may identify progression by BICR. 
In addition, all participants will be followed up for survival status after intervention 
discontinuation every 3 months (±14 days) from the date of the date of the Safety Follow-up 
Visit until death, withdrawal of consent, or the end of the study (ie, progression/survival 
follow-up), as per the SoA. Participants will be followed up for time to second progression or 
death (PFS2) and subsequent anticancer therapy use after intervention discontinuation every 

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3 months (±14 days) from the date of randomization until death, withdrawal of consent, or the 
end of the study (ie, progression/survival follow-up), as per SoA. The study may continue 
monitoring participants for OS up to the scheduled final analysis, beyond planned interim 
analyses, to provide more refined estimates of treatment effects for survival. 
See Section 6.7 for a description of assessments following study DCOs. 
Independent Data Monitoring Committee (IDMC): An IDMC comprised of independent 
experts will be convened to review unblinded safety data and make recommendations to 
continue, amend, or stop the study based on safety findings. In addition, the IDMC may be 
requested to review efficacy data. For the interim analyses, the IDMC will review unblinded 
interim data and inform the Sponsor whether the interim boundaries specified in Section 9.5 
are crossed. Full details of the IDMC procedures, processes, and interim analyses can be 
found in the IDMC Charter. 
Statistical methods 
The study is sized for dual primary endpoints to characterize the PFS and OS benefit of 
Dato-DXd versus ICC in intent-to-treat (ITT) population. This comprises all participants 
randomized into the study, excluding participants randomized in mainland China after the 
global cohort last participant randomized, and will be analyzed according to randomized 
treatment regardless of the treatment received (ITT principle). The study will be considered 
positive (a success) if either the PFS analysis results and/or the OS analysis results are 
statistically significant. 
The primary, final analysis of PFS will be performed when approximately 419 PFS BICR 
events occur, approximately 2 months after the last participant is randomized in the study; 419 
PFS BICR events from the ITT population across the Dato-DXd and ICC treatment groups 
will represent 60% maturity of data. Assuming the true PFS hazard ratio is 0.55 for Dato-DXd 
versus ICC, the study will have a greater than 99% power to demonstrate statistical 
significance at the 1.0% level (using a 2-sided test). This assumes median PFS times of 
4.7 months and 8.5 months in ICC and Dato-DXd, respectively when the PFS times are 
exponentially distributed. The smallest treatment difference that could be statistically 
significant at the final analysis is a hazard ratio of 0.775.  
The final analysis of OS will be performed when approximately 444 OS events have occurred 
across the Dato-DXd and ICC treatment groups (63% maturity). Assuming the true OS hazard 
ratio is 0.75 for Dato-DXd versus ICC, the study will have 85% power to demonstrate 
statistical significance at the 5.0% level (using a 2-sided test). This assumes the PFS primary 
analysis crosses the efficacy threshold, and allowing 2 interim analyses to be conducted at 
information fractions of approximately 40% and 80% of the target events, respectively (per 
the O’Brien and Fleming approach). The smallest treatment difference that could be 

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statistically significant at the final analysis is a hazard ratio of 0.824. If the PFS primary 
analysis does not cross the efficacy threshold, the OS analysis will have 83% power to 
demonstrate statistical significance at the 4.0% level (using a 2-sided test). The smallest 
treatment difference that could be statistically significant at the final analysis is a hazard ratio 
of 0.817. Calculations assume median OS times of 19.0 months and 25.3 months in ICC and 
Dato-DXd, respectively when the survival times are exponentially distributed.  
The study may continue monitoring participants for OS up to the scheduled final analysis, 
beyond planned interim analyses, to provide more refined estimates of treatment effects for 
survival.  
A nonuniform accrual of participants (with k = 1.5) is assumed when estimating the analysis 
times. The total proportion of participants randomized at time t [t ≤ 19 months] following the 
start of the study is assumed to be (t/19)k.  
Hypotheses will be tested using a multiple testing procedure (MTP) with an alpha-exhaustive 
recycling strategy. To strongly control the familywise type I error rate at the 5.0% level 
(2-sided), an alpha level of 1.0% will be allocated to the PFS dual primary analysis and the 
remaining 4.0% alpha level will be allocated to the OS analyses. If the PFS dual primary 
analysis crosses the efficacy threshold, the 1.0% type I error allocated to the PFS endpoint will 
be reallocated to the OS endpoint for a total 2-sided type I error of 5.0%.  
Safety data will be summarized descriptively and will not be formally analyzed unless 
otherwise specified. 
1.2 
Schema  
The study schema is presented in Figure 1.

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Figure 1 
Study Design  
 
 

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1.3 
Schedule of Activities  
The procedures for this study are presented in the SoA (Table 1). Assessments in the event of 
suspected ILD/pneumonitis are presented separately in Table 2. 
 

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g 
Includes ocular history (since prior ocular events may predispose to or cause dry eye/keratitis), as well as history, type and frequency of tobacco use, e-cigarette use, vaping 
(including dates).  
h 
Triplicate ECGs will be taken at screening and EoT. Triplicate ECGs will be taken in close succession, while in a supine/semi-recumbent position. Single ECGs should be 
taken during treatment as clinically indicated.  
i 
The same test must be used for the participant throughout the study. ECHO/MUGA not required at EoT unless clinically indicated. 
j 
Vital signs and SpO2 should be performed both before and after study intervention administration (where applicable), and as clinically indicated during treatment. Participant 
should remain at the site for at least 1-hour post-infusion (where applicable) for close observation for IRRs.  
k 
Pulmonary function tests at a minimum should include spirometry (minimum requirement of: FVC [L], FVC % predicted, FEV1 [L], FEV1 % predicted, FEV1/FVC %). 
DLCO will be performed (when feasible); however, for participants with prior severe and/or clinically significant pulmonary disorders, DLCO is a requirement. 
l 
Ophthalmologic assessments (by a licensed eye care provider) including but not limited to visual acuity testing, fluorescein staining, intraocular pressure, slit-lamp 
examination and fundoscopy will be performed at screening, and then every 3 cycles from C1D1 onwards (eg, C4D1, C7D1, C10D1 etc) within 14 days prior to scheduled 
cycle Day 1 visit (but not after the scheduled visit), in addition to as clinically indicated while on trial, and at EoT. (see Section 8.2.5.5 for additional information). Please 
refer to the Dato-DXd Site Ophthalmologic Assessment Manual for further details. 
m 
A daily Oral Care Protocol (OCP) will be started before study drug initiation, and it must be maintained throughout the study until 28 days after last dose. An oral care kit will 
be provided at study enrolment and monthly thereafter until the safety FU visit, which will include a toothbrush, toothpaste, dental floss, and an alcohol-free mouthwash. An oral care plan 
participant information guide should be given to each randomized participant before study drug initiation. Strongly consider initiation of dexamethasone oral solution (see Section 
8.2.5.6 for details). 
n 
Data collection may be conducted by phone if not tied to a visit. 
o 
All AEs occurring after the participant signs the ICF and up to 28 (+7) days after the last dose of study drug (ie, the safety follow-up period), whether observed by the 
Investigator or reported by the participant, will be recorded on the AE eCRF page (see Section 8.3 for additional information). 
p 
Negative serum pregnancy test performed within 72 hours before study intervention at screening and repeat urine or serum pregnancy tests (per institutional guideline) 
performed within 72 hours before infusion of each cycle and at EoT and during safety follow-up. A positive urine pregnancy test result must immediately be confirmed using 
a serum test. 
q 
Prior HIV serology (anti-HIV with or without HIV RNA, as appropriate), hepatitis B serology (HBsAg, anti-HBs, and anti-HBc with or without HBV DNA, as appropriate), 
and hepatitis C serology (anti-HCV antibody with or without HCV RNA, as appropriate) testing results can be used if performed within 120 days before enrolment. In this 
case, there is no need for a repeat test during the 28-day screening period. 
r 
Participants must be tested for HIV if acceptable by local regulations or an IRB/EC. If an HIV infection meets the criteria outlined in Section 5.2, monitoring of the 
participants’ viral RNA load and CD4+ cell count should be monitored per local SoC (eg, every 3 months). 
s 
To be performed within 8 hours prior to the start of Dato-DXd infusion, except for the EoT visit, during which samples can be collected anytime during this visit.  
t 
To be performed within 1 hour after the end of Dato-DXd infusion. 
u 
An additional PK sample should be taken 5 hours (±1 hour) from the start of Dato-DXd infusion on C1D1. 
v 
Not applicable to participants in mainland China.  
w 
The sample for genetic research will be obtained at Day 1 pre-dose. If, for any reason, the sample is not drawn at Day 1, it may be taken at any visit until the last study visit. 
Only 1 sample should be collected per participant for genetics during the study. 

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x 
The baseline tumor assessment must be performed within 28 days before randomization and as close as possible to the start of treatment. The assessment should include CT 
(preferred) or MRI, with IV contrast, of the chest, abdomen (including the entire liver and both adrenal glands), and pelvis. Any other areas of disease involvement should be 
additionally imaged at screening based on known metastasis sites or by the signs and symptoms of individual participants. The follow-up assessments should include 
CT/MRI with IV contrast of the chest, abdomen and pelvis and any other area where disease was identified at baseline. The assessment must continue until 1 visit (per 
original schedule) after radiographic disease progression (as assessed by Investigator), whether or not the participant is still on treatment. The same imaging technique (CT 
or MRI) used to characterize each identified and reported lesion at baseline will be used in the subsequent tumor assessments. 
y 
Participants with brain metastases at baseline must have the lesions recorded as part of the RECIST assessment and must have a brain scan performed per the tumor imaging 
schedule until radiological progression per RECIST. For participants in whom CNS metastases are first discovered at the time of screening, the treating investigator should 
consider delay of randomization and study intervention to document stability of CNS metastases with repeat imaging at least 4 weeks later (in which case, repeat of all 
screening activity may be required). 
z 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-ray should be recorded as NTLs and followed by the same method (CT, MRI, 
or X-ray), as indicated in the SoA. 
aa 
The site should complete the “Hospital Admission (HOSPAD)” form at the site at every scheduled clinic visit up to and including the post study treatment discontinuation 
follow up visit. If the participant discontinues study treatment for reasons other than RECIST progression, the HOSPAD form should continue to be administered until 
progression has been confirmed. Study mandated visits should not be included as a hospital admission. 
bb 
Only applicable to participants who are required to attend study visits on Day 8 of each cycle (ie, those randomized to receive Investigators Choice of Chemotherapy which 
are administered by IV infusion). 
Note: All assessments on treatment days are to be performed prior to study intervention administration, unless otherwise indicated. Following the DCO for the primary analysis, 
PK assessments will be discontinued. Data collection following final study analysis until the end of the study is described in Section 8.

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Table 2 
Assessments if ILD/Pneumonitis is Suspected during the Intervention 
Period 
Procedure 
Details in CSP Section 
ILD/pneumonitis investigation 
Section 8.2.5.3 
Detailed past medical history and concomitant medications 
Section 8.2.5.3 
Physical examination, including auscultation of lung field 
Section 8.2.5.3 
HRCT of the chest if feasible (otherwise non-contrast chest CT is acceptable) 
Section 8.2.5.3 
Arterial blood gases if clinically indicated 
Section 8.2.5.3 
Pulmonary function tests and pulse oximetry (SpO2) 
Sections 8.2.5.2 and 8.2.5.3 
Bronchoscopy and bronchoalveolar lavage should be considered if clinically 
indicated and feasible 
Sections 8.2.5.3  
Pulmonologist consultation (infectious diseases consultation, as clinically 
indicated) 
Section 8.2.5.3 
Blood culture, complete blood count, and differential white blood cell count; 
other blood tests could be considered as needed 
Section 8.2.5.3 
Troponin measurements to rule out cardiac etiology 
Section 8.2.5.3 
Additional optional blood sample for plasma exploratory ILD/pneumonitis 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed a 
Sections 8.2.5.3 and 8.6.1 
Additional optional blood sample for serum exploratory ILD/pneumonitis 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed a 
Sections 8.2.5.3 and 8.6.1 
Note: Other tests could be considered, as needed (eg, COVID-19 test). 
a 
Whenever ECGs, vital signs and blood draws are scheduled for the same day, the assessments should occur 
in the following order: ECG, vital signs and then blood draws. The timing of the ECG and vital signs 
assessments must allow for the blood draw (eg, PK blood sample) to occur at the scheduled time points 
specified in Table 1. Pulse oximetry (SpO2) will be performed at the same time as vital signs. 
2 
INTRODUCTION  
Datopotamab deruxtecan (Dato-DXd, DS-1062a) is an antibody-drug conjugate (ADC) that 
comprises a recombinant humanized anti-TROP2 IgG1 monoclonal antibody, which is 
covalently conjugated to a drug linker via thioether bonds. 
Antibody-drug conjugates are targeted anticancer medicines that deliver cytotoxic 
chemotherapy (‘payload’) to cancer cells via a linker attached to a monoclonal antibody that 
binds to a specific target expressed on cancer cells. Antibody-drug conjugates provide a 
unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue.  
Dato-DXd binds to trophoblast cell surface protein 2 (TROP2), also known as 
tumor-associated calcium signal transducer 2. Dato-DXd is in development as a candidate 
therapy for cancer. 

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2.1 
Study Rationale  
Single agent chemotherapy remains the cornerstone of therapy for patients with HR-positive, 
HER2-negative metastatic breast cancer who have exhausted endocrine therapy options. 
However, patient prognosis is poor, and durable antineoplastic therapy options are necessary 
to improve outcomes in this patient population (see Section 2.2.1 for further details). 
TROP2 is a type I transmembrane glycoprotein originally identified in human trophoblast 
cells (Fornaro et al 1995, Alberti et al 1992, Lipinski et al 1981). TROP2 is highly expressed 
in a number of normal tissues and several cancers and has been recognized as a novel 
promising antigen for ADCs due to its high expression in breast tumors (Pau Ni et al 2010). 
Furthermore, increased TROP2 mRNA in breast cancer has been shown to be a predictor of 
lymph node involvement, distant metastasis, and poor OS (Zhao et al 2018).  
The potential for TROP2 ADCs in the treatment of breast cancer has been demonstrated with 
the FDA approval of sacituzumab govitecan (TRODELVY; IMMU-132; Gilead Sciences, 
Inc.) for patients with locally advanced and metastatic TNBC who have received at least 
2 prior systemic therapies, at least one of them for metastatic disease. Most recent data in 
HR-positive, HER2-negative metastatic breast cancer population treated with sacituzumab 
govitecan, who have received at least 2 prior lines of therapy, with a median follow-up of 
11.5 months, has shown that the ORR was 31.5% (95% CI: 19.5, 45.6; 17 partial responses); 
median DoR was 8.7 months (95% CI: 3.7, 12.7), median PFS was 5.5 months (95% CI: 3.6, 
7.6), and median OS was 12 months (95% CI: 9.0, 18.2) (Kalinsky et al 2020). Of note, 
significant toxicities in sacituzumab govitecan treated participants have been reported, which 
include myelosuppression and diarrhea (Bardia et al 2020). Furthermore, the efficacy of ADCs 
in breast cancer has been demonstrated from the approval of ENHERTU (T-DXd) and 
KADCYLA (T-DM1), two HER2-targeted ADCs indicated for HER2-positive breast cancer 
(Modi et al 2020, Von Minckwitz et al 2019). 
Dato-DXd is a TROP2 ADC (administered via IV infusion, Q3W) that binds to TROP2, is 
internalized, and after enzymatic processing, the topoisomerase I inhibitor, MAAA-1181a, is 
released, leading to inhibition of tumor growth, DNA damage, and apoptosis of target cells. 
The cytotoxic payload of Dato-DXd is the same as T-DXd. Preclinical data has demonstrated 
that Dato-DXd exerts specific cell growth inhibitory activity against TROP2-expressing cells, 
but it does not have cell growth inhibitory against TROP2-negative cells.  
Within the Dato-DXd clinical development program, preliminary data supporting the use of 
Dato-DXd in participants with HR-positive, HER2-negative breast cancer are available from 
an ongoing phase 1 FIH study, TROPION-PanTumor01 (NCT03401385), which is evaluating 
escalating doses of Dato-DXd (0.27 mg/kg to 10 mg/kg) in participants with advanced 
NSCLC and TNBC, relapsed or refractory to SoC therapy. These data have demonstrated 
highly encouraging efficacy across dose groups, with tumor responses observed at doses of 4, 

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6, and 8 mg/kg and an acceptable and manageable toxicity profile (see Section 2.2.2.1). An 
additional cohort of participants with HR-positive, HER2-negative breast cancer is currently 
recruiting as of March 2021. 
Given the biological rationale and encouraging preliminary safety and efficacy data obtained 
from the TROPION-PanTumor01 study, the current study is designed to provide a robust and 
detailed understanding of the efficacy and safety of Dato-DXd when compared with 
Investigator’s choice of standard-of-care single-agent chemotherapy (eribulin, capecitabine, 
vinorelbine, or gemcitabine; henceforth referred to as ICC) in participants with inoperable or 
metastatic HR-positive, HER2-negative breast cancer who have been treated with one or two 
prior lines of systemic chemotherapy, for which an unmet medical need remains. 
2.2 
Background  
2.2.1 
HR-positive, HER2-negative, inoperable/metastatic breast cancer  
Breast cancer is the most common cancer in the world, with an estimated 2.2 million new 
cases in 2020 globally (11.7% of all new cancers). Breast cancer is also the fifth most 
common cause of death from cancer, with an estimated 684000 deaths in 2020 (Sung et al 
2021). In Europe, an estimated 531000 patients were diagnosed with breast cancer in 2020, 
and 141000 died from the disease. Despite advances in the diagnosis and treatment of breast 
cancer, around 6% of women diagnosed with breast cancer in the US have metastatic disease 
at time of diagnosis, and up to 30% of women with early-stage non-metastatic breast cancer 
will develop metastatic disease (O'Shaughnessy 2005). Although treatable, metastatic breast 
cancer remains virtually incurable, with a median survival of approximately 3 years and a 
5-year survival rate of approximately 25% (Cardoso et al 2018).  
Currently, clinical practice typically uses a surrogate classification of three breast cancer 
subtypes, based on molecular characteristics: HER2-positive, HR-positive but HER2-negative, 
and triple-negative. Tumors expressing ER and/or PR are considered HR-positive breast 
cancers, whereas tumors that do not express ER, PR or HER2 are defined as TNBC (Harbeck 
et al 2019). Approximately 70% of all breast cancers are HR-positive, HER2-negative 
(Howlader et al 2014).  
In patients with metastatic HR-positive, HER2-negative breast cancer, the preferred initial 
treatment of choice is endocrine therapy, given either alone or in combination with targeted 
therapies such as CDK4/6 inhibitors, PI3-K, and mTOR inhibitors (Matutino et al 2018, André 
et al 2019). Within these, CDK4/6 as a class has shown to improve both PFS and OS in a 
meta-analysis (Cardoso et al 2018); however, the optimal sequence and integration of the 
agents is not fully established and is largely determined by geographic availability, which 
treatments were previously administered, the response obtained, and individual patient and 
disease characteristics. 

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In patients with metastatic HR-positive, HER2-negative breast cancer, who have exhausted or 
are not suitable for endocrine therapy, first-line chemotherapy is the SoC, with sequential 
single-agent chemotherapy (such as eribulin, capecitabine, gemcitabine, vinorelbine) generally 
preferred over combination therapy due to lack of consistent OS benefit and poor tolerability 
with combination therapy (Cardoso et al 2020, NCCN Guidelines 2020). 
The following baseline clinico-pathological characteristics/factors could be clinically relevant 
to the targeted study population of interest for this study:  
• Proportion of patients with 1 versus 2 prior lines of chemotherapy in the metastatic or 
inoperable setting  
• Prior CDK4/6 inhibitor use (yes versus no) 
• History of brain metastasis (yes versus no). 
These and other factors may be recorded in IRT and could be included as part of routine 
monitoring throughout enrolment of the study. Unexpected variations could be evaluated by 
the Sponsor (see Appendix A). 
2.2.1.1 
Unmet medical need  
The SoC of single agent chemotherapy in the HR-positive, HER2-negative metastatic breast 
cancer population has led to reported response rates of approximately 23%, a median PFS of 
7 to 10 months, and a median OS of 26 to 36 months (Jerusalem et al 2018, Kaufman et al 
2015, Twelves et al 2016). After two prior lines of chemotherapy, a median PFS of between 4 
and 5 months and a median OS of between 14 and 24 months has been reported (Twelves et al 
2016, Brufsky 2011, Miller et al 2005, Sparano et al 2010, Barrios 2010, Thomas et al 2007). 
Data after three lines of chemotherapy report a median PFS of approximately 3 to 4 months 
and median OS of between 11 to 16 months (Cortes et al 2011, Yardley et al 2013, Martín et al 
2007, Yuan et al 2019). These data indicate that patients who are not suitable for, or who have 
exhausted, endocrine treatment options have an increasingly poor prognosis, with the greatest 
unmet medical need arising in patients who have received two or three prior lines of 
chemotherapy, for whom median survival is currently less than 2 years. 
Chemotherapy is also associated with significant toxicities, including hematologic adverse 
effects, gastrointestinal toxicities including diarrhea, nausea, vomiting, alopecia, and skin 
reactions (Gradishar et al 2005, Miller et al 2007, Piccart-Gebhart et al 2008), which can have 
a significant impact on patient quality of life. Consequently, new and novel treatments for 
participants with HR-positive, HER2-negative advanced breast cancer are still needed to 
improve prognosis, control disease and prevent symptoms while minimizing toxicity, and 
therefore represents an area of considerable unmet medical need. A new class of therapy with 
better efficacy and relatively fewer side effects would therefore be a preferred option in this 

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treatment setting, to offer an alternative after traditional standard chemotherapies. 
2.2.2 
Dato-DXd  
Dato-DXd is being co-developed by Daiichi Sankyo and AstraZeneca as an anticancer agent.  
To date, clinical (preliminary safety and efficacy) data is currently available from one ongoing 
study (TROPION-PanTumor01; sponsored by Daiichi Sankyo). A summary of recent data 
from this study is presented in Section 2.2.2.1. Please refer to the Dato-DXd IB for a list of all 
studies in the Dato-DXd clinical development program, including participant exposure.  
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of Dato-DXd is provided in the IB. 
2.2.2.1 
TROPION-PanTumor01 study  
This ongoing Phase I FIH study evaluated escalating doses (0.27 to 10 mg/kg) of Dato-DXd in 
advanced solid tumors in participants with unresectable advanced NSCLC, and is currently in 
the dose expansion phase evaluating selected doses of Dato-DXd in participants with NSCLC, 
TNBC, and ER-positive, HER2-negative breast cancer who have been refractory to or 
relapsed on standard treatment or for which no standard treatment is available. 
At the efficacy DCO date, 30 July 2021, preliminary efficacy data from the ongoing 
DS1062-A-J101 study were available. A total of 254 participants were evaluable for response 
assessments (210 with NSCLC and 44 with TNBC), defined as participants who received at 
least 1 dose of Dato-DXd and had pre-treatment and at least 1 post-treatment tumor 
assessment or discontinued from study drug. For participants with TNBC, the DCR was 
76.2% (13 PRs and 16 SDs in 42 participants) in the 6 mg/kg dose group and 100% (1 PR and 
1 SD in 2 participants) in the 8 mg/kg dose group. 
Preliminary safety summary, as of 30 July 2021, in participants with breast cancer (TNBC and 
HR+/HER2-breast cancer) are summarized below. A total of 75 (93.8%) participants 
experienced at least 1 TEAE. The most frequently (≥ 15% of participants) reported TEAEs 
were nausea (45 [56.3%] participants), stomatitis (37 [46.3%] participants), alopecia 
(24 [30.0%] participants), fatigue (24 [30.0%] participants), vomiting (22 [27.5%] 
participants), constipation (16 [20.0%] participants), mucosal inflammation (18 [22.5%] 
participants), and headache (17 [21.3%] participants). 
A total of 28 (35.0%) participants experienced ≥ Grade 3 TEAEs. The most commonly 
(> 2.5% of participants) reported ≥Grade 3 events by investigator-reported PT were 
lymphocyte count decreased (4 [5.0%] participants), stomatitis (4 [5.0%] participants), fatigue 
(3 [3.8%] participants), and lymphopenia (3 [3.8%] participants). A total of 1 (1.3%) 
participant had TEAEs associated with study treatment discontinuation due to 
investigator-reported PT of pneumonitis. A total of 1 (1.3%) participant experienced TEAEs 

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biopsy, which will provide real-time next-generation sequencing results from the 
FoundationOne®CDx, that may help guide next treatment options. 
Overall, participants enrolling onto this study will have a 1:1 chance of the receiving either the 
experimental drug Dato-DXd, or a standard chemotherapy agent. All participants will be 
contributing to the process of developing new therapies in an area of great unmet medical 
need. 
2.3.3 Overall Benefit: Risk Conclusion  
There is an unmet medical need for efficacious and safe therapies in treatment of HR-positive, 
HER2-negative inoperable or metastatic breast cancer in order to improve clinical outcomes. 
The extensive expression of TROP2 in breast cancers and the proof-of-concept shown by 
sacituzumab govitecan in HR-positive, HER2-negative (and TNBC) metastatic breast cancer 
has demonstrated the strong rationale of using an anti-TROP2-ADC in the HR-positive, 
HER2-negative population (Bardia et al 2021, Kalinsky et al 2020). 
Preliminary results from the TNBC cohort of the TROPION-PanTumor01 study have shown 
promising efficacy of Dato-DXd at a dose of 6 mg/kg Q3W and support the further evaluation 
of Dato-DXd in the HR-positive, HER2-negative breast cancer population. In this cohort, the 
most common TEAEs were nausea, stomatitis, alopecia, fatigue, vomiting, constipation, 
mucosal inflammation, and headache. The most common Grade ≥ 3 TEAEs were lymphocyte 
count decreased, stomatitis, fatigue, and lymphopenia. One participant had TEAEs associated 
with study treatment discontinuation and one participant experienced TEAEs associated with 
an outcome of death. 
The 2 most relevant risks considered for the benefit/risk assessment are the important 
identified risk of ILD/pneumonitis and the identified risk of IRR. Both of these risks can be 
fatal. Several measures have been put into place within the CSP to mitigate the incidence of 
pulmonary toxicities, including eligibility criteria that prohibit participants with pre-existing 
pulmonary co-morbidities from entering the study. In addition, baseline pulmonary function 
tests will be performed for all participants. Participants will be monitored closely throughout 
the study and clinical and laboratory assessments will be performed before every cycle. 
Toxicity Management Guidelines are also provided to assist with the management of the most 
commonly reported AEs and AESIs (see the Annex document to this CSP).  
Consequently, compared to the safety profile of SoC chemotherapies, Dato-DXd is a potent 
anticancer therapy with the potential to provide an improved meaningful clinical benefit and a 
more favorable safety profile. Furthermore, the long half-life of Dato-DXd also enables a 
single IV, Q3W regimen, providing convenience to patients. It is therefore of key importance 
to evaluate the role of Dato-DXd in the HR-positive, HER2-negative inoperable or metastatic 
breast cancer population who have had progression of disease on 1 or 2 lines of chemotherapy, 

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and considering the measures to minimize risks to participants, the benefit/risk assessment 
supports the proposed study.  

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3 
OBJECTIVES AND ENDPOINTS  
Table 4 
Objectives and Endpoints 
Objectives 
Endpoints 
Dual Primary 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR. 
• PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by BICR, or 
death due to any cause.  
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinically progresses prior to RECIST 1.1.  
The measure of interest is the hazard ratio of PFS. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of OS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• OS is defined as time from randomization until the date of 
death due to any cause.  
The comparison will include all randomized participants as 
randomized, regardless of whether the participant withdraws 
from therapy or receives another anticancer therapy. 
The measure of interest is the hazard ratio of OS. 
Secondary 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of ORR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment. 
• ORR is defined as the proportion of participants who have a 
confirmed CR or PR, as determined by the 
BICR/Investigator assessment, per RECIST 1.1. 
The analysis will include all randomized participants as 
randomized.  
Data obtained from randomization up until  
progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of ORR, 
regardless of whether the participant withdraws from therapy. 
Participants who go off treatment without a response or 
progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR. 
The measure of interest is the odds ratio of the ORR. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DoR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• DoR is defined as the time from the date of first documented 
confirmed response until date of documented progression 
per RECIST 1.1, as assessed by BICR/Investigator 
assessment or death due to any cause. 
The analysis will include all randomized participants as 
randomized who have a confirmed response, regardless of 
whether the participant withdraws from therapy, receives 
another anticancer therapy or clinically progresses prior to 
RECIST 1.1 progression. 
The measure of interest is the median of DoR. 

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Objectives 
Endpoints 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per investigator assessment. 
• PFS is defined as time from randomization until 
progression per RECIST 1.1, as assessed by investigator 
assessment, or death due to any cause.  
The analysis will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from therapy, receives another anticancer therapy, or 
clinically progresses prior to RECIST 1.1. 
The measure of interest is the hazard ratio of PFS. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of DCR in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer, 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting, per BICR and per investigator 
assessment. 
• DCR at 12 weeks is defined as the percentage of 
participants who have a confirmed CR or PR or who have 
SD, per RECIST 1.1, as assessed BICR/per investigator 
assessment and derived from the raw tumor data for at least 
11 weeks after randomization.  
Data obtained from randomization up until progression, or the 
last evaluable assessment in the absence of progression, will 
be included in the assessment of DCR, regardless of whether 
the participant withdraws from therapy. Participants who 
receive a subsequent therapy prior to week 11 will not be 
considered to have disease control in the analysis. 
The analysis will include all randomized participants as 
randomized. 
The measure of interest is the odds ratio of the DCR. 
To assess pain in participants treated with 
Dato-DXd compared to ICC. 
• TTD in pain as measured by the pain scale from EORTC 
QLQ-C30 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants.  
The measure of interest is the hazard ratio of TTD in pain.  
To assess physical functioning in 
participants treated with Dato-DXd 
compared to ICC. 
• TTD in physical functioning as measured by the physical 
functioning scale from EORTC QLQ-C30 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants.  
The measure of interest is the hazard ratio of TTD in physical 
functioning.  
To assess global health status/quality of life 
(GHS/QoL) in participants treated with 
Dato-DXd compared to ICC. 
• TTD in GHS/QoL as measured by the GHS/QoL scale from 
EORTC QLQ-C30 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change from 
baseline that reaches a clinically meaningful deterioration 
threshold. The analysis will include all randomized 
participants.  
The measure of interest is the hazard ratio of TTD in 
GHS/QoL. 

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Objectives 
Endpoints 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TFST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• TFST is defined as the time from randomization until the 
start date of the first subsequent anticancer therapy after 
discontinuation of randomized treatment, or death due to 
any cause. 
The analysis will include all randomized participants as 
randomized, regardless of progression status. 
The measure of interest is the hazard ratio of TFST. 
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of TSST in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• TSST is defined as the time from randomization to until the 
start date of the second subsequent anticancer therapy after 
discontinuation of first subsequent treatment, or death due to 
any cause. 
The analysis will include all randomized participants as 
randomized, regardless of progression status on study 
treatment or first subsequent treatment. 
The measure of interest is the hazard ratio of TSST.  
To demonstrate the superiority of Dato-DXd 
compared to ICC by assessment of PFS2 in 
participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer 
who have been treated with 1 or 2 lines of 
chemotherapy in the inoperable/metastatic 
setting. 
• PFS2 will be defined as the time from the randomization to 
the earliest of the progression event (following the initial 
progression), subsequent to first subsequent therapy, or 
death. The date of second progression will be recorded by 
the Investigator in the eCRF and defined according to local 
standard clinical practice. 
The comparison will include all randomized participants as 
randomized regardless of whether the participant withdraws 
from subsequent therapy and regardless of missed visits. 
The measure of interest is the hazard ratio of PFS2. 
To assess the PK of Dato-DXd 6mg/kg IV 
Q3W. 
• Plasma concentrations of Dato-DXd, total anti-TROP2 
antibody, and MAAA-1181a (payload).  
To investigate the immunogenicity of 
Dato-DXd 6mg/kg IV Q3W. 
• Presence of ADA. 
Safety 
To assess the safety and tolerability profile 
of Dato-DXd compared to ICC. 
Safety and tolerability will be evaluated in terms of adverse 
events (graded by CTCAE version 5.0), and also in terms of: 
• ECOG PS 
• Vital signs, body weight, physical examination  
• Clinical chemistry, hematology, and urinalysis assessments 
• ECG, ECHO/MUGA and Ophthalmologic assessments 
Exploratory 
To assess participant-reported symptomatic 
AEs and treatment tolerability. 
Proportion of participants experiencing different levels of 
symptomatic AEs as measured by selected items from the 
PRO-CTCAE and EORTC Item Library (IL; ie, EORTC 
IL117) and reporting different levels of overall tolerability as 
measured by the PGI-TT. 
The analysis will include all dosed participants.  
The measure of interest will be proportion of participants 
reporting different levels of symptomatic AEs and overall 
tolerability. 

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Objectives 
Endpoints 
To assess participant-reported global 
impression of the severity of overall cancer 
symptoms. 
Proportion of participants reporting different levels of global 
impression of the severity of overall cancer symptoms as 
measured by PGIS. 
The analysis will include all randomized participants. 
The measure of interest will be proportion of participants 
reporting different levels of global impression of the severity 
of overall cancer symptoms. 
To assess participant-reported global 
impression of change in health status. 
Proportion of participants reporting different levels of global 
impression of change in health status as measured by PGIC. 
The analysis will include all randomized participants. 
The measure of interest will be proportion of participants 
reporting different levels of global impression of change in 
health status.  
To assess participant-reported symptoms, 
functioning and health-related QoL. 
• TTD in fatigue and other symptoms as measured by EORTC 
QLQ-C30 
• TTD in other functioning as measured by EORTC 
QLQ-C30 
• Change from baseline of symptom, functioning and 
GHS/QoL scores as measured by EORTC QLQ-C30  
The analysis will include all randomized participants.  
The measure of interest will be hazard ratio of TTD in fatigue 
and other symptoms, TTD in other functioning, and mean 
change from baseline of symptom, functioning and GHS/QoL 
scores.  
To assess breast and arm symptoms in 
participants treated with Dato-DXd 
compared to ICC. 
• TTD in breast symptoms as measured by the breast 
symptoms scale from EORTC QLQ-BR45/IL116 
• TTD in arm symptoms as measured by the arm symptoms 
scale from EORTC QLQ-BR45/IL116 
TTD is defined as time from the date of randomization to the 
date of deterioration. Deterioration is defined as change 
from baseline that reaches a clinically meaningful 
deterioration threshold. The analysis will include all 
randomized participants.  
• The measure of interest is the hazard ratio of TTD in breast 
symptoms/arm symptoms. 
To assess participant-reported health status. 
• VAS score, its change from baseline and 5-dimension scores 
as measured by EQ-5D-5L 
The analysis will include all randomized participants.  
The measure of interest will be mean and mean change from 
baseline of VAS score, and proportion of participants 
reporting different levels of each of 5-dimension scores.  
Association of TROP2 or other tumor 
derived biomarkers with response and 
tolerability to Dato-DXd and ICC. a 
 
• Correlation of biomarkers with clinical response (BoR, 
DoR, PFS, OS and other relevant efficacy endpoints) and/or 
development of cancer  
• Correlation of biomarkers with safety and tolerability 
endpoints 
Analysis may include, but is not limited to, the analysis of 
tumor biomarkers which include DNA, RNA, proteins or 
metabolite analysis 

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Objectives 
Endpoints 
Association of exploratory biomarkers in 
tumor, plasma, whole blood, or serum 
collected before, during treatment or at 
disease progression with disease status 
and/or response and tolerability to 
Dato-DXd. a  
• Correlation of biomarkers with clinical response (BoR, 
DoR, PFS, OS and other relevant efficacy endpoints) and/or 
development of cancer  
• Correlation of biomarkers with safety and tolerability 
endpoints 
Analysis may include, but is not limited to, the analysis of 
tumor biomarkers which include DNA, RNA, proteins or 
metabolite analysis 
Assessment of ctDNA mutational profile 
and dynamic changes as an indicator for 
early response and/or relapse on Dato-DXd, 
and assessment of molecular and genomic 
determinants of response to Dato-DXd in 
tumor and blood. a 
• Assessment of ctDNA levels and mutational status of 
cancer-associated genes in ctDNA, including dynamic 
changes on treatment and correlation with clinical response 
on Dato-DXd and ICC, and correlation of gene expression 
and cancer gene mutational profile with clinical response. 
To explore the impact of treatment and 
disease on health care resource use. 
• The HOSPAD module will be used to collect information on 
key health care resource use beyond study mandated visits. 
a Optional biomarker samples will not be collected in mainland China. 

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4 
STUDY DESIGN  
4.1 
Overall Design  
This is a Phase 3, open-label, randomized study of Dato-DXd versus ICC in participants with 
inoperable or metastatic HR-positive, HER2-negative breast cancer who have been treated 
with one or two prior lines of systemic chemotherapy in the inoperable or metastatic setting. 
For an overview of the study design, see Figure 1. 
Approximately 700 participants will be randomized in a 1:1 ratio to one of 2 intervention 
arms. If required for regulatory submission purposes, the recruitment of participants in 
mainland China may continue beyond the close of the global cohort, to include approximately 
an additional 20 randomized participants in the mainland China cohort. The mainland China 
cohort is defined as all participants from sites in mainland China randomized into the study. A 
participant randomized in the mainland China cohort prior to the last participant randomized 
in the global cohort will be included in both the global and mainland China cohorts. A 
participant randomized in mainland China after the last participant was randomized in the 
global cohort will be included only in the mainland China cohort. 
Randomization will be stratified by the following prognostic and/or predictive factors: 
• Number of previous lines of chemotherapy (1 versus 2) 
• Geographic region (Region 1 [US, Canada, Europe] versus Region 2 [Rest of World]) 
• Prior use of CDK4/6 inhibitor (Yes versus No) 
A 50% cap will be applied to participants who have had 2 prior lines of chemotherapy in the 
inoperable/metastatic setting. 
CDK4/6 inhibitors are being increasingly utilized as part of standard of care for patients with 
HR+ breast cancer. To ensure that majority of participants have received prior CDK4/6 
inhibitor therapy in the HER2 negative, HR-positive population, a cap of 49% will be applied 
to participants who have NOT received prior CDK4/6 inhibitor therapy. 
 
The study intervention arms are:  
• 
Arm 1: Dato-DXd (6 mg/kg IV on Day 1, Q3W) 
• 
Arm 2: ICC: 
− Capecitabine (1000 or 1250 mg/m2 oral BID on Days 1 to 14, Q3W); choice between 
the 2 doses will be determined by standard institutional practice. 
− Gemcitabine (1000 mg/m2 IV on Day 1 and Day 8, Q3W) 
− Eribulin mesylate (1.4 mg/m2 IV on Days 1 and 8, Q3W) 
− Vinorelbine (25 mg/m2 IV on Days 1 and 8, Q3W) 

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Further details of all study interventions are provided in Section 6. All participants will 
receive study intervention until Investigator-defined disease progression according to 
RECIST 1.1, or until unacceptable toxicity, withdrawal of consent, or another criterion for 
discontinuation is met (see Section 7 for further details). Continued treatment with the same 
study drug post-progression may be allowed, based on prior discussion with study physician 
on case-by-case basis. No crossover between study treatment arms will be allowed. 
The study is powered to assess the efficacy of Dato-DXd compared to ICC for the dual 
primary objectives of PFS (per RECIST 1.1, as assessed by BICR) and OS. Other measures of 
efficacy (ORR, DoR, DCR, TFST, TSST, PFS2) and HRQoL will also be evaluated during 
the study, in addition to the safety and tolerability profile of Dato-DXd, PK parameters, and 
immunogenicity. Details of all study objectives and corresponding endpoints are provided in 
Section 3. 
All participants must have available a FFPE tumor sample (block preferred, or minimum of 20 
freshly cut slides), at the time of screening. This can be from either the primary disease setting 
(surgical resection or diagnostic sample), or from a metastatic lesion (excluding bone) for 
tissue-based analysis (including but not restricted/limited to IHC staining of potential 
predictive biomarkers as well as tumor mutational analysis). The mandatory FFPE tumor 
sample submitted for analysis should be obtained as close to the time of diagnosis of 
metastatic or inoperable disease as possible. 
If neither an adequate FFPE block nor the minimum of 20 slides are available, a patient may 
still be considered eligible. In this situation, approval by the Study Team for patient’s entry 
into the study is required. If there is no written confirmation of the availability of an 
appropriate tumor sample prior to enrolment, the participant will not be eligible for the study. 
At the time of enrolment all participants must have an ECOG PS of 0 or 1. 
Note: Sample collection in mainland China will follow local regulatory approval. 
A summary of the study periods and timings of study visits and main efficacy assessments is 
provided in Figure 2. 
Country-specific study requirements are provided in Appendix L. 

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Figure 2 
Study Flow Chart 
 

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4.1.1 
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis  
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with SARS-CoV-2 or similar pandemic 
infection), which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimize risks to study integrity. Where allowable by local health 
authorities, ethics committees, healthcare provider guidelines (eg, hospital policies) or local 
government, these changes may include the following options:  
• Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the ICF should be signed at the participant’s next contact with the study 
site). 
• Rescreening: Extended rescreening period to confirm eligibility to participate in the 
clinical study can be performed in previously screened participants. The investigator 
should confirm this with the designated study physician.  
• Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV). 
• Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix J. 
4.2 
Scientific Rationale for Study Design  
4.2.1 
Rationale for Study Design  
This randomized, open-label, 2-arm study will investigate Dato-DXd monotherapy versus ICC 
(eribulin, vinorelbine, capecitabine, or gemcitabine). The open-label design was chosen due to 
the differing dosing schedules of the ICC treatments; however, the trial will be conducted as 
“sponsor-blind” and the specific study intervention (Dato-DXd or ICC) to be taken by a 
participant will be assigned in a randomized manner. To maintain the integrity of the study, 
Sponsor personnel directly involved in the study conduct will not undertake or have access to 
efficacy data aggregated by treatment arm prior to final data readout for the dual primary 

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endpoint of PFS. At Sponsor discretion, the sponsor blind may be dropped if the dual primary 
endpoint of PFS achieves statistical significance at its primary analysis. 
4.2.2 
Rationale for Choice of Comparator Treatments  
Chemotherapy (single agent or doublet) is considered the main treatment option for patients 
who have exhausted or are not suitable for endocrine therapy in the metastatic setting. 
Combination chemotherapy has shown higher ORR, however, could not clearly show an OS 
benefit (Schott 2021). In addition, to balance the OS benefits with the toxicities between 
single agent and combination therapy, single agent sequential chemotherapies are 
recommended. Preferred agents in this setting include capecitabine, gemcitabine, vinorelbine, 
and eribulin (NCCN Guidelines 2020, Cardoso et al 2020).  
Capecitabine is frequently the first choice because of oral administration and low risk of 
alopecia and myelotoxicity. In the large phase 2 study in participants with metastatic breast 
cancer, capecitabine monotherapy achieved an ORR of 20% and median OS of 12.6 months 
(Blum et al 1999). Gastrointestinal side effects and hand-foot syndrome were the most 
commonly occurring adverse events.  
Eribulin has demonstrated anti-tumor activity as single-agent in metastatic breast cancer 
participants. In the EMBRACE trial, eribulin significantly improved OS in heavily pre-treated 
metastatic breast cancer participants as compared to SoC (median OS of 13.1 months versus 
10.6 months). The primary toxicity with eribulin was neutropenia whereas peripheral 
neuropathy was the most common adverse event leading to discontinuation of eribulin (Cortes 
et al 2011).  
Vinorelbine has demonstrated activity even in heavily pre-treated participants with metastatic 
breast cancer. In a Phase 3 study of vinorelbine monotherapy versus gemcitabine plus 
vinorelbine, median PFS in the single-agent vinorelbine arm was 4.0 months and OS was 
16.4 months (Martín et al 2007). Vinorelbine rarely induces total alopecia or severe 
gastrointestinal events or symptomatic cardiac events. The major dose-limiting hematological 
toxicity associated with vinorelbine is neutropenia (Domenech and Vogel 2001). 
Gemcitabine is active in metastatic breast cancer, with a response rate of approximately 25% 
and a median DoR of 13.5 months. A median OS of 15.2 months has also been reported 
(Possinger et al 1999). The drug is relatively well tolerated; alopecia and gastrointestinal 
toxicity are mild, and its use is not associated with significant neuropathy. Thrombocytopenia 
can be a dose-limiting toxicity. Gemcitabine appears to cross the blood brain barrier and may 
be a good option in participants with a history of CNS metastases (Gridelli et al 1999). 

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4.2.3 
Rationale for Stratification Factors  
4.2.3.1 
Stratification based on previous lines of chemotherapy  
The proposed dual primary endpoints of this study are PFS and OS, which are expected to 
differ in their magnitude dependent on whether a participant has received 1 or 2 lines of prior 
chemotherapy (see Section 2.2.1.1 for further details). Therefore, stratification by lines of 
chemotherapy (1 versus 2) has been chosen. Additionally, the study will also cap enrolment at 
50% for participants who have received 2 prior lines of chemotherapy. 
4.2.3.2 
Stratification based on prior CDK4/6 inhibitor use  
Differences in the magnitude of benefit in PFS and OS are also expected in participants 
receiving TROP2 inhibitors, dependent on whether treatment with a prior CDK4/6 inhibitor 
has been received. In HR-positive, HER2-negative participants treated with sacituzumab 
govitecan (a TROP2 ADC approved for use in metastatic TNBC by in the US), a subgroup 
analysis performed on prior CDK4/6 inhibitor use (no prior use versus prior use) demonstrated 
notable differences in median PFS, OS, and ORR (Kalinsky et al 2020). It is expected that the 
majority of study participants will have received CDK4/6 inhibitors. There are however global 
regions where CDK4/6 inhibitors are not yet adopted, and as such patients may be enrolled, 
stratification based on prior CDK4/6 inhibitor use are proposed. 
4.2.3.3 
Stratification based on geographical region  
Mortality rates from breast cancer vary by geographic region, due to regional differences in 
drug availability and medical practice. In many western countries, mortality rates due to breast 
cancer are decreasing, which has been attributed to a combination of early detection using 
mammographic screening and improved treatment options. In contrast, mortality rates in many 
South American, African, and Asian countries increased (Youlden et al 2012). Given these 
examples of differences in outcomes in various regions, stratification based on geographical 
region is proposed. 
4.2.4 
Rationale for Primary Efficacy Endpoints  
The primary dual endpoints of the study are OS and PFS by BICR, according to RECIST 1.1 
in the ITT. These endpoints are in line with the guidelines outlined by the NCI Breast Cancer 
Steering Committee Working Group Report (Seidman et al 2018), which recommends OS to 
be a primary endpoint in poor prognosis disease settings, and PFS to be a most robust and 
appropriate endpoint in HR-positive, HER2-negative disease, which has longer post-
progression survival.  
Overall survival is a clinically meaningful and direct measure of overall efficacy in metastatic 
breast cancer disease, and both the EMA (EMA 2017) and FDA (FDA 2018) advice consider 
OS as the most persuasive and reliable endpoint. However, both Agencies also consider PFS 
as an acceptable endpoint, dependent on the disease under study and other factors. For a 
randomized Phase 3 study, PFS is a relevant measure of clinical benefit that demonstrates 

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superiority of a new antineoplastic therapy, particularly in a setting where patients may 
frequently change chemotherapy agents due to side effects or progressive disease. 
Progression-free survival is an objective endpoint and is potentially less affected by post 
discontinuation therapies (as opposed to OS). A sufficiently prolonged PFS may therefore be 
considered in itself a clinically relevant effect, provided detriments on other important 
endpoints can be excluded, particularly if the magnitude of effect is large and the therapy has 
an acceptable risk/benefit profile. When rigorously tested, a robust treatment effect based on 
PFS complemented by no detriment in OS, can offer treatments to be made available early for 
patients with limited options especially in studies with long OS. 
Given these factors, and in recognizing the value of both PFS and OS as measures of overall 
efficacy, both are planned as dual primary endpoints. 
4.2.5 
Rationale for Other Study Endpoints  
The secondary endpoints of this study are in line with the recommendations outlined in the 
NCI Breast Cancer Steering Committee Working Group Report (Seidman et al 2018). 
The secondary participant-reported pain, physical functioning and global health status/quality 
of life endpoints, assessed using EORTC QLQ-C30, as well as participant-reported 
symptomatic AEs measured by selected items from the PRO-CTCAE/EORTC IL117 will 
show the overall influence of the benefits and toxicity of the treatment from the participant’s 
perspective and will aid in understanding the benefit/risk evaluation. These PRO 
questionnaires are well-established instruments that have been previously included in cancer 
clinical studies. 
Biological samples will be used to explore potential biomarkers in tumor, plasma, and/or 
serum, which may predict the progression of cancer (and associated clinical characteristics) 
and/or tumor response. By mandating tumor sample collection as part of the study design, 
TROP2 expression will be tested retrospectively by IHC, to explore correlation with treatment 
response. Increased TROP2 mRNA in breast cancer has been shown to be a predictor of 
lymph node involvement, distant metastasis, and poor OS (Zhao et al 2018). In one 
heterogenous breast cancer series, TROP2 analysis by IHC showed 92.6% (38/42) of tumors 
expressed TROP2 (Yang et al 2021). Internal AstraZeneca analysis of TROP2 expression also 
shows broad levels of expression in > 90% of HR-positive breast cancer clinical samples 
(unpublished data). 
The safety and tolerability of Dato-DXd will be assessed by the standard safety endpoints. 
Careful consideration has been given to the mitigation of risks related to the mode of action 
and the nature of the target, which will be closely monitored during the study.  

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4.3 
Justification for Dose  
4.3.1 
Dato-DXd  
The 6.0 mg/kg IV dose of Dato-DXd was selected based on preliminary results of the ongoing 
Phase 1, 2-part (dose escalation and dose expansion), multicenter, nonrandomized, open-label, 
multiple dose, first-in-human study (Study DS1062-A-J101) in participants with solid tumors. 
In this study, Dato-DXd showed a generally tolerable safety profile in participants with 
NSCLC across a dose range of 0.27 mg/kg to 8.0 mg/kg. During the dose escalation phase, the 
non-tolerated dose for Dato-DXd was 10.0 mg/kg, where 2 participants had Grade 3 
dose-limiting toxicities of mucosal inflammation and stomatitis. One participant at 6.0 mg/kg 
had a dose-limiting toxicity of Grade 3 maculopapular rash. The maximum tolerated dose 
(8.0 mg/kg) was determined during the dose escalation phase. 
However, an ongoing review of emerging Phase 1 study data has allowed a closer evaluation 
of the benefit/risk balance by dose. Based on these data, the Dato-DXd 6 mg/kg dose has a 
more favorable benefit/risk balance than the 8 mg/kg dose; thus, the 6 mg/kg is the optimal 
monotherapy dose for further development of Dato-DXd in clinical studies. 
Based on review of the safety data as of 16 November 2021, Dato-DXd exhibited an 
acceptable safety profile with established risk monitoring and risk mitigation measures for the 
important identified risks of ILD/pneumonitis and IRR as well as the AESIs of 
ILD/pneumonitis, IRR, oral mucositis/stomatitis, mucosal inflammation other than oral 
mucositis/stomatitis, and ocular surface toxicity. 
Overall, the safety and tolerability profile of Dato-DXd 6 mg/kg remains acceptable and 
manageable. The 6 mg/kg dose has a better benefit/risk profile than the 8 mg/kg dose and thus 
supports continued clinical development of Dato-DXd at this dose. 
The mean terminal half-life of Dato-DXd was 4.82 days at the 6.0 mg/kg dose, thus 
supporting a Q3W dosing schedule. 
For information on dose modifications for Dato-DXd, see Section 6.6. 
4.3.2 
Investigator Choice of Chemotherapy (ICC)  
The dosages of the ICC agents (capecitabine, gemcitabine, vinorelbine, eribulin) to be used in 
the current study are based on recommendations in the Prescribing Information for each agent, 
and are in accordance with current international breast cancer treatment guidelines (NCCN 
Guidelines 2020, Cardoso et al 2020). 
In specific relation to capecitabine, 2 dose options have been selected for use (to be 
determined by standard institutional practice), as dose tolerance is different between some 
patients due to pharmacogenetic differences (Midgley and Kerr 2008). For example, in the 
FDA label for capecitabine, Japanese patients had a lower concentration (Cmax) of drug at the 

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same dose given to Caucasian patients (Capecitabine USPI 2015). 
4.4 
End of Study Definition  
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs 
under FDA and EU regulatory requirements: 
• 
European Union requirements define study completion as the last visit of the last subject 
for any protocol related activity. 
• 
United States FDA requirements defines 2 completion dates: 
− Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome 
measure, whether the clinical study concluded according to the pre-specified protocol 
or was terminated. In the case of clinical studies with more than one primary outcome 
measure with different completion dates, this term refers to the date on which data 
collection is completed for all the primary outcomes. 
− Study Completion Date – is defined as the date the final participant is examined or 
receives an intervention for purposes of final collection of data for the primary and 
secondary outcome measure and AEs (for example, last participant’s last visit), 
whether the clinical study concludes according to the pre-specified protocol or is 
terminated. 
A participant is considered to have completed the study if they have completed all phases of 
the study, including the last visit shown in the SoA (Section 1.3), and undergone determination 
of OS. 
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings. 
See Section 6.7 for details on participant management following the final DCO, as well as 
following study completion. 
5 
STUDY POPULATION  
The target population of interest in this study is participants with inoperable or metastatic 
HR-positive, HER2-negative breast cancer who have been treated with one or two prior lines 
of systemic chemotherapy in the inoperable/metastatic setting.  
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
Participants who do not meet the eligibility criteria requirements are screen failures; refer to 
Section 5.4.  

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Country-specific study requirements are provided in Appendix L. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1 
Participant must be ≥ 18 years at the time of screening.  
Type of Participant and Disease Characteristics 
2 
Inoperable or metastatic HR-positive, HER2-negative breast cancer (per ASCO/CAP 
guidelines, on local laboratory results); ie, is documented as HR-positive (either ER 
and/or PgR positive [ER or PgR ≥ 1%]) and HER2-negative. If a participant had multiple 
results after metastatic disease, the most recent local test result will be used to confirm 
eligibility (Allison et al 2020, Wolff et al 2018).  
3 
Progressed on and not suitable for endocrine therapy per investigator assessment, and 
treated with 1 to 2 lines of prior standard of care chemotherapy in the 
inoperable/metastatic setting. Participant must have documented progression on their 
most recent line of chemotherapy.  
Note: If a chemotherapy drug is changed within 28 days of use to another drug in the same class (ie, 
antimetabolite to antimetabolite) for any reason, the first drug is not counted as a line. 
Targeted agents (such as mTOR inhibitors, PD-1/PD-L1 inhibitors, PARP inhibitors), endocrine therapies, 
and CDK4/6 inhibitors on their own do not contribute to the count of prior lines of chemotherapy; however, 
regimens with such agents in combination with metastatic chemotherapy should be classified as one line of 
chemotherapy. 
4 
Eligible for one of the chemotherapy options listed as ICC (eribulin, capecitabine, 
vinorelbine, gemcitabine), per investigator assessment.  
Note: Participants who previously received any of these agents are eligible for enrolment to another ICC 
agent in this study. 
5 
ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to day of first 
dosing. 
6 
At least 1 measurable lesion not previously irradiated that qualifies as a RECIST 1.1 
Target Lesion at baseline and can be accurately measured at baseline as ≥ 10 mm in the 
longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with CT or 
MRI, which is suitable for accurate repeated measurements.  
Note: Participants with bone-only metastases are not permitted. 
7 
Participants with a history of previously treated neoplastic spinal cord compression, or 
clinically inactive brain metastases, who require no treatment with corticosteroids or 
anticonvulsants, may be included in the study, if they have recovered from the acute toxic 

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effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of 
radiotherapy and study enrolment. 
8 
Adequate organ and bone marrow function within 7 days before day of first dosing as 
follows: 
- 
Hemoglobin: ≥ 9.0 g/dL. Red blood cell/plasma transfusion is not permitted within 
1 week prior to screening assessment. 
- 
Absolute neutrophil count:  1500/mm3. Granulocyte colony-stimulating factor 
administration is not permitted within 1 week prior to screening assessment. 
- 
Platelet count:  100000/mm3. Platelet transfusion is not permitted within 1 week 
prior to screening assessment. 
- 
Total bilirubin: ≤ 1.5 × ULN if no liver metastases; or ≤ 3 × ULN in the presence of 
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver 
metastases at baseline. 
- 
ALT and AST: ≤ 3 × ULN for AST/ALT; however, if elevation is due to liver 
metastases, ≤ 5.0 × ULN is allowed. 
- 
Calculated creatinine clearance: ≥ 30 mL/min as calculated using the Cockcroft-
Gault equation (using actual body weight):  
   Female:   CrCl =  
 
    Weight (kg) × (140 - Age)       × 0.85 
(mL/min) 
 
72 × serum creatinine (mg/dL) 
   Male:   
CrCl =  
 
    Weight (kg) × (140 - Age)    
(mL/min) 
 
72 × serum creatinine (mg/dL) 
9 
LVEF ≥ 50% by either an echocardiogram or MUGA within 28 days of first dosing. 
10 Has had an adequate treatment washout period before Cycle 1 Day 1, defined as: 
- Major surgery: ≥ 3 weeks. 
- Radiation therapy including palliative radiation to chest: ≥ 4 weeks (palliative 
radiation therapy to other areas ≥ 2 weeks). 
- Anticancer therapy including hormonal therapy: ≥ 3 weeks (for small molecule 
targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer). 
- Antibody-based anticancer therapy: ≥ 4 weeks with the exception of receptor 
activator of nuclear factor kappa-B ligand (RANKL) inhibitors (eg, denosumab for 
the treatment of bone metastases). 
- Immunotherapy (non-antibody-based therapy): ≥ 2 weeks or 5 times the terminal 
elimination T½ of the agent, whichever is longer. 

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- Chloroquine/hydroxychloroquine: > 14 days. 
11 All participants must have available a FFPE tumor sample (block preferred, or a 
minimum of 20 freshly cut slides), at the time of screening.  This can be from either the 
primary disease setting (surgical resection or diagnostic sample), or from a metastatic 
lesion (excluding bone) for tissue-based analysis (including but not restricted/limited to 
IHC staining of potential predictive biomarkers as well as tumor mutational analysis). 
The mandatory FFPE tumor sample submitted for analysis should be obtained as close to 
the time of diagnosis of metastatic or inoperable disease as possible. If neither an 
adequate FFPE block nor the minimum of 20 slides are available, a patient may still be 
considered eligible. In this situation, approval by the Study Team for patient’s entry into 
the study is required. 
Note: Sample collection in mainland China will comply with local regulatory approval. 
12 Minimum life expectancy of 12 weeks at screening. 
Sex  
13 Male or female.  
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies; however, oral estrogens 
are not permitted. 
Reproduction 
14 Negative pregnancy test (serum) for women of childbearing potential. 
15 Female participants must be post-menopausal for at least 1 year, surgically sterile, or 
using one highly effective form of birth control (a highly effective method of 
contraception is defined as one that can achieve a failure rate of less than 1% per year 
when used consistently and correctly). For female contraception, please refer to 
Appendix G. Women of childbearing potential who are sexually active with a non-
sterilized male partner must agree to use one highly effective method of birth control. 
They should have been stable on their chosen method of birth control starting at a 
minimum of 3 months before C1D1 to at least 7 months after the last dose (see 
Appendix G for complete list of highly effective birth control methods). Female 
participants must refrain from egg cell donation and breastfeeding while on study and for 
at least 7 months after the last dose of study intervention. Non-sterilized male partners of 
a woman of childbearing potential must use a male condom plus spermicide (condom 
alone in countries where spermicides are not approved) throughout this period. 
16 Male participants who intend to be sexually active with a female partner of childbearing 
potential must be surgically sterile or using a highly effective method of contraception 

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(see Appendix G) from the time of screening throughout the total duration of the study 
and the drug washout period (at least 4 months after the last dose of study intervention) to 
prevent pregnancy in a partner. Male participants must not donate or bank sperm during 
this same time period. Not engaging in heterosexual activity (sexual abstinence) for the 
duration of the study and drug washout period is an acceptable practice if this is the 
preferred usual lifestyle of the participant; however, periodic or occasional abstinence, the 
rhythm method, and the withdrawal method are not acceptable methods of contraception. 
Female partners of male participants are allowed to use HRT for contraception. 
Informed Consent 
17 Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol. 
18 Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of sample for optional genetic research that supports Genomic 
Initiative.  
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1 
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled 
systemic diseases, uncontrolled hypertension, history of allogeneic organ transplant, and 
active bleeding diseases, ongoing or active infection, or significant or cardiac or 
psychological conditions) which, in the investigator’s opinion, makes it undesirable for 
the participant to participate in the study or that would jeopardize compliance with the 
protocol.  
2 
History of another primary malignancy except for malignancy treated with curative intent 
with no known active disease within 3 years before the first dose of study intervention 
and of low potential risk for recurrence. Exceptions include basal cell carcinoma of the 
skin and squamous cell carcinoma of the skin that has undergone potentially curative 
therapy, adequately resected non-melanoma skin cancer, curatively treated in situ disease, 
or other solid tumors curatively treated. 
3 
Persistent toxicities caused by previous anticancer therapy (excluding alopecia), not yet 
improved to CTCAE Version 5.0 Grade ≤ 1 or baseline. Note: participants may be 
enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 
2 for at least 3 months prior to first dosing and managed with SoC treatment) which the 
investigator deems related to previous anticancer therapy, including (but not limited to):  
- Chemotherapy-induced neuropathy. 

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− Fatigue. 
- Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 
endocrinopathies which may include: 
▪ Hypothyroidism/hyperthyroidism. 
▪ Type I diabetes. 
▪ Hyperglycaemia. 
▪ Adrenal insufficiency 
o 
Adrenalitis. 
− Skin hypopigmentation (vitiligo). 
4 
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected 
infections (eg, prodromal symptoms); or inability to rule out infections. 
Note: Participants with localized fungal infections of skin or nails are eligible. 
5 
Known active or uncontrolled hepatitis B or C infection. Participants are eligible if they: 
a. Have been curatively treated for HCV infection as demonstrated clinically and by 
viral serologies 
b. Have received HBV vaccination with only anti-HBs positivity and no clinical signs 
of hepatitis 
c. Are HBsAg- and anti-HBc+ (i.e., those who have cleared HBV after infection) and 
meet conditions i-iii below: 
d. Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet 
conditions i-iii below: 
i. 
HBV DNA viral load < 2000 IU/mL 
ii. 
Have normal transaminase values, or, if liver metastases are present, 
abnormal transaminases, with a result of AST/ALT <3 × ULN, which are 
not attributable to HBV infection 
iii. 
Start or maintain antiviral treatment if clinically indicated as per the 
investigator 
6 
Known HIV infection that is not well controlled. All of the following criteria are required 
to define an HIV infection that is well controlled: undetectable viral RNA, CD4+ count 
> 350 cells/mm3, no history of AIDs-defining opportunistic infection within the past 
12 months, and stable for at least 4 weeks on same anti-HIV retroviral medications 
(meaning there are no expected further changes in that time to the number or type of 
antiretroviral drugs in the regimen). If an HIV infection meets the above criteria, 
monitoring of viral RNA load and CD4+ count is recommended. Participants must be 
tested for HIV if acceptable by local regulations or an IRB/EC. 

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7 
Uncontrolled or significant cardiac disease, including myocardial infarction or 
uncontrolled/unstable angina within 6 months prior to C1D1, CHF (New York Heart 
Association Class II to IV), uncontrolled or significant cardiac arrhythmia, or 
uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood 
pressure > 110 mmHg). 
8 
Investigator judgment of 1 or more of the following: 
− Mean resting corrected QTcF interval > 470 ms, obtained from triplicate ECGs 
performed at screening. 
− History of QT prolongation associated with other medications that required 
discontinuation of that medication, or any current concomitant medication known to 
prolong the QT interval and cause Torsades de Pointes. 
− Congenital long QT syndrome, family history of long QT syndrome, or unexplained 
sudden death under 40 years of age in first-degree relatives. 
9 
History of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening. 
Note: Participants found to have ILD/pneumonitis on baseline screening chest CT are not eligible. 
10 Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli 
within three months of first dosing, severe asthma, severe COPD, restrictive lung disease, 
pleural effusion etc), or any autoimmune, connective tissue or inflammatory disorders 
with pulmonary involvement (ie, Rheumatoid arthritis, Sjogren's, sarcoidosis etc), or prior 
pneumonectomy. 
11 Leptomeningeal carcinomatosis. 
12 Clinically significant corneal disease. 
13 Known active tuberculosis infection (clinical evaluation that may include clinical history, 
physical examination and radiographic findings, or tuberculosis testing in line with local 
practice). 

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Prior/Concomitant Therapy 
14 Any of the following prior anticancer therapies: 
− Any treatment (including ADC) containing a chemotherapeutic agent targeting 
topoisomerase I 
− TROP2-targeted therapy 
− Prior treatment with same ICC agent  
(Note: Participants are eligible for enrolment into this study if they able to receive treatment with another 
ICC agent not previously received; see Inclusion Criterion 4) 
15 Any concurrent anticancer treatment, with the exception of bisphosphonates, denosumab, 
for the treatment of bone metastases.  
16 Concurrent use of systemic hormonal replacement therapy (eg, estrogen). However, 
concurrent use of hormones for non-cancer related conditions (eg, insulin for diabetes) is 
acceptable. 
17 Major surgical procedure (excluding placement of vascular access) or significant 
traumatic injury within 3 weeks of the first dose of study intervention or an anticipated 
need for major surgery during the study. 
18 Receipt of live, attenuated vaccine within 30 days prior to the first dose of study 
treatment. 
19 Criterion removed in Protocol version 3.0. 
Prior/Concurrent Clinical Study Experience 
20 Previous treatment in the present study.  
21 Participation in another clinical study with a study intervention or investigational 
medicinal device administered in the last 4 weeks prior to first dosing, randomization into 
a prior Dato-DXd or T-DXd (trastuzumab deruxtecan) study regardless of treatment 
assignment, or concurrent enrolment in another clinical study, unless it is an observational 
(noninterventional) clinical study or during the follow-up period of an interventional 
study. 
22 Participants with a known hypersensitivity to Dato-DXd, or any of the excipients of the 
product (including, but not limited to, polysorbate 80). 
23 Known history of severe hypersensitivity reactions to other monoclonal antibodies. 

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Other Exclusions 
24 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). 
25 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements. 
26 For women only, currently pregnant (confirmed with positive pregnancy test) or 
breastfeeding, or who are planning to become pregnant.  
 
5.3 
Lifestyle Considerations  
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after: 
• 
Participants must follow the contraception requirements outlined in Appendix G. 
• 
Participants should not donate blood or blood components while participating in this 
study and through 28 (+7) days after the last dose of study intervention. Preservation of 
ova and sperm should be considered prior to enrolment in this study. 
• 
Use of tobacco products, e-cigarettes and vaping is strongly discouraged, but not 
prohibited. Any prior or current use of these products should be recorded in the eCRF. 
Restrictions relating to concomitant therapies are described in Appendix I 2. 
5.4 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a single time. Rescreened participants should be assigned the same participant 
number (ie, E-code) as for the initial screening. However, rescreening should be documented 
so that any effect on study results can be assessed.  
All assessments must be repeated for rescreening unless they are within 28 days of 
randomization. 
Screen failure participants should have the reason for study withdrawal recorded in the eCRF 
as “eligibility criteria not fulfilled” (ie, participant does not meet the required 

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remain on throughout the administration time.  
Refer to the Pharmacy Manual for detailed information about preparation and handling of 
Dato-DXd.  
6.2.1.2 
Administration of Dato-DXd  
Pre-medication is required prior to any dose of Dato-DXd and must include antihistamines 
and acetaminophen, with or without glucocorticoids. Participants should remain at the site for 
at least 1-hour post-infusion of every dose of Dato-DXd for close observation for possible 
IRRs. 
It is also highly recommended that participants receive prophylactic anti-emetic agents prior 
to infusion of Dato-DXd and on subsequent days as needed. Antiemetics such as 5-HT3 
receptor antagonists, NK1 receptor antagonists and steroids (eg, dexamethasone) should be 
considered and administered in accordance with the prescribing information or institutional 
guidelines. 
Dato-DXd must reach room temperature prior to administration. 
Incompatibilities have been observed with 0.9% sodium chloride for injection and must not be 
used for drug administration; additionally these solutions must not be co-infused in the same 
IV line as Dato-DXd. 
Dato-DXd will be administered using an IV bag containing 5% dextrose injection through an 
IV administration set, using local practices. Do not shake the prepared IV bag. 
The infusion must be administered with a 0.2- or 0.22-μm filter; acceptable configurations 
include an IV set containing an in-line filter or the attachment of a separate filter to the distal 
end of the IV tubing. 
Dato-DXd infusion time is approximately 90 minutes (±10 minutes) for the first infusion. If 
the first infusion is well tolerated and the participant does not experience an infusion-related 
reaction, then the minimum infusion time for subsequent cycles is 30 minutes.  
In case of interruptions, the total cumulative time from needle puncture of the Dato-DXd vial 
to the end of infusion must not exceed 4.5 hours with the IV bag kept at room temperature, 
otherwise a new dose must be prepared from new vials to complete the dose. 
Do not co-administer other drugs through the same IV line. 
After the content of the IV bag is administered, the IV line will be flushed with a volume of 
5% dextrose for injection equal to the IV-line volume, at the same rate as infusion according 
to local practices, to ensure the full dose is administered. 

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The total infusion time recorded in the EDC system reflects when the infusion IV bag is 
empty; this time does not include the post-infusion flush.  
If an IRR (such as fever and chills, with and without nausea/vomiting, pain, headache, 
dizziness, dyspnea, hypotension) is observed during administration, the infusion speed should 
be reduced by 50% and participants should be closely monitored. 
The participant’s weight at screening (baseline) will be used to calculate the initial dose. If, 
during the course of treatment, the participant’s weight changes by ≥ ±10%, the participant’s 
dose will be recalculated based on the participant’s updated weight. After the re-calculation, 
the participant’s updated weight will be used as the new baseline weight. The site may follow 
local institutional policy for recalculating dose based on weight changes less than 10%.  
6.2.1.3 
Monitoring of Dato-DXd Administration  
Participants will be monitored during and after infusion of Dato-DXd. Vital signs will be 
measured according to the SoA and Section 8.2.2. 
Management of study intervention-related toxicities are described in the TMGs for Dato-DXd, 
(see the Annex document to this CSP). As with any biologic product, IRRs to dose 
administration are possible. Therefore, appropriate drugs and medical equipment to treat acute 
anaphylactic reactions must be immediately available, and study personnel must be trained to 
recognize and treat anaphylaxis. 
6.2.1.4 
Storage of Dato-DXd  
The investigator, or an appropriate delegate, will ensure that all study intervention is stored in 
a secured area, at appropriate temperatures and as specified on the label, and in accordance 
with applicable regulatory requirements. A calibrated temperature monitoring device will be 
used to record the temperature conditions in the drug storage facility. A temperature log will 
be used to record the temperature of the storage area. Temperature excursions outside the 
permissible range listed in the clinical supply packaging are to be reported to the 
Study Monitor upon detection. Storage conditions stated in the respective IBs may be 
superseded by the label storage instructions. 
Investigational product vials are stored at 2 °C to 8 °C (36 °F to 46 °F) and must not be 
frozen. Investigational product must be kept in original packaging until use to prevent 
prolonged light exposure.  
6.2.2 
Investigator’s Choice of Chemotherapy  
Participants will receive ICC (eribulin, capecitabine, vinorelbine and gemcitabine) at the doses 
specified in Table 5. The choice of chemotherapy must be pre-defined prior to randomization. 
The number of treatment cycles for ICC is not fixed. Refer to the local label for details on 
handling.  

Cli nical St u d y Pr ot oc ol  - 1. 0 E ur o pea n U ni o n ( L ocal A me n d me nt 1 E ur o pea n U ni o n)  
Astra Ze n eca  
Dat o p ota ma b der u xteca n ( Dat o -D X d, D S -1 0 6 2a)  - 2 0 2 3 -5 0 9 6 3 1 -3 7  
 
C O N FI D E N TI A L A N D  P R O P RI E T A R Y  
7 0  of 2 4 1  
T he I C C a ge nts will eit her be l oc all y s o urce d b y t he st u d y site or ce ntr all y s u p plie d b y 
Astra Z e neca a n d will be a d mi nistere d acc or di n g t o Prescri bi n g I nf or m ati o n or treat me nt 
g ui da nce i n ge n eral use b y t he i n vesti gati n g site. U n der certai n circ u msta n ces w he n l ocal 
s o urci n g b y t he st u d y site is n ot feasi ble, Astra Ze n eca will ce ntrall y s u p pl y t he dr u g, w hic h 
will be la belle d wit h l ocal la n g ua ge tra nslat e d te xt i n acc or da nce wit h re g ul at or y g ui deli nes.  
6. 3  
Me as ures t o Mi ni mize Bi as: R a n d o miz ati o n a n d Bli n di n g   
6. 3. 1  
P artici p a nt E nr ol m e nt a n d R a n d o miz ati o n   
All partici pa nts will be  ce ntrall y assi g ne d t o ra n d o mize d st u d y i nter ve nti o n usi n g a n I R T. 
Bef ore t he st u d y is i nitiate d, t he call/l o g -i n directi o ns a n d user g ui des f or t he I R T will be 
pr o vi de d t o eac h site.  
If a partici pa nt wit h dra ws fr o m t he st u d y, t he n t heir e nr ol me nt c o de ca n n ot be re use d. 
Wit h dra w n partici pa nts will n ot be re place d.  
I n vesti gat ors s h o ul d kee p a rec or d (ie, t he p artici p ant scree ni n g l o g) of partici pa nts w h o 
e ntere d s cree ni n g.  
At scree ni n g/ bas eli ne ( u p t o 2 8 da ys bef ore C 1 D 1), t he i n vesti gat ors ( or s uita bl y trai ne d 
dele gate) will:  
•  
O btai n si g ne d i nf or me d c o nse nt bef ore a n y st u d y -s pecific pr oce d ures are p erf or me d. If 
la b orator y or i ma gi n g pr oce d ures were perf or me d f or alter nate reas o ns pri or t o si g ni n g 
c o nse nt, t hese ca n be use d f or scree ni n g p ur p oses wit h c o nse nt of t he partici pa nt. 
H o we ver, all scree ni n g la b orat or y a n d i ma gi n g r es ults m ust ha ve bee n o btai ne d wit hi n 
2 8  da ys of ra n d o mizati o n e xce pt f or vir us a nti b o d y test res ults a n d he patitis B vir us 
s urface a nti ge n, w hic h ca n be use d if perf or me d wit hi n 1 2 0 da ys bef ore scree ni n g.  
•  
Partici pa nts will be i de ntifie d t o t he I R T per c o u ntr y re g ulati o ns. O btai n a u ni q ue 7 -di git 
e nrol me nt n u m ber ( E -c o de) t hr o u g h t he I R T i n t h e f oll o wi n g f or mat: 
. T his n u m ber is t he partici pa nt’s u ni q ue i de ntifier a n d is use d 
t o i de ntif y t he partici pa nt o n t he e C R Fs. 
•  
Deter mi ne partici pa nt eli gi bilit y (see Secti o ns 5. 1  a n d 5. 2 ). 
•  
O btai n si g ne d i nf or me d c o nse nt f or t he o pti o nal Ge n o mics I nitiati ve. Partici pa nts w h o 
deci de n ot t o si g n t he s pecific ge netic I C F, b ut t he ge neral st u d y I C F, are eli gi ble f or 
st u d y e nr ol me nt a n d all ot her st u d y pr oce d ures.  
At ra n d o mizati o n, o nce t he partici pa nt is c o nfir me d t o be eli gi ble, t he i n vesti gat or ( or s uita bl y 
trai ne d dele g ate) will: 
P P D
P P D

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• 
Select the ICC treatment (based on the most appropriate option for the participant) that 
the participant would receive if randomized to the ICC group prior to randomization of 
the participant. This must be completed for all participants. The selection will be recorded 
in the IRT system. 
• 
Assign a randomized treatment group via the IRT. Randomization codes will be assigned 
strictly sequentially within each stratum and site/country/region as participants become 
eligible for randomization. The system will randomize the eligible participant to one of 
the 2 treatment groups.  
 
If the participant is ineligible and not randomized, the IRT should be accessed to terminate the 
participant in the system. 
Participants will begin treatment on Day 1. Participants must not be randomized and treated 
unless all eligibility criteria have been met. 
6.3.2 
Procedures for Handling Incorrectly Enrolled or Randomized 
Participants  
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Participants who 
are enrolled but subsequently found not to meet all the eligibility criteria must not be 
randomized or started on study intervention and must be withdrawn from the study. 
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the participant 
from treatment. The AstraZeneca study physician must ensure all decisions are appropriately 
documented and that the potential benefit/risk profile remains positive for the participant. 
6.3.3 
Methods for Assigning Treatment Groups  
The actual treatment given to participants will be determined by the randomization scheme in 
the IRT. The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers. One randomization 
list will be produced for each of the randomization strata. A blocked randomization will be 
generated, and all centers will use the same list in order to minimize any imbalance in the 
number of participants randomized to each treatment group. 
Randomization codes will be assigned strictly sequentially (refer to the 3 stratification factors 
in Section 4.1), as participants become eligible for randomization. When study intervention is 
provided centrally by AstraZeneca, the IRT will provide the kit identification number to be 
allocated to the participant at the randomization visit and subsequent treatment visits. If 

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medication is provided locally, IRT will not provide kit numbers. 
6.3.4 
Methods for Ensuring Blinding  
This is an open-label study for the personnel at study sites; however, the trial will be 
conducted as “sponsor-blind” and the specific study intervention (Dato-DXd or ICC) to be 
taken by a participant will be assigned using an IRT. To maintain the integrity of the study, 
AstraZeneca personnel directly involved in the study conduct will not undertake or have 
access to efficacy data aggregated by treatment arm prior to final data readout for the primary 
endpoint. Before the first participant is randomized, a Study Integrity Plan document will be 
generated, in which data access levels for relevant AstraZeneca personnel will be pre-
specified. 
6.4 
Study Intervention Compliance  
When participants are dosed at the study site (applicable to Dato-DXd and ICC agents 
gemcitabine, eribulin and vinorelbine), they will have study intervention prepared, dispensed 
and administered by the investigator or designee, under medical supervision. The date, and 
time (if applicable), of the administered study intervention will be recorded in the source 
documents and recorded in the eCRF. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing in accordance with local treatment 
verification practices. Deviation(s) from the prescribed dosage regimen should be recorded in 
the eCRF. 
When participants self-administer study intervention(s) at home (as applicable to the ICC 
agent capecitabine), compliance with study intervention will be assessed at each visit. 
Compliance will be assessed by direct questioning and counting returned tablets, as well as by 
the review of participant completed dosing diaries during the site visits and documented in the 
source documents and eCRF. A record of the number of capecitabine tablets dispensed to and 
taken by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention delays 
and/or dose reductions will also be recorded in the eCRF. 
The Investigational Product Storage Manager is responsible for managing the study 
intervention from receipt by the study site until the destruction or return of all unused study 
intervention.  
6.5 
Concomitant Therapy  
Any concomitant treatment, procedure, vaccine, or other medication considered necessary by 
the investigator for the participant’s safety and wellbeing (including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) or other specific categories of 
interest, that the participant is receiving from the time of screening or receives during the 
study, including the 28 (+7) day safety follow-up period following the last dose of study 

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intervention must be recorded in the eCRF along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
The Study Clinical Lead should be contacted if there are any questions regarding concomitant 
or prior therapy. 
If any concomitant therapy is administered due to new or unresolved AE, it should be 
recorded. 
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator. 
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix I 2. 
For participants randomized to receive ICC, refer to the local Prescribing Information with 
regard to warnings, precautions, and contraindications.  
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix I 1. 
 
All concomitant medications administered during the study should be recorded until the end of 
the safety follow-up period. Concomitant medications administered as treatment for drug-
related AESIs should be recorded in eCRF until either event resolution, end of study, trial 
termination, withdrawal of consent, or subject death. 
 
Drug-drug Interactions 
Nonclinical PK studies have indicated that MAAA 1181a (payload: deruxtecan) is primarily 
metabolized by CYP3A4 and is a substrate for OATP1B1, OATP1B3, MATE2-K, P-gp, 
BCRP, and MRP1. 
No formal drug-drug interaction studies with Dato-DXd have been conducted in humans. 
Since drug-drug interactions are primarily driven by MAAA-1181a, the drug component of 
Dato-DXd, a drug-drug interaction study of trastuzumab deruxtecan, which has the same 
payload, is considered of relevance. Recent results from a clinical drug-drug interaction study 
of trastuzumab deruxtecan (Study NCT03383692) showed that co-administration of a dual 
inhibitor of OATP1B/CYP3A, ritonavir, and a strong CYP3A inhibitor, itraconazole, increased 
MAAA-1181a AUC17d by 22% and 18%, respectively. Therefore, the effect of the 
CYP3A/OATP1B inhibitors on MAAA-1181a is not considered clinically meaningful and as a 

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result, concomitant use of CYP3A/OATP1B inhibitors with Dato-DXd is allowed. However, 
caution must be followed by the investigator in case of concomitant use of Dato-DXd and 
CYP3A inhibitors, or drugs that inhibit OATP1B1, OATP1B3, MATE2-K, P-gp, BCRP, and 
MRP1. Patients must be closely monitored in these cases. 
Concomitant use of drugs that inhibit MATE2-K, P-gp, BCRP, and MRP1 is allowed, 
although participants should be closely monitored for adverse reactions. Because the urinary 
excretion of MAAA-1181a is expected to be low, MATE2-K (which is involved in the 
excretion of substrates into urine) is expected to have minimal impact on the exposure of 
MAAA-1181a. In addition, multiple efflux transporters such as P-gp and BCRP are involved 
in the excretion of MAAA-1181a; therefore, the risk of interactions with these inhibitors is 
also expected to be low. Likewise, because the expression of MRP1 in the liver is low, the 
inhibition of MRP1 is expected to have little impact. 
Concomitant use of drugs that are substrates of OAT1 and OATP1B1 is allowed. Because the 
exposure of MAAA-1181a is expected to be low with Dato-DXd at doses administered in 
clinical studies, the inhibition of OAT1 and OATP1B1 by MAAA-1181a is expected to have 
little impact on drugs that are substrates of OAT1 and OATP1B1. 
There is a hypothetical interaction between Dato-DXd and hydroxychloroquine and/or 
chloroquine, therefore concomitant treatment with hydroxychloroquine or chloroquine is not 
allowed whilst a participant is on Dato-DXd and ≥ 14 days of washout is required before 
starting Dato-DXd administration. If treatment with chloroquine or hydroxychloroquine 
treatment is absolutely required, study intervention must be interrupted. If chloroquine or 
hydroxychloroquine is administered for any reason, the study intervention must be interrupted, 
and a washout period of ≥14 days is required before restarting study intervention. 
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix I 1. 
6.6 
Dose Modification  
Dosing modification guidelines and TMGs are included in the Annex document to this CSP. 
Dose delays are permitted for Dato-DXd. Dose reductions are permitted for Dato-DXd. All 
dose reductions and delays (including any missed doses), and the reasons for the 
reductions/delays are to be recorded in the eCRF. 
Refer to Section 4.3.1for the justification for dose for Dato-DXd. 
6.6.1 
Dose Delays  
Dose delays are permitted for Dato-DXd treatment and the dosing interval for the next 
Dato-DXd cycle may be shortened, as clinically feasible to gradually align with the schedule 

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of tumor efficacy assessment. Two consecutive doses must be administered at least 19 days 
apart. 
Study treatment dose delay for conditions other than toxicity resolution should be kept as 
short as possible. A dose can be delayed for up to 3 consecutive cycles (63 days) from the 
planned date of administration (ie, 84 days from the last infusion date). If a participant is 
assessed as requiring a dose delay longer than 3 consecutive cycles (ie, > 84 days from last 
infusion date to the planned date of administration on a Q3W schedule), the 
subject/participant must discontinue study treatment (see Figure 3).
Figure 3
Dose Delay Schema for Dato-DXd
Treatment cycles for a participant for whom Dato-DXd dosing is temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last Dato-DXd dose.
In the event of a dose interruption occurring prior to completion of PK/pharmacodynamic 
blood sampling in the study, investigators should contact the study clinical lead for guidance 
regarding scheduling of these procedures.
6.6.2
Dose Delays for Reasons Other Than Treatment-related Toxicity
Study treatment dose delay for conditions other than toxicity resolution should be kept as 
short as possible. If a participant cannot restart study treatment within 84 days from the last 
infusion date for resolution of intercurrent conditions not related to PD or toxicity, the case 
should be discussed with the Study Clinical Lead.

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6.6.3 
Dose Reductions  
In case a dose reduction is necessary, Dato-DXd will be modified as follows.  
Up to 2 dose reductions will be permitted for participants receiving Dato-DXd (see Table 6 for 
dosing levels). Once the dose of Dato-DXd has been reduced, no dose re-escalation is 
permitted. After the permitted dose reductions, if further toxicity meeting the requirement for 
dose reduction occurs, the participant will be withdrawn from the study intervention.  
In a rare circumstance, one additional dose reduction may be possible on a case-by-case basis 
only after discussion and agreement between the Investigator and Sponsor. 
Table 6 
Dose Reduction Levels of Dato-DXd 
Starting Dose (Dose Level 1) 
Dose Level -1 
Dose Level -2 
6.0 mg/kg IV, Q3W 
4.0 mg/kg IV, Q3W 
3.0 mg/kg IV, Q3W 
 
Investigators should consider dose reductions or discontinuations of Dato-DXd according to 
the participant’s condition and after discussion with the study clinical lead or designee (see the 
Annex document to this CSP for details of when dose reductions may be required). 
Refer to Section 4.3 for the justification of dose for Dato-DXd. 
6.6.4 
Management of Toxicities  
Full TMGs for Dato-DXd are included in the Annex document to this CSP. The most current 
version of the TMGs for Dato-DXd is provided to the investigative site as an Annex document 
to the CSP and is maintained within the Site Master File. Please refer to the Annex document 
to this CSP for the management of drug-induced ILD/pneumonitis. 
Specific criteria for interruption, re-initiation, dose reduction and/or discontinuation of 
Dato-DXd are listed in the Annex document to this CSP, which is applicable only to TEAEs 
that are assessed as related to use of Dato-DXd by the investigator(s). For non-drug related 
TEAEs, follow standard clinical practice. Appropriate clinical experts should be consulted as 
deemed necessary. 
On improvement of an AE for which Dato-DXd was temporarily interrupted, Dato-DXd may 
be restarted at the same dose at the discretion of the investigator. If a further episode of the 
same AE subsequently requires dose interruption, or if a different AE subsequently requires 
dose interruption, Dato-DXd may be restarted at a 1 dose level reduction on improvement of 
the AE or discontinued if the participant is receiving the lowest protocol-specified dose level. 
Appropriate and optimal treatment of the toxicity should be attempted prior to considering 

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dose modifications. Prior to discontinuation of study intervention due to toxicities, please 
consult with the study clinical lead. 
If a participant experiences a clinically significant and/or unacceptable toxicity, dosing will be 
interrupted or permanently discontinued in accordance with the TMGs and supportive therapy 
administered as required. 
All dose modifications (interruption, reduction, and/or discontinuation) should be based on the 
worst preceding toxicity (CTCAE version 5.0). 
For management of toxicities due to ICC, refer to the locally approved Prescribing 
Information or manage in accordance with institutional guidelines. 
6.7 
Continued Access to Study Intervention After the End of the 
Study  
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact. No intervention is planned 
after the end of the study. 
After the final DCO for this study, AstraZeneca will continue to supply open-label treatment 
in the continued access phase of this study and after completion of this study to participants 
who received Dato-DXd or centrally supplied ICC while, in the opinion of the investigator, 
the participant is benefiting until PD occurs (as judged by the investigator), or until meeting 
any other discontinuation criteria as defined in Section 7.1.  
Participants should be followed according to the institution’s SoC assessments. No further 
data collection is required, except for reporting of SAEs. 
Participants who were randomized to receive other study interventions (ie, locally supplied 
ICC), or who discontinue from the study, should continue appropriate treatment at the 
discretion of the investigator. 
Where possible, if commercial supply of Dato-DXd is available in the local market then this 
route should be used. In the event that product development reaches a point where alternative 
product supply options become available, then these alternative product supply options will be 
discussed by AstraZeneca with the investigator. AstraZeneca will work with the investigator to 
transition the participant(s) to alternative supply, where possible. 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants currently receiving treatment with Dato-DXd may be 
transitioned to such a study. The roll-over or extension study would ensure treatment 
continuation with visit assessments per its protocol, as applicable. Any participant who would 

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be proposed to move to such a study would be given a new informed consent, as applicable. 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
Discontinuation of Study Intervention  
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will 
remain in the study to be evaluated for PFS (if the participant has not progressed according to 
RECIST 1.1), PFS2, OS, TFST and TSST. The investigator should instruct the participant to 
contact the site before or at the time if study intervention is stopped. A participant that decides 
to discontinue study intervention will always be asked about the reason(s) and the presence of 
any AEs. The reason for discontinuation should be documented in the source document and 
the appropriate section of the eCRF. 
Participants who have permanently discontinued from further receipt of study intervention 
will need to be discontinued from the IRT. All study intervention should be returned by the 
participant at their next on-site study visit or unscheduled visit. 
Participants may be discontinued from study intervention in the following situations:  
• 
RECIST 1.1-defined radiological progression (refer to Section 8.1.1 and Appendix F).  
• 
An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing.  
• 
Any AE that meets criteria for discontinuation defined in the TMGs (see the Annex 
document to this CSP), or as defined in the local Prescribing Information for the ICC 
agents. 
• 
Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. A participant who discontinues treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments (see Section 7.2). 
• 
Severe non-compliance with the CSP as judged by the investigator or AstraZeneca. 
• 
Pregnancy or intent to become pregnant (refer to Appendix G and Section 8.3.14). 
• 
Initiation of subsequent anticancer therapy, including another investigational agent. 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study. 
Crossover within the study is not permitted. 

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7.1.1 
Follow-up of Participants Post Discontinuation of Study Intervention  
All participants who discontinue the study intervention will be followed up for safety 
assessments 28 (+7) days after their last dose of study intervention. Additional assessments to 
be performed at the time of the safety follow-up visit are detailed in the SoA (Table 1). For 
ILD/pneumonitis, safety follow-up will continue until the resolution of ILD/pneumonitis. 
Participants who have discontinued study intervention prior to objective RECIST 1.1-defined 
radiological progression, regardless of whether or not they have commenced subsequent 
anticancer therapy, will be followed up with tumor and survival assessments as indicated in 
the SoA (Table 1) until one visit after investigator-defined PD according to RECIST 1.1, or 
death regardless of whether or not the participant started a subsequent anticancer therapy, 
unless they have withdrawn all consent to study-related assessments. 
See the SoA (Table 1) for data to be collected at the time of intervention discontinuation (ie, 
the end-of-treatment visit) and follow-up and for any further evaluations that need to be 
completed. 
7.1.2 
Follow-up of Participants to PFS2  
Following objective progression, participants will have their subsequent progression status 
recorded every 3 months (±14 days) per local standard clinical practice to assess PFS2. 
Assessments will be performed according to the local practice, and formal RECIST 1.1 
measurements will not be collected for assessment of PFS2. See Section 8.1.3 for additional 
information. 
7.1.3 
Follow-up for Survival  
Participants will be followed up for survival status as indicated in the SoA (Table 1) until 
death, withdrawal of consent, or the end of the study. Survival information may be obtained 
via telephone contact with the participant or the participant’s family, by contact with the 
participant’s current physician, or local death registries (if allowed by local regulations). 
Additional assessments to be performed at the time of survival follow-up are detailed in the 
SoA (Table 1). The study may continue monitoring participants for OS up to the scheduled 
final analysis, beyond planned interim analyses, to provide more refined estimates of 
treatment effects for survival. 
Telephone calls to assess survival will be made at an increased frequency leading up to and 
after the DCO date for the analysis (these contacts will be made until the date of the database 
lock). If participants are confirmed to be alive, or if the death date is after the DCO date, then 
these participants will be censored at the date of DCO. 

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7.2 
Participant Withdrawal from the Study  
• 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options to ensure the collection of endpoints and 
safety information, including new AEs and follow-up of any ongoing AEs and 
concomitant medications (eg, telephone contact 28 [+7] days after study intervention is 
discontinued, a contact with a relative or treating physician, or information from medical 
records). 
• 
At the time of withdrawal from the study, if possible, an EoT visit and a safety follow-up 
visit should be conducted, as shown in the SoA (Table 1). See SoA for data to be 
collected at the time of study withdrawal and follow-up and for any further evaluations 
that need to be completed. 
− The participant will discontinue the study intervention and be withdrawn from the study 
at that time. 
• 
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• 
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the informed consent and local regulation. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team. 
7.3 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and no contact has been established by the time the study is completed (see 
Section 4.4), such that there is insufficient information to determine the participant’s status at 
that time. 
Participants who decline to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing participants 
throughout the study period. If contact with a missing participant is re-established, the 
participant should not be considered lost to follow-up and evaluations should resume 
according to the protocol. 
The following actions must be taken if a participant fails to return to the clinic for a required 

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study visit: 
• 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls, texts 
or emails and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• 
Should the participant continue to be unreachable, he/she will be considered to have been 
lost to follow-up from the study. 
• 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant during survival follow-up within legal and ethical boundaries for all 
participants randomized, including those who did not get study intervention. Public 
sources may be searched for vital status information. If vital status is determined as 
deceased this will be documented, and the participant will not be considered lost to 
follow-up. Sponsor personnel will not be involved in any attempts to collect vital status 
information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
In order to support key efficacy endpoints of PFS and OS, the survival status of all 
participants in the ITT population and the Safety Analysis Set should be re-checked; this 
includes those participants who withdrew consent or are classified as “lost to follow-up.” 
• 
Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status (the applicable eCRF modules will be updated). 
• 
In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status. 
8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA (Table 1). Data collection 
following study analysis until the end of the study is described below.  
• 
Protocol waivers or exemptions are not allowed. 

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• 
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• 
Adherence to the study design requirements, including those specified in the SoA (Table 
1), is essential and required for study conduct. 
• 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Table 1). 
 
Data Collection Following Study Analysis until the End of the Study 
Following the DCO for the primary PFS efficacy endpoint, assessments for PK will be 
discontinued. Participants will continue with all other assessments as indicated in the SoA 
(Table 1). 
For SAE reporting and laboratory assessment collection after final analysis, see 
Section 8.3.12. After the final DCO and database closure, only SAEs will be reported for the 
purposes of this study (see Section 8.3.12). 
8.1 
Efficacy Assessments  
Efficacy assessments of PFS, ORR, DoR, and DCR will be evaluated based on RECIST 1.1 
tumor assessments.  
8.1.1 
Imaging Tumor Assessments  
Tumor assessments use images from CT (preferred) or MRI, with IV contrast, of the chest, 
abdomen (including the entire liver and both adrenal glands), and pelvis, collected during 
screening/baseline and at regular (follow-up) intervals during study intervention as defined in 
the SoA (Table 1). 
An MRI (preferred) or CT of the brain will also be collected for all participants at baseline. 
Follow-up brain scans are subsequently mandatory for all participants randomized with stable 
brain metastases at baseline, whilst participants without brain metastases do not need 
additional brain scans for subsequent tumor assessments, unless clinically indicated.  
All participants should have a baseline whole body bone scan or skeletal survey. For 
participants with no bone lesion, a historical bone scan documenting absence of bone lesions 

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performed no more than 12 weeks before randomization could be provided. For participants 
with documented bone lesion at baseline, the bone scan must be performed no more than 
28 days before randomization. Bone scintigraphy is the preferred modality. If a participant had 
a Choline PET-CT, or Diffusion Weighted MRI as part of the routine clinical management 
performed less than 28 days before randomization, it may be utilized as screening scan to 
document bone disease. Bone lesions identified on bone scan at baseline must be confirmed 
by CT, MRI, or X-ray to be recorded as NTLs and followed by the same method (CT, MRI, or 
X-ray), as indicated in the SoA (Table 1). 
Any other areas of disease involvement should be additionally imaged at screening based on 
known metastasis sites or by the signs and symptoms of individual participants.  
The imaging modality used for baseline tumor assessment, CT/MRI for chest and abdomen 
and MRI for brain, should be kept the same consistently at each subsequent follow-up 
assessment throughout the study if possible. It is important to follow the tumor assessment 
schedule as closely as possible (refer to the SoA [Table 1]) relative to randomization.  
New lesions may also be identified by fluorodeoxyglucose-PET scans, X-ray, bone 
(scintigraphy) scans. If an unscheduled assessment was performed (eg, to investigate clinical 
signs/symptoms of progression) and the disease has not progressed, every attempt should be 
made to perform the subsequent imaging at the next regularly scheduled visit. Digital copies 
of all scans should be maintained at the site as source documents.  
Screening/baseline imaging should be performed no more than 28 days before randomization 
and ideally should be performed as close as possible to and prior randomization. 
Treatment continues until RECIST 1.1-defined radiological progression by Investigator 
assessment (refer to Appendix F). Following disease progression, 1 additional follow-up scan 
should be performed as per imaging schedule (ie, either 6 weeks or 9 weeks later). In the event 
the investigator identified progression does not match with the BICR evaluation, this 
additional scan may identify progression by BICR.  
If an unscheduled assessment is performed (eg, to investigate clinical signs/symptoms of 
progression) and the participant has not progressed, every attempt should be made to perform 
the subsequent assessments at the next scheduled visit.  
The RECIST 1.1 assessments of baseline images identify TLs and NTLs. On-study images are 
evaluated for TLs and NTLs chosen at baseline, and for NLs when they appear. This allows 
determination of follow-up TL response, NTL lesion response, the presence of unequivocal 
NLs, and overall time point responses (CR, PR, SD, PD, or NE). 

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8.1.2 
Central Reading of Scans  
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed iCRO for quality control, storage, and for BICR. Digital copies of all 
original scans should be stored at the investigator site as source documents. Electronic image 
transfer from the sites to the iCRO is strongly encouraged. A BICR of images will be 
performed at the discretion of AstraZeneca.  
Results of these independent reviews will not be communicated to investigators, and results of 
investigator tumor assessments will not be shared with the central reviewers. 
The management of participants will be based upon the results of RECIST 1.1 assessments 
conducted by the Investigator. After the primary PFS analysis, central review of scans will no 
longer be required, and investigators will be advised when to stop sending copies of the scans 
to the iCRO conducting the central review; however, digital copies of all original scans should 
continue to be stored at the investigator site as source documents. 
Further details of the BICR will be documented in an Independent Review Charter. 
8.1.3 
Time to Second Progression or Death  
Following objective progression, participants will have their subsequent progression status 
recorded every 3 months (±14 days) per local standard clinical practice to assess PFS2.  
A participant’s PFS2 status is defined according to the local practice and may involve any of:  
• objective radiological progression (preferred),  
• symptomatic progression, or  
• death.  
Scans will be performed according to the local practice and formal RECIST 1.1 measurements 
will not be collected for assessment of PFS2. The second progression event must have 
occurred during or after anticancer treatment with a subsequent treatment after the progression 
event used for the primary variable PFS or death. The date of PFS2 assessment and 
investigator opinion of progression status (progressed or non-progressed) at each assessment 
will be recorded in the source documents and the eCRF. 
8.1.4 
Overall Survival  
Assessments for survival will be conducted every 3 months (±14 days) following objective PD 
or treatment discontinuation until the end of the study. Survival information may be obtained 
via telephone contact with the participant, participant’s family, by contact with the 
participant’s current physician, or local death registries as described in Section 7.2. The study 
may continue monitoring participants for OS up to the scheduled final analysis, beyond 

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planned interim analyses, to provide more refined estimates of treatment effects for survival. 
8.1.5 
Clinical Outcome Assessments (COA)  
A COA is any assessment that may be influenced by human choices, judgment, or motivation 
and may support either direct or indirect evidence of treatment benefit. COAs can be reported 
by a participant (PRO), a clinician (ClinRO), an observer (ObsRO), or through a 
performance-based assessment (FDA-NIH BEST Resource). A COA may be used in clinical 
studies to provide either direct or indirect evidence of treatment benefit. It is important to 
examine the impact of therapy on symptoms, function, and other health-related QoL of the 
participant to aid understanding of the risk-benefit profile. 
Patient Reported Outcome (PRO) assessment is one type of COA and is a general term 
referring to all outcomes and symptoms that are directly reported by the participant. Patient 
Reported Outcomes have become important in evaluating the efficacy and tolerability of study 
interventions in clinical studies and will aid in understanding of the benefit/risk evaluation 
(Kluetz et al 2018).  
The following PRO instruments will be administered in this study (see Appendix H): 
• EORTC QLQ-C30 (see Section 8.1.5.1) 
• EORTC IL116: selected breast and arm symptom scales from EORTC QLQ-BR45/IL (see 
Section 8.1.5.2) 
• Selected items from PRO-CTCAE (see Section 8.1.5.3) 
• EORTC IL117: selected symptomatic AE items from EORTC IL (see Section 8.1.5.4) 
• PGI-TT (see Section 8.1.5.5) 
• PGIS (see Section 8.1.5.6) 
• PGIC (see Section 8.1.5.7) 
• EQ-5D-5L (see Section 8.1.5.8) 
Patient Reported Outcome questionnaires will be administered according to the SoA (Table 1). 
The PRO questionnaires will be completed by participants if a linguistically validated version 
is available in their language for the country in which they live. 
8.1.5.1 
EORTC QLQ-C30  
The EORTC QLQ-C30 was developed by the EORTC QoL Group 1993. It consists of 30 item 
and measures symptoms, functioning, and global health status/QoL (Aaronson et al 1993) for 
all cancer types. Questions are grouped into 5 multi-item functional scales (physical, role, 
emotional, cognitive, and social), 3 multi-item symptom scales (fatigue, pain, and 
nausea/vomiting), a 2-item global QoL scale, 5 single items assessing additional symptoms 

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commonly reported by cancer participants (dyspnea, loss of appetite, insomnia, constipation, 
and diarrhea), and 1 item on the financial impact of the disease. The EORTC QLQ-C30 is a 
valid and reliable PRO instrument in this participant population. 
8.1.5.2 
EORTC IL116: selected breast and arm symptom scales from EORTC QLQ-
BR45/IL  
The EORTC QLQ-BR45 is an updated version of the BR23, a validated breast cancer-specific 
module used in conjunction with the core QLQ-C30 to assess breast cancer-specific HRQoL 
(Bjelic-Radisic et al 2020; Sprangers et al 1996). New breast cancer treatments and 
diagnostics prompted the update of the QLQ-BR23 to include an additional 22 items. Items 
are scored on a 4-point verbal rating scale: “Not at All,” “A Little,” “Quite a Bit,” and “Very 
Much”. Scores are transformed to a 0 to 100 scale, where higher scores for functioning scales 
or items indicate better functioning, whereas higher scores for symptom scales or items 
represent a worse level of symptoms.  
The current study will only include the breast symptoms and arm symptoms scales (7 items) 
from the BR45, ie, EORTC IL116. 
8.1.5.3 
PRO-CTCAE  
The PRO-CTCAE was developed to evaluate symptomatic toxicity in participants in cancer 
trials. The PRO-CTCAE will only be administered in those countries where a linguistically 
validated version is available. PRO-CTCAE is an item library of symptoms experienced by 
participants while undergoing treatment of their cancer. It has been carefully and 
systematically developed based on the NCI-CTCAE to provide participant-reported 
assessment of common adverse effects of cancer treatments, including a library of 124 items, 
representing 78 symptomatic toxicities. The items have previously undergone extensive 
qualitative and quantitative evaluation to support their validity and reliability (Basch et al 
2014, Dueck et al 2015, Hay et al 2014). For each symptomatic AE (eg, headache), there are 
up to three questions related to key symptom attributes, including the symptom frequency, 
severity, and interference with daily activities. Each question uses a 7-day recall with a 5-point 
ordinal response scale.  
The items pre-selected for this study include mouth/throat sores, decreased appetite, nausea, 
vomiting, constipation, diarrhea, abdominal pain, shortness of breath, cough, rash, hair loss, 
hand-foot syndrome, numbness/tingling, and fatigue. These items are based on a review of the 
core symptom set from NCI, expected treatment-related symptoms, and in consideration of 
symptoms that are already captured in the other PRO instruments with a view to minimize 
participant burden. The free text item in the PRO‑CTCAE instrument is not included in the 
study, as the utility of this information and the analysis method have not been established.  
8.1.5.4 
EORTC IL117: selected symptomatic AE items from EORTC IL  
The EORTC IL is an online platform comprised of more than 900 individual items from over 

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60 EORTC questionnaires. As the static questionnaires might not always be sufficient to meet 
the demands of quickly evolving treatment modalities, selecting items from EORTC IL offers 
new opportunities to leverage existing EORTC items for capturing the additional symptoms 
that are relevant to a given study.  
The pre-selected items for this study will include dry eyes, mouth pain, and sore mouth (ie, 
EORTC IL117). These items were selected using the same methodologies as described in 
Section 8.1.5.3 (PRO-CTCAE) to measure additional participant-reported symptomatic AEs 
which are not captured in the PRO-CTCAE. The recall period is during the past week. Items 
are scored on a 4-point verbal rating scale: "Not at all", "A little", "Quite a bit", and "Very 
much". 
8.1.5.5 
PGI-TT  
The PGI-TT item is included to assess how a participant perceives the overall burden of 
treatment-related side effects of cancer treatment over the past 1 week. Participants will be 
asked to choose the response that best describes the level of burden by the side effect of their 
cancer treatment over the past week. The response options are: “not at all”, “a little bit”, 
“somewhat”, “quite a bit”, and “very much”. This item is included to aid in the interpretation 
of other PRO measures and to evaluate the overall impact of treatment-related side effects. 
8.1.5.6 
PGIS  
The PGIS item is included to assess how a participant perceives the overall severity of cancer 
symptoms over the past 1 week. Participants will be asked to choose the response that best 
describes the severity of their overall cancer symptoms over the past week. The response 
options are: “none”, “mild”, “moderate”, and “severe”. This item is included to aid in the 
interpretation of other PRO measures and to evaluate the overall impact of treatment on the 
global severity of cancer symptoms. 
8.1.5.7 
PGIC  
The PGIC item is included to assess how a participant perceives their overall change in health 
status since the start of study treatment. This is single-item questionnaire and participants will 
choose from response options ranging from “Much better” to “Much worse”. 
8.1.5.8 
EQ-5D-5L  
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility. 
The EQ-5D-5L, developed by the EuroQoL Group, is a generic questionnaire that provides a 
simple descriptive profile of health and a single index value for health status for economic 
appraisal (EuroQol 2019). The EQ-5D-5L questionnaire comprises 6 questions that cover 
5 dimensions of health (eg, mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Respondents also assess their health today using the EQ-VAS, which 

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ranges from 0 (worst imaginable health) to 100 (best imaginable health) (see Appendix H). 
8.1.5.9 
Administration of Electronic PRO (ePRO) Questionnaires  
Patient Reported Outcome questionnaires will be self-administered electronically at home by 
the participants using an application installed on their personal mobile device, or a handheld 
device (if their personal device is not compatible or preferred) at the time points indicated in 
the SoA (Table 1). Participants should complete the ePROs prior to or at the sites if the 
assessment time point coincides with a scheduled site visit. Participants must be instructed to 
bring their device to all visits. 
Each site must allocate the responsibility for the administration of the ePRO instruments to a 
specific individual (eg, a research nurse or study coordinator) and, if possible, assign a 
back-up person to cover if that individual is absent. 
A web back-up may be available to answer the questionnaires if there are technical problems 
with the device. 
Approximately 10 to 20 minutes is required for participants to complete the questionnaires. 
The below instructions should be followed when collecting PRO data: 
• 
The research nurse or appointed site staff should explain to participants the value and 
relevance of these data, so they are motivated to comply with questionnaire completion. 
Inform the participant that these questions are being asked to find out, directly from them, 
how they feel. 
• 
Participants must not be onboarded onto the ePRO application (ie, must not have their 
account set up or invitation email sent) until the actual day of their C1D1 visit. This is 
required to ensure that the correct C1D1 date is registered in the ePRO system.  
• 
It is vital that the ePRO reporting is initiated prior to dosing or any other study procedure 
on C1D1, as specified in the SoA (Table 1) to capture the effect of the study intervention. 
The ePRO device must be charged and fully functional at the beginning of the baseline 
(ie, C1D1) visit to ensure that the PROs can be completed at the start of the visit. 
• 
The participant should bring their device to each site visit so the research nurse or 
appointed site staff can check if there are available PRO questionnaire to be completed 
and that the device is functioning properly. 
• 
Patient Reported Outcome questionnaires completed at the sites must be completed prior 
to treatment administration or any other study procedures performed at the site and ideally 
before any discussions of health status (following informed consent), including 
medication treatments, and before discussion of PD to avoid biasing the participant’s 
responses to the questions. As feasible, site staff should also ensure PRO questionnaires 

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are completed prior to other study procedures, such as collection of laboratory samples, to 
further minimize bias. 
• 
On completion of the questionnaire at the site, the device should be handed back to the 
research nurse or appointed staff, who should check that all questionnaires were 
completed. 
• 
When each instrument is due to be completed, the following order must be observed 
(however although the order will be pre-programmed into the ePRO):  
− EORTC QLQ-C30 
− EORTC IL116 
− PRO-CTCAE 
− EORTC IL117 
− PGI-TT 
− PGIS 
− PGIC 
− EQ-5D-5L 
• 
Patient Reported Outcome questionnaires should be completed by the participant in a 
quiet and private location. 
• 
The participant should be given sufficient time to complete the PRO questionnaires at 
their own speed. 
• 
The research nurse or appointed site staff should stress that the information is not 
routinely shared with study staff. Therefore, if the participant has any medical problems, 
he/she should discuss them with the doctor or research nurse separately from the ePRO 
assessment. 
• 
The research nurse or appointed site staff must train the participant on how to use the 
ePRO device/application using the materials and training provided by the ePRO vendor. 
• 
The research nurse or appointed site staff must provide guidance on whom to call if there 
are problems with the device when the participant is completing the ePRO at home. 
• 
All PRO questionnaires are to be completed using the ePRO application and/or assigned 
device. If technical or other device-related issues prohibit completion on the device, an 
appropriate back-up option may be considered with prior approval from AstraZeneca. 
• 
The research nurse or appointed site staff must remind the participant that there are no 
right or wrong answers and avoid introducing bias by not clarifying items. 
• 
The participant must not receive help from relatives, friends, or clinic staff deciding on 
answers to the ePRO questionnaires. The responses are the participant's alone. 

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• 
If a participant uses visual aids (eg, glasses or contact lenses) for reading and does not 
have them when he or she attends the site visit, the participant may be exempted from 
completing the PRO questionnaires at that site visit. 
• 
Site staff must not read or complete the ePRO questionnaires on behalf of the participant. 
If the participant is unable to read the questionnaire (eg, is blind or illiterate or not fluent 
in the available language), that participant is exempted from completing PRO 
questionnaires but may still participate in the study. If the participant cannot complete the 
PRO questionnaires due to reasons other than being blind, illiterate, or not fluent in an 
available language, the AstraZeneca study team must be contacted to determine if they 
can be exempted. Participants exempted in any regard should be flagged appropriately by 
the site staff in the source documents and in the designated eCRF. 
• 
Questions must not be translated from an available language in the device into the 
language for the participant speaks. 
• 
Reminders should be provided to participants as needed to ensure compliance with the 
assessment schedules. 
• 
The research nurse or appointed site staff must monitor compliance since minimizing 
missing data is a key aspect of the study success. 
• 
Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a participant could not 
complete assessments, in the source documents and in the designated eCRF. If the site 
receives an email notification regarding the participant’s compliance, appropriate action 
will be taken (eg, discussion with participant to improve compliance, a check in call from 
the site to ask the participant if they have any difficulties in completing questionnaires on 
schedule, etc). A solution to enhance/resolve compliance should be discussed with the 
participant. Discussion and compliance review should be reflected in source documents. 
8.2 
Safety Assessments  
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.2.1 
Physical Examinations  
Physical examination, as well as assessment of height and weight, will be performed at the 
timings specified in the SoA (Table 1); investigators should pay special attention to clinical 
signs related to previous serious illnesses, as new or worsening abnormalities may qualify as 
AEs; see Section 8.3.5 for details. 
A full physical examination includes assessment of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), oral (mouth), lymph nodes, thyroid, musculoskeletal (including spine and extremities), 
urogenital, dermatological, gastrointestinal, endocrine, hematologic/lymphatic, and 
neurological systems.  

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Targeted physical examinations are to be used by the investigator on the basis of clinical 
observations and symptomatology. A targeted physical examination includes at a minimum, 
assessments of the skin, lungs, oral, cardiovascular system, and abdomen (liver and spleen). 
8.2.2 
Vital Signs  
Vital signs will be performed at timelines as specified in the SoA (Table 1). Temperature, 
pulse rate, respiratory rate, pulse oximetry (SpO2), and blood pressure will be assessed. The 
participant should remain at the site for at least 1-hour post-infusion for close observation for 
possible IRRs (for participants receiving Dato-DXd only). 
Blood pressure and pulse measurements will be assessed in a supine, semi-recumbent, or 
seated position with a completely automated device, whenever possible. Manual techniques 
will be used only if an automated device is not available. Blood pressure and pulse 
measurements should be preceded by at least 5 minutes of rest for the participant in a quiet 
setting without distractions (eg, television, cell phones). 
Vital signs will be evaluated and recorded in eCRF.  
Where applicable, blood pressure and pulse rate should be collected prior to the beginning of 
study intervention infusion (measured once from approximately 30 minutes before up to 
0 minutes [ie, the beginning of the infusion]) and at the end of the infusion. These 
measurements may also be taken more frequently if clinically indicated. 
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5.  
For any AEs of infusion reactions, the vital signs values should be entered into the eCRF. 
8.2.3 
Electrocardiograms  
Triplicate 12-lead ECGs will be performed at screening and at the EoT visit. The 3 individual 
ECG tracings should be obtained in succession, no more than 2 minutes apart. The full set of 
triplicates should be completed within 5 minutes. Subsequent ECGs will only be taken in 
triplicate if abnormalities were noted at screening.  
Electrocardiograms will be performed at timelines as specified in the SoA (Table 1) after the 
participant has been resting supine/semi-recumbent for at least 5 minutes and recorded while 
the participant remains in that position using an ECG machine that automatically calculates 
the heart rate and measures PR, QRS, QT, and QTcF intervals, as possible.  
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities detected require triplicate ECG results. 

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Situations in which ECG results should be reported as AEs are described in Section 8.3.5. 
Whenever ECGs, vital signs, and blood draws are scheduled for the same nominal time, ECG 
assessments should occur first, then vital signs assessments, and then blood draws; the timing 
of the first 2 assessments should be such that it allows the blood draw (eg, PK blood sample) 
to occur at the timepoints indicated in the SoA (Table 1). 
8.2.4 
Clinical Safety Laboratory Assessments  
Blood and urine samples for determination of clinical chemistry, hematology, coagulation, and 
urinalysis will be taken at the visits indicated in the SoA (Table 1). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF. Laboratory assessments for off-schedule study drug 
dosing may be entered in the eCRF as unscheduled visits. 
The clinical chemistry, hematology and urinalysis will be performed at a local laboratory at or 
near to the investigator site. Sample tubes and sample volumes may vary depending on 
laboratory method used and routine practice at the site. 
Other safety laboratory tests include assessment for pregnancy (serum at screening and urine 
at all other time points), and hepatitis B and C serology, and HIV antibody test.  
Pregnancy tests may be performed at the site using a licensed test. A negative result from a 
serum pregnancy test (which must have a sensitivity of at least 25 mIU/mL) must be available 
at the screening visit. Pregnancy tests should be conducted within 72 hours prior to 
randomization for all female participants of childbearing potential. Repeat pregnancy tests 
(urine beta-human chorionic gonadotropin or serum test per institutional guideline) should be 
performed 72 hours before infusion of each cycle and at the EoT visit. If a positive urine 
pregnancy test result is confirmed using a serum test in a female participant of childbearing 
potential, then the participant should not be treated.  
Abnormal clinically significant laboratory results should be repeated as soon as possible 
(preferably within 24 to 48 hours).  
The laboratory variables to be measured are presented in Table 7.  
 
 

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Table 7 
Laboratory Safety Variables 
Hematology/Haemostasis (Whole Blood) 
Clinical Chemistry (Serum or Plasma) 
Hemoglobin 
Creatinine 
White blood cell count 
Bilirubin, total 
Leukocyte differential count (absolute count and/or %; 
neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Alkaline phosphatase 
AST 
Platelet count 
ALT 
Hematocrit 
Albumin 
Red blood cell count 
Potassium 
Urinalysis 
Calcium (total) or Calcium (ionized) 
Hemoglobin/Erythrocytes/Blood 
Sodium 
Protein/Albumin 
Lactate dehydrogenase 
Glucose 
Protein, total 
 
Urea nitrogen or blood urea nitrogen or urea 
 
Magnesium 
 
Chloride 
 
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated and recorded on the eCRF. Situations in which laboratory 
safety results should be reported as AEs are described in Section 8.3.5. 
All participants with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from study intervention must be followed and have further tests performed 
until the laboratory values have returned to Grade 1 or 2, unless these values are not likely to 
improve because of the underlying disease. 
NB. If a participant has an AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, refer to 
Appendix E for further instructions.  
8.2.5 
Other Safety Assessments  
8.2.5.1 
Echocardiogram/Multigated Acquisition Scan  
An echocardiogram or MUGA scan to assess LVEF will be performed at the visits indicated in 
SoA (Table 1). The modality of the cardiac function assessments must be consistent for a 
given participant (ie, if echocardiogram is used for the screening assessment for a given 
participant, then echocardiogram should also be used for subsequent scans for that 
participant). The participants should also be examined using the same machine and operator 
whenever possible, and quantitative measurements should be taken (ie, accurate to 1% and not 

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estimated to 5%). 
The EoT echocardiogram/MUGA scan is not required unless clinically indicated. If a 
participant has any clinically significant decrease in LVEF (greater than 10 percentage points 
to below 50%), there should be follow-up within 4 weeks until resolution. 
Situations in which echocardiogram or MUGA results should be reported as AEs are described 
in Section 8.3.5. 
8.2.5.2 
Pulmonary Function Tests  
Pulse oximetry (SpO2) should be evaluated by the investigator or the delegate physician at the 
time points outlined in the SoA and as clinically indicated. The SpO2 should be measured at 
the same time as vital signs. 
Pulmonary function tests should include basic spirometry at a minimum with optional 
additional components as mentioned in Table 8. 
Table 8 
Spirometry Component 
Required spirometry components 
Optional spirometry components 
FVC (L) 
PEF 
FVC % predicted 
DLCO 
FEV1 (L) 
FEV6 
FEV1 % predicted 
TLC 
FEV1/FVC % 
RV 
 
 
Diffusion capacity of the lungs for carbon monoxide will be performed/encouraged if feasible, 
but for participants with prior severe and/or prior clinically significant pulmonary disorders, 
DLCO is a requirement. In event of suspected ILD/pneumonitis, refer to Section 8.2.5.3 
additional pulmonary assessments. 
8.2.5.3 
ILD/Pneumonitis Investigation  
For suspected ILD/pneumonitis (ie, if new or worsening pulmonary symptoms [eg, dyspnea, 
cough or fever] or radiological abnormality suggestive of ILD/pneumonitis is observed), 
treatment with Dato-DXd should be delayed and a full investigation is required as described in 
the Dato-DXd TMGs (see the Annex document to this CSP). 
Evaluations should include: 
• 
Detailed past medical history (including concomitant medications, ocular history, and 
previous use of tobacco, e-cigarettes, and/or vaping, etc.) 
• 
Physical examination, including auscultation of lung field 

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• 
Arterial blood gases (if clinically indicated) 
• 
Pulmonary function tests (see Section 8.2.5.2) and pulse oximetry (SpO2)  
• 
Bronchoscopy and bronchoalveolar lavage should be considered if clinically indicated 
and feasible. 
• 
HRCT of the chest (if feasible, otherwise non-contrast chest CT is acceptable [1 to 2 mm 
slice thickness recommended]). If both a non-contrast chest HRCT scan for assessment of 
ILD/pneumonitis and a diagnostic IV contrast enhanced chest CT scan for tumor response 
assessment (as part of chest-abdomen-pelvis imaging) are to be acquired in the same 
imaging session, HRCT should be performed first. 
• 
Pulmonologist consultation (infectious disease consultation as clinically indicated) 
• 
Blood culture, complete blood count, and differential white blood cell count; other blood 
tests could be considered as needed. 
• 
Troponin measurements will be done to rule out cardiac etiology. 
• 
Additional optional blood samples for serum exploratory ILD/pneumonitis biomarker 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed (see Section 8.6.1) 
• 
Additional optional blood sample for plasma exploratory ILD/pneumonitis biomarker 
analysis as soon as ILD/pneumonitis is suspected and/or diagnosed (see Section 8.6.1). 
Other tests may be considered, as needed (eg, COVID-19 test). 
The results of the full diagnostic workup (including HRCT, blood and sputum culture, 
hematological parameters, etc) is to be captured in the eCRF. A full diagnostic workup is 
strongly recommended to exclude alternative causes, such as lymphangitic carcinomatosis, 
infection, allergy, cardiogenic edema, or pulmonary hemorrhage. In the presence of 
confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a 
diagnosis of ILD/pneumonitis should be considered and the TMGs should be followed (see 
the Annex document to this CSP). 
When ILD/pneumonitis is suspected during study treatment, the following markers should be 
collected where possible: 
• 
Interstitial lung disease/pneumonitis markers: KL-6, SP-D, and β-D-glucan 
• 
Tumor markers: particular tumor markers that are related to disease progression 
(carcinoembryonic antigen) 
• 
Additional clinical chemistry: C-reactive protein, lactate dehydrogenase 
8.2.5.4 
ECOG Performance Status  
Eastern Cooperative Oncology Group performance status will be assessed at the times 
specified in the SoA (Table 1) based on the following: 

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0 
Fully active; able to carry out all usual activities without restrictions. 
1 
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (eg, light housework or office work). 
2 
Ambulatory and capable of self-care, but unable to carry out any work activities; up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair. 
5 
Dead. 
Any significant change from baseline or screening must be reported as an AE. 
8.2.5.5 
Ophthalmologic Assessments  
Ophthalmologic assessments by a licensed eye care provider, including but not limited to 
visual acuity testing, fluorescein staining, intraocular pressure, slit-lamp examination, and 
fundoscopy, will be performed as specified in the SoA (Table 1) by an ophthalmologist, or if 
unavailable, another licensed eye care provider. This will be done at screening, and then every 
3 cycles from C1D1 onwards (eg, C4D1, C7D1, C10D1 etc) within 14 days prior to scheduled 
cycle Day 1 visit (but not after scheduled visit), in addition to being done as clinically 
indicated while on trial, and at EoT. A suitable alternative to fluorescein staining of the cornea 
may be used in exceptional circumstances where fluorescein is not available. An 
ophthalmologic assessment should be considered for any ocular symptoms including, but not 
limited to, dry eye, decreased or blurred vision, foreign-body sensation, photophobia, tearing, 
pain, and eye redness. All ophthalmologic assessments should be entered into the eCRF and 
copies of all consultation reports should be filed in source notes. Please refer to the Dato-DXd 
Site Ophthalmologic Assessment Manual for further details. 
It should be strongly considered for all participants to avoid the use of contact lenses and to 
use artificial tears 4 times daily as preventative measure and up to 8 times daily as clinically 
needed while participating in the trial, starting at C1D1. The use of other eye medications (eg, 
topical corticosteroids) for prophylaxis should be at the discretion of an ophthalmologist, or if 
unavailable, another licensed eye care provider. Data from the ophthalmologic assessments on 
the first 100 randomized participants (approximately 50 in each arm, Dato-DXd and ICC) will 
be reviewed by a dedicated Ophthalmologic Data Review Committee (Section 9.6.3). The 
proposed data cutoff will be after completion of the last ophthalmologic assessment and a 
minimum of 2 assessments per participant for the first approximately 100 randomized 
participants. Until data collection has been completed and reviewed on the first approximately 
100 participants, ophthalmologic assessments will continue for enrolled participants, and 
participants should continue to be advised to strongly consider using artificial tears and 
avoiding use of contact lenses. Data from these ophthalmologic assessments on the first 

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approximately 100 randomized participants will be reviewed by an Ophthalmologic Data 
Review Committee (Section 9.6.3). Review of the Ophthalmologic Data Review Committee 
findings will further inform the ophthalmologic assessment and monitoring plan.  
The Dato-DXd Site Ophthalmologic Assessment Manual will be supplied by AZ, which 
provides assistance to the licensed eye care provider to assess any ocular surface toxicity. 
Any significant change from baseline must be reported as an AE (see Section 8.3.5). 
8.2.5.6 
Oral Care Plan  
A daily Oral Care Protocol (OCP) will be started before study drug initiation for all 
randomized participants (both Dato-DXd and ICC arms), and it must be maintained 
throughout the study as specified in the SoA (Table 1). An oral care kit will be provided at study 
enrolment and monthly thereafter until the safety FU visit, which will include a toothbrush, 
toothpaste, dental floss, and an alcohol-free mouthwash, as well as an oral care plan participant 
information guide will be provided to each randomized participant before study drug initiation.  
Participants should adhere to the following guidance:  
• 
Gently brush their teeth after meals and at bedtime using a soft or ultra-soft toothbrush (or 
swab) and a bland-flavored fluoride-containing toothpaste.  
• 
Floss their teeth every day, if able to do so without pain or causing gingival bleeding. 
• 
For participants receiving ICC, daily use of alcohol-free mouthwash is recommended. 
• 
For participants receiving Dato-DXd: 
Daily use of prophylaxis with a steroid-containing mouthwash (eg, dexamethasone oral 
solution 0.1 mg/mL 10 mL 4 times daily swish for 1 to 2 minutes then spit out; or a 
similar mouthwash regimen using an alternative steroid advocated by institutional/local 
guidelines) is highly recommended. 
− Note: Participants are allowed to take oral nystatin suspension or other topical 
antifungal agents after the steroid-containing mouthwash according to clinician 
preference based on institutional/local guidelines. 
• 
In the absence of a prophylactic steroid-containing mouthwash, daily use of inert, bland 
mouth rinses (eg, with a non-alcoholic and/or bicarbonate-containing mouthwash, 4 to 
6 times a day). 
• Prophylactic cryotherapy (ice chips or ice water held in the mouth throughout the 
infusion) should also be considered. 
 
The algorithm in Figure 4 may be used as a guidance to select an appropriate prophylaxis 
mouthwash: 

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Figure 4 
Prophylactic Mouthwash Algorithm 
 
As per Investigator judgment, a professional dental evaluation before study drug initiation and 
dental treatment if indicated, may reduce the risk of local and systemic infections from 
odontogenic sources. 
For further information, refer to the Dato-DXd TMGs (see the Annex document to this CSP). 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting  
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix B. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorized representative).  
Grade ≥ 3 ocular surface toxicity events should be reported in the EDC system within 
24 hours of awareness. 
The investigator and any designees are responsible for detecting, documenting, recording, and 
reporting events that meet the definition of an AE. 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information  
Adverse events and SAEs (other than ILD/pneumonitis) will be collected from the time of 
signature of the ICF, throughout the treatment period and including the safety follow-up 

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period (28 [+7] days) after the discontinuation of study intervention). All ILD/pneumonitis 
events regardless of severity should be reported beyond the 28 + 7-day safety follow-up 
period. All AESIs, regardless of severity or seriousness, must be followed until either event 
resolution, end of study, including any post-treatment follow-up, trial termination, withdrawal 
of consent, or participant death. If an event that starts post the defined safety follow-up period 
noted above is considered to be due to a late onset toxicity to study intervention, then it should 
be reported as an AE or SAE as applicable. 
Collection and reporting of AEs and SAEs after the final DCO is described in Section 8.3.12. 
Pre-existing medical conditions that may have been identified by mandatory screening 
procedures (eg, cataract on baseline ophthalmologic assessment, benign cyst on baseline 
imaging, etc.) should be recorded as medical history in the eCRF.  
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor. 
The following should be reported by the investigator in eCRF EDC AE page(s) in the clinical 
study database/paper SAE report form within 24 hours of becoming aware: 
• 
SAEs (see Section 8.3.2). 
• 
All potential ILD/pneumonitis cases, including both serious and non-serious potential 
ILD/pneumonitis cases (potential ILD/pneumonitis is described by the Event 
Adjudication Site Manual). 
• 
Hepatic events (both serious and non-serious) which meet the PHL criteria defined as an 
elevated ALT or AST ≥3 × ULN and an elevated TBL ≥ 2× ULN regardless if it is due to 
disease progression per investigator assessment that may occur either at different time 
points or simultaneously at any time during this study should always be reported to the 
sponsor. These events must be reported in the eCRF, with the investigator’s assessment of 
seriousness, severity, causality, and a detailed narrative. If the participant discontinues 
study intervention due to liver enzyme abnormalities, the participant will have additional 
clinical and laboratory evaluations as described in Appendix E in order to determine the 
nature and severity of the potential liver injury. 
• 
Grade ≥ 3 IRR. 
• 
Grade ≥ 3 ocular surface toxicity events.  
• 
Grade ≥ 2 keratitis events (includes keratitis, punctate keratitis, and ulcerative keratitis). 
• 
Overdose (see Section 8.4).  
Additional relevant information regarding the AESIs, regardless of seriousness, is to be 
collected through targeted questionnaires within the clinical study database (see 

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Section 8.3.11). 
8.3.2 
Follow-up of AEs and SAEs  
Any AE that is unresolved at the participant’s last AE assessment in the study should be 
followed up by the investigator for as long as medically indicated, but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 
participant with ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Adverse event variables 
The following variables will be collected for each AE: 
• 
Adverse event (verbatim). 
• 
The date when the AE started and stopped. 
• 
CTCAE grade/changes in CTCAE grade (report only the maximum CTCAE grade for a 
calendar day). 
• 
Whether the AE is serious or not (Appendix B). 
• 
Investigator causality rating against the study intervention(s) (yes or no). 
• 
Action taken with regard to study intervention(s). 
• 
Adverse event caused participant’s withdrawal from study (yes or no). 
• 
Administration of treatment for the AE. 
• 
Outcome. 
In addition, the following variables will be collected for SAEs: 
• 
Date AE met criteria for SAE. 
• 
Date investigator became aware of SAE. 
• 
Seriousness criteria. 
• 
Date of hospitalization. 
• 
Date of discharge. 
• 
Probable cause of death. 
• 
Date of death. 
• 
Autopsy performed. 
• 
Causality assessment in relation to study procedure(s). 
• 
Causality assessment to other medication. 
The grading scales found in the NCI-CTCAE Version 5.0 will be utilized for all events with an 
assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 

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CTCAE grades should be used. A copy of the CTCAE can be downloaded from the Cancer 
Therapy Evaluation Program website (http://ctep.cancer.gov).  
8.3.3 Causality Collection  
The investigator should assess causal relationship between study intervention and each AE, 
and answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?” 
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as “yes”. 
A guide to the interpretation of the causality question is found in Appendix B to the CSP. 
8.3.4 Adverse Events Based on Signs and Symptoms  
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit/you were 
last asked?”, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
8.3.5 Adverse Events Based on Examinations and Tests  
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
echocardiogram/MUGA scans, ECOG performance status, and ophthalmologic assessments 
will be summarized in the CSR.  
Deterioration as compared with baseline in protocol-mandated laboratory values, vital signs, 
ECGs, and ECHO/MUGA scans should therefore only be reported as AEs if they fulfil any of 
the SAE criteria, are the reason for discontinuation of treatment with the study intervention or 
are considered to be clinically relevant as judged by the investigator (which may include but 
not limited to consideration as to whether treatment or non-planned visits were required or 
other action was taken with the study intervention, eg, dose adjustment or study intervention 
interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 

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parameters should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to PD, should not be reported 
as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.6 Hy’s Law  
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN may 
need to be reported as SAEs. A targeted questionnaire in the eCRF needs to be filled out for 
every case that meets these pre-specified laboratory criteria. 
8.3.7 Disease Progression  
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new metastases or progression of existing metastasis to the primary cancer 
under study should be considered as PD and not an AE. Events, which are unequivocally due 
to PD, should not be reported as an AE during the study. Death due to disease progression 
should be recorded on the Death eCRF. 
8.3.8 Disease Under Study  
Symptoms of disease under study are those which might be expected to occur as a direct result 
of breast cancer. Events which are unequivocally due to disease under study should not be 
reported as an AE during the study unless they meet SAE criteria or lead to discontinuation of 
the study intervention. 
8.3.9 
New Cancers  
The development of a new cancer should be regarded as an AE and will generally meet at least 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study intervention and are identified after the participant’s inclusion in 
this study. They do not include metastases of the original cancer. 
8.3.10 
Deaths  
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows: 

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• 
Death clearly resulting from PD should be documented in the eCRF in the Statement of 
Death page. It should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to PD under study, the AE causing the death 
must be reported as an SAE within 24 hours. It should also be documented in the 
Statement of Death page in the eCRF. The report should contain a comment regarding the 
co-involvement of PD, if appropriate, and should assign the main and contributory causes 
of death. 
• 
Deaths with an unknown cause should always be reported as an SAE and documented in 
the Statement of Death page in the eCRF, but every effort should be made to determine a 
cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames. 
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study intervention, then it should also 
be reported as an SAE. 
8.3.11 
Adverse Events of Special Interest  
Adverse events of special interest are events of scientific and medical interest specific to the 
further understanding of the Dato-DXd safety profile and require close monitoring and rapid 
communication by investigators to AstraZeneca. An AESI can be serious or non-serious. All 
AESIs will be recorded in the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. Serious AESIs will be recorded and reported as per 
Section 8.3.13. 
For the Dato-DXd clinical program, based on the available preclinical data, review of the 
cumulative literature, reported toxicities for drugs with a similar monoclonal antibody and 
payload of Dato-DXd, and biological plausibility, the following are considered AESIs:  
• ILD/pneumonitis  
• IRR  
• Oral mucositis/stomatitis 
• Mucosal inflammation other than oral mucositis/stomatitis 
• Ocular surface toxicity 
All AESIs, regardless of severity or seriousness, must be followed until either event 
resolution, end of study, trial termination, withdrawal of consent, or participant death. 

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Concomitant medications administered as treatment for drug-related AESIs should be 
recorded until either event resolution, end of study, trial termination, withdrawal of consent, or 
participant death. 
ILD/pneumonitis  
Interstitial lung disease/pneumonitis is considered an important identified risk for Dato-DXd 
based on a comprehensive cumulative review of the available safety data from the clinical 
development program as well as the results of potential ILD/pneumonitis cases reviewed by 
the independent ILD Adjudication Committee, available data from recent 
epidemiology/literature, biological plausibility, and safety information from drugs with a 
similar monoclonal antibody and payload as Dato-DXd. Refer to the current IB for a summary 
of preliminary clinical study data. 
All potential ILD/pneumonitis cases should be reported within 24 hours, including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD/pneumonitis is 
described in the Event Adjudication Site Manual). A targeted questionnaire is built within the 
eCRF to collect relevant additional information for these potential cases regardless of 
seriousness. 
Interstitial lung disease/pneumonitis should be ruled out if a participant develops radiographic 
changes potentially consistent with ILD/pneumonitis or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever. For 
further guidance on the management of suspected ILD/pneumonitis events, refer to 
Section 8.2.5.3 and the Annex document to this CSP. 
If the AE is suspected to be ILD/pneumonitis, treatment with study intervention should be 
interrupted pending further evaluations. Evaluations should include those outlined in 
Section 8.2.5.3. If the AE is confirmed to be ILD/pneumonitis, follow the management 
guidance outlined in the TMGs (see the Annex document to this CSP). All events of 
ILD/pneumonitis, regardless of severity or seriousness, will be followed until resolution 
including after Dato-DXd discontinuation. An autopsy in cases of Grade 5 ILD/pneumonitis is 
encouraged. An independent ILD Adjudication Committee for the Dato-DXd program is 
responsible for reviewing all cases of potential ILD/pneumonitis. See Section 9.6.2 for further 
details.  
IRR 
Infusion-related reaction is an identified risk for Dato-DXd. A Grade 3 IRR was reported and 
was assessed by an external consultant as anaphylaxis. A targeted questionnaire for ≥ Grade 3 
IRR will be available as an eCRF to collect relevant additional information for these potential 
cases. All grade ≥ 3 events of IRR, regardless of seriousness, must be reported in EDC within 
24 hours. Refer to the current IB for a summary of preliminary clinical study data. 

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Pre-medication is required prior to any dose of Dato-DXd and must include antihistamines 
and acetaminophen with or without glucocorticoids. If there are any signs or symptoms of a 
grade 1 or 2 IRR, the infusion of Dato-DXd must be either slowed down or interrupted based 
on severity of the infusion-related reaction (see Section 6.2.1.2). If the IRR is grade 3 or 4, or 
if there are any signs of anaphylaxis, the infusion of Dato-DXd must be discontinued. Please 
refer to the IRR management guidance outlined in the TMGs (see the Annex document to this 
CSP). 
Oral Mucositis/Stomatitis 
Oral mucositis/stomatitis AEs are considered as identified risks and AESIs associated with 
Dato-DXd treatment. Oral mucositis/stomatitis is considered as a separate AESI from mucosal 
inflammation other than oral mucositis/stomatitis. Recommendations for preventing and 
treating oral mucositis/stomatitis are outlined in the SoA (Table 1), Section 8.2.5.6, and the 
TMGs (see the Annex document to this CSP).  
Mucosal Inflammation other than Oral Mucositis/Stomatitis 
Mucosal inflammation AEs are considered as identified risks associated with Dato-DXd 
treatment and as a separate AESI from oral mucositis/stomatitis. 
Ocular Surface Toxicity 
Ocular surface toxicity (eg, dry eye, keratitis) is considered an AESI associated with 
Dato-DXd. Dry eye is considered as an identified risk and keratitis as a potential risk within 
this AESI. Participants are advised to use artificial tears daily and to avoid contact lenses. 
Recommendations for preventing and treating ocular surface toxicity are available in the SoA 
(Table 1), Section 8.2.5.5 and the TMGs (see the Annex document to this CSP). 
The Dato-DXd Site Ophthalmologic Assessment Manual will be supplied by AstraZeneca to 
provide assistance to the licensed eye care provider to assess any ocular surface toxicity. 
8.3.12 
Safety Data to be Collected Following the Final Data Cutoff of the 
Study  
For participants continuing to receive study intervention after the final DCO, AEs and SAEs 
will be collected, but only SAEs will be reported. In addition, it is recommended that 
investigators monitor all participant’s safety laboratory results periodically during treatment 
with study intervention in order to manage AEs, consistent with the TMGs (see the Annex 
document to this CSP). All data after the final DCO and database closure will be recorded in 
the participant notes but, with the exception of SAEs, will not otherwise be reported for the 
purposes of this study. 
All SAEs that occur in participants still receiving study intervention (or within the 
28 [+7] days following the last dose of study intervention) after the final DCO must be 

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reported as detailed in Section 8.3.13.  
8.3.13 
Reporting of Serious Adverse Events  
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF. For further 
guidance on the definition of an SAE, see Appendix B. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar 
days of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours of when he or she becomes aware of it. 
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative. 
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone followed by completion of a paper 
SAE form. 
The AstraZeneca representative will advise the investigator/study site staff how to proceed.  
The reference document for definition of expectedness is the IB for Dato-DXd, and respective 
EU SmPCs for the active comparator products. 
8.3.14 
Pregnancy  
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca. 
Female participants must not donate, or retrieve for their own use, ova from the time of 
Screening and throughout the study treatment period, and for at least 7 months after the final 
study drug administration. 

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8.3.14.1 
Maternal Exposure  
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately. The sponsor must be notified of any female participant or female 
partner of a male participant who becomes pregnant while receiving or within 7 months of 
discontinuing Dato-DXd. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly) should be followed up and documented even if the 
participant was discontinued from the study. 
If any pregnancy occurs during the course of the study, the investigator or other site personnel 
must inform the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.13) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy. 
8.3.14.2 
Paternal Exposure  
Non-sterilized male participants who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
the duration of the study (from the time of screening) and for 4 months after the last dose of 
study intervention.  
Participants in the ICC (capecitabine, eribulin, vinorelbine or gemcitabine) arm should follow 
the local Prescribing Information relating to contraception, the time limits for such 
precautions, and any additional restrictions for ICC agents. 
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) occurring from the date of the first dose of study intervention 
until 7 months after the last dose of study intervention should be followed up and documented 
in the medical record and provided to the AstraZeneca Patient Safety data entry site. Consent 

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from the partner must be obtained before the information is collected and reported to 
AstraZeneca. 
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRBs/IECs prior to use. 
8.3.15 
Medication Error, Drug Abuse, and Drug Misuse  
8.3.15.1.1 Timelines  
If an event of medication error, drug abuse or drug misuse occurs in the course of the study, 
then the investigator or other site personnel informs the appropriate AstraZeneca 
representatives within one calendar day, ie, immediately but no later than 24 hours of when 
he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-threatening or follow-up 
Fatal/Life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.13) and within 30 days for all other 
medication errors. 
8.3.15.2 
Medication Error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP/study intervention or AstraZeneca NIMP that either causes 
harm to the participant or has the potential to cause harm to the participant. 
The full definition and examples of a medication error can be found in Appendix B 4. 
8.3.15.3 
Drug Abuse  
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
IMP/study intervention or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect. 
The full definition and examples of drug abuse can be found in Appendix B 4. 
8.3.15.4 
Drug Misuse  
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study intervention(s) or AstraZeneca NIMPs, outside 
the intended use as specified in the protocol and includes deliberate administration of the 
product by the wrong route. 

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The full definition and examples of drug misuse can be found in Appendix B 4. 
8.3.16 
Medical Device Deficiencies  
This section is not applicable. 
8.4 
Overdose  
The use of Dato-DXd in doses exceeding that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of overdose of Dato-DXd, and 
possible symptoms of overdose are not established. An overdose with associated AEs is 
recorded as the AE diagnosis/symptoms on the relevant AE modules in the eCRF and on the 
Overdose eCRF module. 
• 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.13) and within 30 days 
for all other overdoses. 
For participants receiving ICC (capecitabine, eribulin, vinorelbine or gemcitabine), refer to the 
local Prescribing Information for treatment of cases of overdose. If any overdose is associated 
with an AE or SAE, record the AE/SAE diagnosis or symptoms in the relevant AE modules 
only of the eCRF. 
8.5 
Human Biological Samples  
Instructions for the collection, handling, storage and shipping of biological samples will be 
provided in the study-specific laboratory manual. Samples should be stored in a secure storage 
space with adequate measures to protect confidentiality.  
Samples may be stored for a maximum of 15 years from the end of the study (as defined in the 
Section 4.4) in line with consent and local requirements, after which they will be 
destroyed/repatriated. 
• 
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier). 

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▪ 
Samples may be disposed of or anonymized by pooling. Additional analyses may be 
conducted on the anonymized, pooled samples to further evaluate and validate the 
analytical method. Any results from such analyses may be reported separately from 
the CSR. 
▪ 
Samples collected in mainland China will be stored and disposed of according to 
local laws and regulations. PK samples collected in mainland China will be destroyed 
after finalization of Bioanalytical Report or completion of CSR.  
• 
Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 5 years from the CSR publication. ADA samples collected in China will be 
disposed of within 1 year of CSR publication. Additional use includes, but is not limited 
to, further characterization of any ADAs, evaluation of novel and emerging biomarkers, 
confirmation and/or requalification of the assay, and/or diagnostic assay development. 
The results from future analysis will not be reported in the CSR.  
For further details on Handling of Human Biological Samples, see Appendix C.  
8.5.1 
Pharmacokinetics  
Whole blood samples will be collected for participants receiving Dato-DXd treatment for 
measurement of plasma concentrations of Dato-DXd, total anti-TROP2 antibody, and 
MAAA-1181a, per the schedule specified in the SoA (Table 1). The actual date and time 
(24-hour clock time) of each sample should be recorded. 
Samples may also be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor (eg, for safety reasons). The timing of 
sampling may be altered during the course of the study based on newly available data (eg, to 
obtain data closer to the time of peak or trough matrix concentrations) to ensure appropriate 
monitoring.  
8.5.1.1 
Determination of Drug Concentration  
Samples for determination of Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a 
concentration in plasma will be assayed by bioanalytical test sites operated by or on behalf of 
AstraZeneca, using an appropriately validated bioanalytical method. Full details of the 
analytical method used will be described in a separate Bioanalytical Report. 
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report. 
8.5.2 
Immunogenicity Assessments  
Whole blood samples for determination of ADA for Dato-DXd in plasma will be collected 
from participants receiving Dato-DXd per the schedule specified in the SoA (Table 1). The 

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ADA samples may also be further tested for characterization of the ADA response. The ADA 
titer, and the presence of neutralizing ADA will be tested for positive ADA samples. 
Samples will be assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, 
using an appropriately validated bioanalytical method. Full details of the methods used will be 
described in a separate report. 
8.6 
Human Biological Sample Biomarkers  
8.6.1 
Collection of Mandatory Samples for Biomarker Analysis  
Participant consent to the study includes participation in the mandatory biomarker assessment 
components of the study.  
Samples for biomarker assessment are required and will be collected from all participants in 
this study as specified in the SoA (Table 1). In mainland China, tumor sample collection and 
tests will follow local regulatory requirements. 
The following mandatory samples will be collected from all randomized participants: 
Tumor tissue 
Tumor samples are mandatory for all participants in this study and must be available at the 
time of screening. This can be from either the primary disease setting (surgical resection or 
diagnostic sample), or from a metastatic lesion (excluding bone). The mandatory FFPE tumor 
sample submitted for analysis should be obtained as close to the time of diagnosis of 
metastatic or inoperable disease as possible. 
If neither an adequate FFPE block nor the minimum of 20 slides are available, a patient may 
still be considered eligible. In this situation, approval by the Global Study Team for patient’s 
entry into the study is required.  
If a block is not available, a minimum of 20 slides of freshly prepared, unstained, 
4 to 5-micron sections from the archival tumor block. As uncontrolled oxidation processes 
affect tumor sections, tumor tissue blocks are preferred.  
Tumor lesions used for fresh biopsies should not be the same lesions used as RECIST 1.1 
target lesions, unless there are no other lesions suitable for biopsy and in this instance only 
core needle (not excisional/incisional) biopsy is allowed. Collection of tumor cells from fluid 
such as ascites or pleural effusion is not permitted. The tumor sample must not be taken from 
a previously irradiated lesion.  
In mainland China, tumor sample collection and testing will follow local regulatory approval. 
Samples may be tested for biomarkers including (but not limited to) TROP2 protein and gene 

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expression, TROP2-interacting proteins and TOPO-1 expression, and tumor mutational profile 
to evaluate their association with the observed clinical responses to Dato-DXd (including but 
not limited to PFS and OS, as well as key safety endpoints). 
Based on availability of tissue, further additional exploratory biomarkers may be evaluated, 
which may include (but are not limited to), cell death and immunological biomarkers such as 
PD-L1 expression and tumor infiltrating lymphocyte, and gene-expression based tumor 
subtyping. 
Blood-borne Biomarkers 
• Blood samples to perform exploratory circulating biomarker, safety or clinical analyses on 
plasma and serum to identify candidate factors that may correlate with drug response, 
likelihood of clinical benefit and tolerability.  
These analyses may include, but are not limited to, cytokines and chemokines, to assess a 
range of oncology, immunological and safety biomarkers, the detection of the presence of 
viruses. Plasma may also be used for the detection/quantification of autoantibodies 
(against tumor-associated antigens). 
• Blood sample for the isolation of plasma and buffy coat to enable analysis and 
interpretation of ctDNA, to characterize changes in mutational profile (single nucleotide 
variant and copy number alteration) and allele frequency, between baseline and on-
treatment as a predictive marker for clinical outcomes as exploratory endpoints. 
The buffy coat layer obtained during the plasma isolation process of the baseline sample 
will be taken, to enable assessment, analysis and interpretation of ctDNA:  
▪ 
ctDNA samples will be analyzed for predictive biomarkers of response to treatment. 
The sample is requested prior to treatment in order to maximize the probability of 
detecting ctDNA where the tumor burden is relatively high. 
▪ 
ctDNA samples taken during treatment and a final sample taken at disease 
progression will be used for additional exploratory research which may include but is 
not limited to interrogation of changes in genetic alterations, ctDNA levels as well as 
the dynamics changes of the biomarkers on treatment and potential mechanisms of 
resistance to treatment. 
• 
Whole blood sample for RNA and DNA to conduct gene expression and mutational 
analyses to understand immunological changes following treatment with Dato-DXd and 
to assess gene signatures that may predict treatment response. 
These samples will be taken at multiple timepoints and analyzed for a range of 
oncology and immunological biomarkers that may correlate with drug response. These 
biomarkers may include but are not limited to T-cell receptor repertoire analysis and analysis 
of gene expression biomarkers associated with immunomodulatory effects. 

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Samples may be retained in all regions to allow for potential diagnostic development, while 
mainland China sample usage will still follow local regulatory approval. 
Test residual tumor samples collected for TROP2 IHC testing from Chinese participants will 
be destroyed or repatriated within 1 year after CSR completion. 
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual. 
8.6.2 
Collection of Optional Biomarker Samples  
Collection of optional samples for biomarker assessment is also part of this study (as specified 
in the SoA; Table 1) and is subject to agreement to optional consent. Collection of some 
optional samples will be mandated at select sites. 
Note: Optional biomarker samples will not be collected in mainland China. 
Optional tumor tissue samples for exploratory biomarker research 
• 
Paired tumor biopsy: A baseline biopsy will be taken (where the participant has provided 
informed consent) before initial dosing of study intervention (at screening or pre-dose on 
C1D1), and a paired (second) biopsy will be taken on-treatment. The paired on-treatment 
biopsy can be collected C2D1 and C2D7. On-treatment sample may also be collected 
outside of this specified timepoint with prior agreement from the Sponsor. Paired pre-
treatment and on-treatment tumor samples must be obtained from the same lesion where 
clinically feasible to maximize the utility for assessment of pharmacodynamic changes. 
These optional paired tumor samples will be mandatory at select sites. 
• 
Tumor biopsy on disease progression: An additional tumor biopsy sample should be 
obtained at termination of treatment/documented RECIST 1.1 disease progression in 
participants that have signed the additional optional consent. These samples will be used 
to explore mechanisms of resistance. The on-study provision of tumor tissue is 
encouraged only if clinically appropriate and not considered detrimental to participant 
care. 
Biopsies at study entry, on treatment, and progression are optional for the majority of 
participants in this study, and participants will not be excluded from the study if these samples 
are not collected. These optional biopsy samples will be mandatory at select sites. 
ILD related samples 
Participants will sign an informed consent for optional tissue samples to be taken in the event 
of suspected or diagnosed ILD.  

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Additional optional blood samples (serum and plasma) will be collected for exploratory 
biomarker analysis as soon as ILD/pneumonitis is suspected and/or diagnosed, if feasible (see 
Section 8.2.5.3). 
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual. 
8.6.3 
Other Study Related Biomarker Assessments  
Already collected samples may be analyzed on different biomarkers thought to play a role in 
efficacy and safety outcomes including, but not limited to, serum analytes, or tissue 
biomarkers and/or specific candidate genes/genome-wide analysis for RNA, to evaluate their 
association with observed clinical responses to Dato-DXd. The presence of viruses may also 
be investigated. 
Additional exploratory analyses may be undertaken on participants’ samples to identify other 
biomarkers of sensitivity and resistance to study interventions and our understanding of 
cancer. These studies would extend the search for other potential biomarkers relevant to the 
effects of Dato-DXd, cancer and/or the response/resistance to the study intervention. This may 
include the development of ways to detect, monitor or treat cancer. These additional 
investigations would be dependent upon clinical outcome, reagent, and sample availability. 
Samples collected in China will not be used for additional exploratory biomarker analyses 
beyond initial TROP2 IHC testing. 
For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and the Laboratory Manual. 
8.7 
Optional Genomics Initiative Sample  
Collection of optional samples for genomics initiative research is also part of this study as 
specified in the SoA (Table 1) and is subject to agreement in the ICF addendum. Samples will 
be collected according to local regulatory approval. 
Blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study. 
See Appendix D for information regarding the storage and destruction of Genomics Initiative 
genetic sample. Details on processes for collection, shipment and destruction of these samples 
can be found in the Laboratory Manual.  
Note: These samples will not be collected in mainland China. 

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8.8 
Medical Resource Utilization and Health Economics  
Health care resource use data associated with medical encounters, will be collected in the 
eCRF by the investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. 
The assessment of health care resource use will increase the understanding regarding the 
relationship between treatment and tumor-related cancer symptoms on resource use. This will 
be captured and analyzed to inform submissions to payers. 
The HOSPAD eCRF module will be used to collect information on key health care resource 
use beyond study mandated visits. To investigate the impact of treatment and disease on health 
care resource use and to conduct exploratory economic analyses, the following variables will 
be captured: 
• 
Planned and unplanned hospital attendances beyond trial protocol-mandated visits 
(including inpatient or outpatient physician visits, emergency room visits, surgeries, day 
cases and admissions) 
• 
Primary sign or symptom the participant presents with 
• 
Length of hospital stay 
• 
Length of any time spent in an intensive care unit 
• 
Number and type of diagnostic and therapeutic tests and procedures 
• 
Any other medical encounters and interventions (including physician or emergency room 
visits, tests and procedures, and medications). 
9 
STATISTICAL CONSIDERATIONS  
Statistical analyses will be performed by AstraZeneca or its representatives.  
A comprehensive SAP will be prepared prior to 3 months post-FSI, with final amendments 
completed prior to database lock. 
9.1 
Statistical Hypotheses  
The hypotheses of interest with regards to the efficacy for the dual primary endpoints are: 
• 
H0: No differences between Dato-DXd and ICC for PFS and OS. 
• 
H1: Differences between Dato-DXd and ICC for PFS and/or OS. 
 
The MTP will define which significance levels should be applied to the interpretation of the 
raw p-values for the dual primary endpoints of PFS and OS. Hypotheses will be tested using a 
MTP with an alpha-exhaustive recycling strategy (Burman et al 2009).  

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To strongly control the familywise type I error rate at the 5.0% level (2-sided), an alpha level 
of 1.0% will be allocated to the PFS dual primary analysis and the remaining 4.0% alpha level 
will be allocated to the OS analyses. If the PFS dual primary analysis crosses the efficacy 
threshold, the 1.0% type I error allocated to the PFS endpoint will be reallocated (Burman et 
al 2009) to the OS endpoint for a total 2-sided type I error of 5.0%. 
Hypotheses will be tested in the MTP using alpha (test mass) splitting and alpha recycling, 
where the test mass that becomes available to the OS analyses (recycled) if the PFS dual 
primary analysis null hypothesis is rejected. Implementation of this pre-defined ordered 
testing procedure, including recycling, will strongly control type I error at 5.0% (2-sided), 
among all dual primary hypotheses. 
To preserve the overall type I error (familywise error rate) in the strong sense, an MTP 
including the dual primary endpoints will be implemented. The MTP will be fully specified in 
the SAP. The MTP for the dual primary endpoints is described in Figure 5. 
Figure 5 
Multiple Testing Procedure 
 
9.2 
Sample Size Determination  
Approximately 1000 participants will be enrolled to achieve approximately 700 participants 
randomly assigned to study intervention.  
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study 
but are not randomly assigned/assigned in the study, are considered “screen failures”, unless 
otherwise specified by the protocol.  
The study is sized for dual primary endpoints to characterize the PFS and OS benefit of 
Dato-DXd versus ICC in the participants with HR-positive, HER2-negative breast cancer who 

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have been treated with one or two prior lines of systemic chemotherapy in the 
inoperable/metastatic setting. The study will be considered positive (a success) if either the 
PFS analysis results and/or the OS analysis results are statistically significant. 
The primary, final analysis of PFS will be performed when approximately 419 PFS BICR 
events occur, approximately 2 months after the last participant is randomized in the study; 
419 PFS BICR events from the ITT population across the Dato-DXd and ICC treatment 
groups will represent 60% maturity of data. Assuming the true PFS hazard ratio is 0.55 for 
Dato-DXd versus ICC, the study will have a greater than 99% power to demonstrate statistical 
significance at the 1.0% level (using a 2-sided test). This assumes median PFS times of 
4.7 months and 8.5 months in ICC and Dato-DXd, respectively when the PFS times are 
exponentially distributed. The smallest treatment difference that could be statistically 
significant at the final analysis is a hazard ratio of 0.775.  
The final analysis of OS will be performed when approximately 444 OS events have occurred 
across the Dato-DXd and ICC treatment groups (63% maturity). Assuming the true OS hazard 
ratio is 0.75 for Dato-DXd versus ICC, the study will have 85% power to demonstrate 
statistical significance at the 5.0% level (using a 2-sided test). This assumes the PFS primary 
analysis crosses the efficacy threshold, and allowing 2 interim analyses to be conducted at 
information fractions of approximately 40% and 80% of the target events, respectively (per 
the O’Brien and Fleming approach [Lan and DeMets 1983]). The smallest treatment 
difference that could be statistically significant at the final analysis is a hazard ratio of 0.824. 
If the PFS primary analysis does not cross the efficacy threshold, the OS analysis will have 
83% power to demonstrate statistical significance at the 4.0% level (using a 2-sided test). The 
smallest treatment difference that could be statistically significant at the final analysis is a 
hazard ratio of 0.817. Calculations assume median OS times of 19.0 months and 25.3 months 
in ICC and Dato-DXd, respectively when the survival times are exponentially distributed. The 
study may continue monitoring participants for OS up to the scheduled final analysis, beyond 
planned interim analyses, to provide more refined estimates of treatment effects for survival. 
Further details of the interim analyses are presented in Section 9.5. 
A nonuniform accrual of participants (with k = 1.5) is assumed when estimating the analysis 
times. The total proportion of participants randomized at time t [t ≤ 19 months] following the 
start of the study is assumed to be (t/19)k.  
Dual Primary Endpoints 
• Dato-DXd versus ICC (PFS in the ITT):  
Assuming the true PFS treatment effect under the alternative hypothesis is a hazard ratio 
of 0.55 for Dato-DXd versus ICC, and the median PFS in ICC is 4.7 months, 419 PFS 
events from the ITT population (60% maturity) will provide greater than 99% power to 
demonstrate statistical significance at the 2-sided alpha level of 1.0%. The smallest 

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treatment difference that is statistically significant will be a hazard ratio of 0.775. 
Assuming a recruitment period of 19 months, this analysis is anticipated to be 21 months 
after the first participant has been randomized. 
• Dato-DXd versus ICC (OS in the ITT): 
Assuming the true OS treatment effect under the alternative hypothesis is a hazard ratio of 
0.75 for Dato-DXd versus ICC, and the median OS in ICC is 19.0 months, 444 OS events 
from the ITT population (63% maturity) will provide approximately 83% power to 
demonstrate statistical significance at the 2-sided alpha level of 4.0%. The smallest 
treatment difference that is statistically significant will be a hazard ratio of 0.817. If the 
PFS dual primary analysis crosses the efficacy threshold, OS will be tested at the 2-sided 
alpha level of 5.0% and the analysis will have 85% power to demonstrate statistical 
significance. The smallest treatment difference that is statistically significant will be a 
hazard ratio of 0.824. With a recruitment period of approximately 19 months it is 
anticipated that the primary/final OS analysis will occur approximately 44 months after 
the first participant has been randomized.  
9.3 
Populations for Analyses  
The populations for analysis are defined in Table 9. 
Table 9 
Populations for Analysis 
Population/Analysis Set 
Description 
Enrolled 
All participants who sign the ICF. 
Intent-to-treat (ITT) 
population 
All participants who are randomized in the study, excluding participants 
randomized in mainland China after the global cohort last participant 
randomized, if applicable.  
The ITT will be used for all the efficacy analyses (including PROs: EORTC 
QLQ-C30, EORTC IL116, EQ-5D-5L, PGIS, PGIC). Treatment groups will be 
compared on the basis of randomized study intervention, regardless of the 
intervention actually received. Participants who were randomized but did not 
subsequently receive study intervention are included in the analysis in the 
intervention group to which they were randomized. 

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Table 9 
Populations for Analysis 
Population/Analysis Set 
Description 
Safety Analysis Set 
(SAS) 
Participants in the ITT who have received at least 1 dose of study intervention. 
Safety data will not be formally analyzed but summarized using the SAS 
according to actual study intervention received (including PROs: PGI-TT, PRO-
CTCAE, EORTC IL117). 
Ophthalmologic Analysis 
Set (OAS) 
Approximately the first 100 randomized participants (approximately 50 per arm, 
Dato-DXd and ICC) in the ITT. See section 8.2.5.5 for details. 
Pharmacokinetic Analysis 
Set (PAS) 
All participants in the ITT randomly assigned to study intervention who received 
at least 1 dose of study intervention for whom any post-dose PK data are 
available and who do not violate or deviate from the protocol in ways that would 
significantly affect the PK analyses. 
The population will be defined by the sponsor Study Physician, 
Pharmacokineticist, and Statistician prior to any analyses being performed. 
 
 
9.4 
Statistical Analyses  
The SAP will be finalized prior to 3 months post-FSI of the first randomized participant, and 
will include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints. 
9.4.1 
General Considerations  
More detail will be provided in the SAP. 
9.4.2 
Efficacy  
9.4.2.1 
Primary Endpoints  
Table 10 
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Primary Endpoints 
Endpoints analyzed 
Notes 
Progression-free survival 
Stratified log-rank test for: 
Dual primary analysis using BICR RECIST 1.1 assessments:  
• 
Dato-DXd versus ICC (ITT population) 
Secondary analysis using Investigator assessment: 
• 
Dato-DXd versus ICC (ITT population) 
Sensitivity analysis for the PFS dual primary analysis (ITT population): 
• 
Evaluation-time bias 
• 
Attrition bias 
• 
Ascertainment bias 
• 
Subsequent anticancer therapy 

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Table 10 
Pre-planned Statistical and Sensitivity Analyses to be Conducted for 
Primary Endpoints 
Endpoints analyzed 
Notes 
Overall survival 
Stratified log-rank test for: 
Dual primary analysis:  
• 
Dato-DXd versus ICC (ITT population)  
 
9.4.2.1.1 
Calculation or Derivation of Tumor Response Variables  
Investigator RECIST 1.1-based assessments 
All RECIST 1.1 assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a participant discontinues study intervention or 
receives another anticancer therapy.  
At each visit, participants will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline and 
previous assessments. Baseline will be assessed within the 28 days prior to randomization. 
The tumor response endpoints (PFS, ORR, DoR, and DCR) will then be derived from the scan 
dates and overall visit responses. 
BICR 
A BICR of radiological scans will be performed on all participants to confirm the robustness 
of the investigator-assessed PFS, ORR, and DoR endpoints.  
All images will be collected centrally, until PFS analysis. Additionally, following 
RECIST 1.1-defined radiological progression by Investigator assessment, 1 additional follow-
up scan should be performed as per imaging schedule (ie, either 6 weeks or 9 weeks later). 
This scan will be used in the PFS dual primary endpoint analysis. 
The imaging scans will be reviewed by 2 independent radiologists using RECIST 1.1 and will 
be adjudicated, if required. For each participant, the BICR will define the overall visit 
response data (CR, PR, SD, PD, or NE) and the relevant scan dates for each time point (ie, for 
visits where response or progression is/is not identified). If a participant has had a tumor 
assessment that cannot be evaluated, then the participant will be assigned a visit response of 
NE (unless there is evidence of progression, in which case the response will be assigned as 
PD). Endpoints (PFS, ORR, DoR, and DCR) will then be derived from the scan dates and 
overall visit responses.  
Further details of the BICR will be documented in an Independent Review Charter. 
9.4.2.1.2 
Progression-Free Survival  
Progression-free survival will be defined as the time from the date of randomization until the 

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date of objective PD per RECIST 1.1 (as assessed by BICR) or death (by any cause in the 
absence of progression), (ie, date of event or censoring – date of randomization + 1). The 
comparison will include all randomized participants, as randomized, regardless of whether the 
participant withdraws from randomized therapy, receives another anticancer therapy or 
clinically progresses prior to RECIST 1.1 progression. Participants who have not progressed 
or died at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment. However, if the participant progresses or dies 
after 2 or more consecutive missed visits, the participant will be censored at the time of the 
latest evaluable RECIST 1.1 assessment prior to the 2 missed visits. (Note: NE visit is not 
considered as missed visit). 
If the participant has no evaluable visits or does not have baseline data, they will be censored 
at the date of randomization, unless they die within 2 scheduled scans of baseline (12 weeks 
[+1 week] allowing for a late assessment within the visit window). 
Analysis Methods 
The dual primary endpoint of PFS will be based on the BICR assessment of PD by 
RECIST 1.1.  
Progression-free survival will be analyzed using a log-rank test stratified by number of 
previous lines of chemotherapy, geographic region, and prior use of CDK4/6 inhibitor. The 
hazard ratio together with its 95% CI and p-value will be presented (a hazard ratio less than 1 
will favor the comparator arm). The hazard ratio and CI will be estimated from a stratified 
Cox proportional hazards model (with ties = Efron), and the CI will be calculated using a 
profile likelihood approach.  
The stratification variables will be defined according to data from the IRT. If the number of 
events in an individual stratum are too small for a meaningful analysis, then a method will be 
applied that will remove stratification factors until there are meaningful number of events per 
strata. Details will be presented in the SAP. 
Kaplan-Meier plots of PFS will be presented by treatment group. Summaries of the number 
and percentage of participants experiencing a PFS event and the type of event (RECIST 1.1 or 
death) will be provided along with median PFS for each treatment. The primary and final 
analysis of PFS will be performed approximately 2 months after the last participant is 
randomized in the study; approximately 419 PFS BICR events across the Dato-DXd and ICC 
treatment groups (60% maturity) are anticipated at that time. 
9.4.2.1.3 
PFS Sensitivity Analyses  
Details of these analyses will be presented in the SAP. 

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Evaluation-time Bias 
A sensitivity analysis will be performed to assess possible evaluation-time bias that may be 
introduced if scans are not performed at the protocol-scheduled time points. The midpoint 
between the time of progression and the previous evaluable RECIST assessment (using the 
final date of the assessment) will be analyzed using a stratified log-rank test, as described for 
the primary analysis of PFS. 
Attrition Bias 
Attrition bias will be assessed by repeating the PFS analysis except that the actual PFS event 
times, rather than the censored times, of participants who progressed or died in the absence of 
progression immediately following two, or more, non-evaluable tumor assessments will be 
included. In addition, and within the same sensitivity analysis, participants who take 
subsequent therapy (note that for this analysis radiotherapy is not considered a subsequent 
anticancer therapy) prior to their last evaluable RECIST assessment or progression or death 
will be censored at their last evaluable assessment prior to taking the subsequent therapy. This 
analysis will be supported by a Kaplan-Meier plot of the time to censoring using the PFS data 
from the primary analysis and where the censoring indicator of the PFS analysis is reversed. 
Ascertainment bias 
Ascertainment bias will be assessed by analyzing the site Investigator data which is a 
secondary efficacy variable (analysis methods presented in Section 9.4.2.2.3).  
If there is an important discrepancy between the primary analysis using the BICR assessments 
and the secondary analysis using investigator assessments, the proportion of participants with 
site but no central confirmation of progression will be summarized; such participants have the 
potential to introduce bias in the central review due to informative censoring. An approach 
that imputes an event at the next visit in the central review analysis may help inform the most 
likely hazard ratio value, but only if an important discrepancy exists. 
Subsequent Anticancer Therapy 
PFS may be impacted for participants who are treated with a subsequent anticancer therapy. 
Therefore, an analysis will be performed censoring a participant at the last available tumor 
assessment prior to taking subsequent anticancer therapy. 
Additional sensitivity analyses may be defined in the SAP. 
9.4.2.1.4 
Overall Survival  
Overall survival is defined as the time from the date of randomization until death due to any 
cause. The comparison will include all randomized participants, as randomized, regardless of 
whether the participant withdraws from randomized therapy or receives another anticancer 

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therapy (ie, date of death or censoring – date of randomization + 1). Any participant not known 
to have died at the time of analysis will be censored based on the last recorded date on which 
the participant was known to be alive.  
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If participants are confirmed to be alive or 
if the death date is after the DCO date, then these participants will be censored at the date of 
DCO.  
Analysis Methods 
Overall survival will be analyzed using the same methodology specified for PFS. The effect of 
Dato-DXd versus ICC will be estimated by the hazard ratio together with its corresponding CI 
and p-value. Kaplan-Meier plots will be presented by treatment group.  
The study may continue monitoring participants for OS up to the scheduled final analysis, 
beyond planned interim analyses, to provide more refined estimates of treatment effects for 
survival. 
9.4.2.1.5 
Subgroup Analysis  
Subgroup analyses will be conducted, comparing PFS (per RECIST 1.1 using BICR 
assessments) and OS between Dato-DXd and ICC in the following subgroups of the ITT (but 
not limited to): 
• 
Number of previous lines of chemotherapy (1 versus 2) 
• 
Geographic region (Region 1 [US, Canada, Europe] versus Region 2 [Rest of World]) 
• 
Prior use of CDK4/6 inhibitor (Yes versus No) 
• 
Prior use of taxanes and/or anthracyclines (taxanes alone, anthracyclines alone, both 
taxanes and anthracyclines, neither taxanes nor anthracyclines) 
• 
Age at randomization (< 65 versus ≥ 65 years of age) 
• 
Race (Asian versus non-Asian) 
• 
Pre-selected choice of chemotherapy (Capecitabine, Gemcitabine, Eribulin mesylate, or 
Vinorelbine) 
• 
Brain metastases (Yes versus No) 
Other baseline variables may also be assessed if there is clinical justification, or an imbalance 
is observed between the treatment groups. The purpose of the subgroup analyses is to assess 
the consistency of treatment effect across expected prognostic and/or predictive factors. 
A forest plot of the PFS hazard ratios (along with the 95% CIs) will be produced for each level 
of the subgroups listed above. 

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The subgroup analyses for the stratification factors will be based on the values entered into the 
IRT; all other factors will be based on values recorded on the eCRF, or from the third-party 
vendor data. 
Additional subgroups of interest and analysis methods will be outlined in the SAP. 
Unless there is a marked difference between the results of the statistical analyses of the PFS 
from the BICR data and that of the site Investigator tumor data, these subgroup analyses will 
only be performed on the PFS endpoint using the BICR data. 
9.4.2.2 
Secondary Endpoint(s)  
9.4.2.2.1 
Objective Response Rate  
Objective response rate is defined as the proportion of participants who have a confirmed CR 
or PR, as determined by the BICR/Investigator assessment, per RECIST 1.1. 
The analysis will include all randomized participants as randomized, with measurable disease 
at baseline. Data obtained from randomization up until progression, or the last evaluable 
assessment in the absence of progression, will be included in the assessment of ORR, 
regardless of whether the participant withdraws from therapy. Participants who go off 
treatment without a response or progression, receive a subsequent therapy, and then respond 
will not be included as responders in the ORR. 
Analysis Methods 
The ORR will be compared between the treatment arms using a logistic regression model 
adjusting for the same stratification factors as the PFS as covariates in the model. The results 
of the analysis will be presented in terms of an adjusted odds ratio (OR) together with its 
associated 95% CI and p-value. If there are not enough responses for a meaningful analysis 
using logistic regression, then a CMH test is presented. The CMH test is stratified using the 
same stratification factors as PFS. The results of the analysis are presented in terms of an OR 
together with the 95% CI and p-value. Further details will be presented in the SAP. 
Comparisons between treatment groups will be made using both BICR RECIST 1.1 and 
investigator assessments. 
Summaries will be produced that present the number and percentage of participants with a 
tumor response (CR/PR). For each treatment arm, BoR will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE). 
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment. It is the best response a participant has had following randomization, but 
prior to starting any subsequent cancer therapy and up to and including RECIST progression 
or the last evaluable assessment in the absence of RECIST progression. Categorization of BoR 
will be based on RECIST using the following response categories: CR, PR, SD, PD, and NE. 

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Best objective response will be determined programmatically based on RECIST from the 
overall visit response using all BICR data up until the first progression event. It will also be 
determined programmatically based on RECIST using all site investigator data up until the 
first progression event. The denominators for each case will be consistent with those used in 
the ORR analysis. 
9.4.2.2.2 
Duration of Response  
Duration of response is defined as the time from the date of first documented confirmed 
response until date of documented progression per RECIST 1.1, as assessed by 
BICR/Investigator assessment or death due to any cause. 
The analysis will include all randomized participants as randomized who have a confirmed 
response, regardless of whether the participant withdraws from therapy, receives another 
anticancer therapy or clinically progresses prior to RECIST 1.1 progression. 
Analysis Methods 
Duration of response will be analyzed by summary statistics and Kaplan-Meier plots. 
Comparisons will be presented for both BICR RECIST 1.1 and investigator assessments.  
9.4.2.2.3 
Progression-Free Survival by Investigator assessment  
PFS by Investigator assessment will be defined as the time from the date of randomization 
until the date of PD per RECIST 1.1 (by Investigator assessment) or death (by any cause in 
the absence of progression), (ie, date of event or censoring – date of randomization + 1). 
The analysis will include all randomized participants as randomized regardless of whether the 
participant withdraws from therapy, receives another anticancer therapy, or 
clinically progresses prior to RECIST 1.1. However, if the participant progresses or dies 
immediately after two or more consecutive missed visits, the participant will be censored at 
the time of the latest evaluable assessment prior to the two missed visits. 
Analysis Methods 
This secondary endpoint of PFS based Investigator assessment will be analyzed using the 
same methodology described in Section 9.4.2.1.2. 
9.4.2.2.4 
Disease control rate  
Disease control rate at 12 weeks is defined as the percentage of participants who have a 
confirmed CR or PR or who have SD, per RECIST 1.1, as assessed BICR/per investigator 
assessment and derived from the raw tumor data for at least 11 weeks after randomization.  
The analysis will include all randomized participants as randomized. Data obtained from 
randomization up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of DCR, regardless of whether the participant 
withdraws from therapy. Participants who receive a subsequent therapy prior to week 11 will 

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not be considered to have disease control in the analysis. 
Analysis Methods 
Disease control rate will be analyzed using the same methodology specified for ORR. 
9.4.2.2.5 
Time to First Subsequent Therapy (TFST)  
Time to first subsequent therapy is defined as the time from randomization until the start date 
of the first subsequent anticancer therapy after discontinuation of randomized treatment, or 
death due to any cause. 
The analysis will include all randomized participants as randomized, regardless of progression 
status. 
Analysis Methods 
Time to first subsequent therapy will be analyzed using the same methodology as that used for 
the analysis of PFS. In addition, medians and a Kaplan-Meier plot of the time to the start of 
subsequent therapy will be presented by treatment arm and the time between progression and 
starting subsequent therapy will be summarized. 
9.4.2.2.6 
Time to Second Subsequent Therapy (TSST)  
Time to second subsequent therapy is defined as the time from randomization to until the start 
date of the second subsequent anticancer therapy after discontinuation of first subsequent 
treatment, or death due to any cause. 
The analysis will include all randomized participants as randomized, regardless of progression 
status on study treatment or first subsequent treatment. 
Analysis Methods 
Time to second subsequent therapy will be analyzed using the same methodology as that used 
for the analysis of TFST. 
9.4.2.2.7 
Time from randomization to second progression or death (PFS2)  
Time to second progression of death will be defined as the time from the randomization to the 
earliest of the progression event (following the initial progression), subsequent to first 
subsequent therapy, or death. The date of second progression will be recorded by the 
Investigator in the eCRF and defined according to local standard clinical practice. 
The analysis will include all randomized participants as randomized, regardless of progression 
status on study treatment or first subsequent treatment. 
Analysis Methods 
Time to second progression or death will be analyzed using identical methods as outlined for 

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PFS. 
9.4.2.2.8 
Clinical Outcome Assessments  
The secondary PRO endpoints include: 
• 
TTD in pain as measured by the pain scale from EORTC QLQ-C30  
• 
TTD in physical functioning as measured by the physical functioning scale from EORTC 
QLQ-C30 
• 
TTD in GHS/QoL as measured by the GHS/QoL scale from EORTC QLQ-C30. 
Time to deterioration (TTD) is defined as time from the date of randomization to the date of 
deterioration. Deterioration is defined as change from baseline that reaches a clinically 
meaningful deterioration threshold. Anchor-based methods using the participant-based 
anchors PGIS and PGIC will be considered to define thresholds for clinically meaningful 
within-participant change used in the TTD endpoints. Other methods including distribution-
based methods, cumulative distribution function, and probability density function curves, and 
methods using other anchors may also be considered. 
Clinically meaningful thresholds will be estimated for the following patient-reported 
outcomes: 
• 
EORTC QLQ-C30: Global health status/QoL, functioning, and select symptom subscales 
including pain and fatigue 
• 
EORTC QLQ IL116: breast symptoms, arm symptoms. 
The analysis to define clinically meaningful change thresholds in the TTD PRO endpoints will 
include all randomized participants using the pooled treatment arms data prior to database 
lock. These TTD PRO endpoints will be analyzed using the same time-to-event analysis 
methodology described in Section 9.4.2.1.2. 
Details of all statistical analyses, including analyses for other exploratory PRO endpoints, will 
be described in full in the SAP. 
9.4.2.2.9 
Pharmacokinetics  
Dato-DXd, total anti-TROP2 antibody, and MAAA-1181a PK concentrations will be listed 
and summarized by visit and scheduled time point. Non-compartment PK parameters that can 
be derived with sparse PK sampling, such as peak and trough concentrations, will be reported 
as data allows. Details of those analysis will be described in SAP. Population PK, and 
exploratory exposure response/safety analyses will be performed. A separate modeling 
analysis plan will be written before the database lock. The population PK analysis and 
exploratory exposure response/safety analysis will be presented separately from the main 
CSR.  

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9.4.2.2.10 Immunogenicity  
Immunogenicity results will be listed by participant, and a summary will be provided by the 
number and percentage of participants who develop detectable anti-Dato-DXd antibodies. The 
immunogenicity titer and neutralizing ADA data will be listed for samples confirmed positive 
for the presence of anti-Dato-DXd antibodies.  
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
efficacy, and safety will be evaluated, if the data allow.  
9.4.2.3 
Exploratory Endpoints  
Details of all statistical analyses for exploratory endpoints (including biomarkers, PRO, and 
medical resource utilization) will be described in full in the SAP. 
9.4.2.3.1 
Biomarkers  
Biomarker status will be assessed for participants in each treatment group according to 
pre-specified criteria that may be detailed in the SAP. The relationship of biomarker 
expression and, if applicable, of exploratory biomarkers to clinical outcomes (including but 
not restricted to) of PFS, ORR, and OS may be presented. Biomarker exploratory analyses 
may be described in a separate analysis plan and may be reported outside the CSR in a 
separate report. The results of this biomarker assessment will be reported either in the CSR 
itself or as an addendum, or separately in a scientific report or publication.  
The results of this biomarker assessment may be pooled with biomarker data from other 
studies with the study intervention to generate hypotheses to be tested in future research. 
9.4.2.3.2 
Medical Resource Utilization and Health Economics  
To investigate the impact of treatment and disease on health care resource use, the following 
variables will be captured: 
• 
Planned and unplanned hospital attendances beyond protocol-mandated visits (including 
physician visits, emergency room visits, day cases, and admissions) 
• 
Primary sign or symptom the participant presents with 
• 
Length of hospital stay, per stay 
• 
Length of any time spent in an intensive care unit 
• 
Procedures and tests 
Where admitted overnight, the length of hospital stay will be calculated as the difference 
between the date of hospital discharge (or death date) and the start date of hospitalization or 
start of study intervention if the start of study intervention is after start date of hospitalization 
(length of hospital stay = end date of hospitalization – start date of hospitalization + 1). 
Participants with missing discharge dates will be calculated as the difference between the last 
day with available data and the start date of hospitalization. The length of intensive care unit 

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stay will be calculated using the same method. 
Analysis Methods 
The potential impact of the disease and treatment on health care resource use will be analyzed 
for the purposes of submissions to payers. Descriptive statistics (as appropriate, including 
means, median, ranges or frequencies, and percentages) will be provided for each treatment 
group on the different types of hospital admissions, the length of stay for participants admitted 
to hospital for at least 1 overnight stay, and the length of stay for participants admitted to 
intensive care/high dependency units, as well as the primary sign or symptom the participant 
presents with. 
9.4.3 
Safety  
Safety summaries will be provided using the SAS. Safety data will be presented using 
descriptive statistics unless otherwise specified. Summary statistics for continuous variables 
will include number of participants, mean, standard deviation, minimum, median, and 
maximum. Frequency tables and shift tables will include number and percentage of 
participants in the respective category. Unless otherwise stated, percentages will be calculated 
out of the population total. 
Baseline 
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of study intervention. Details are described in the SAP. 
Adverse events 
Adverse events will be coded using the most recent version of MedDRA that will be released 
for execution at AstraZeneca, and graded using NCI-CTCAE v5.0. 
The following adverse events are considered treatment emergent: 
• Adverse events with an onset date on or after first dose of study intervention and within 
28 (+7) days after last dose of study intervention or up to the day prior to start of 
subsequent therapy, whichever comes first. 
• Worsening of pre-existing events on or after first dose of study intervention and within 
28 (+7) days after last dose of study intervention or up to the day prior to start of 
subsequent therapy, whichever comes first. 
Adverse events will be presented for each treatment group by System Organ Class, HLT 
and/or PT covering number and percentage of participants reporting at least one event and 
number of events where appropriate.  
An overview of AEs will present for each treatment group the number and percentage of 

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participants with any AE, AEs with outcome of death, serious AEs, and AEs leading to 
discontinuation of study intervention, as well as AEs leading to study intervention dose 
interruptions, AEs leading to study intervention dose reduction and AEs leading to withdrawal 
from study as well as the number of individual occurrences in those categories. 
Treatment emergent adverse events will be presented for each treatment group by System 
Organ class and/or PT covering number and percentage of participants reporting at least one 
event and number of events where appropriate.  
Separate AE tables will be provided taken into consideration relationship as assessed by the 
investigator, maximum CTCAE grading, seriousness, death and events leading to 
discontinuation of study intervention, as well as other action taken related to study 
intervention, and AESIs. 
Key participant information will be presented for participants with AEs with outcome of 
death, SAEs, and AEs leading to discontinuation of study intervention. 
An AE listing for the safety analysis set will cover details for each individual AE. 
Full details of AE analyses will be provided in the SAP. 
Vital signs 
Vital sign parameters will be presented for each treatment group.  
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline.  
Details of vital sign analyses will be provided in the SAP.  
Laboratory parameters 
Laboratory parameters will be presented for each treatment group.  
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
hematology parameters will be presented for observed values and change from baseline.  
Elevation in liver parameters for assessment of Hy’s Law will be reported appropriately.  
A shift table for urinalysis will be presented with baseline assessment against the maximum on 
treatment category.  
Supportive laboratory listings will cover observed values and changes from baseline for each 
individual participant as well as abnormalities. 

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Details of laboratory analyses will be provided in the SAP. 
Other safety endpoint analyses 
Details of analyses of urinalysis, ECGs, and ECHOs/MUGAs will be specified in the SAP. 
9.4.4 
Other Analyses  
9.4.4.1 
Optional Exploratory Genetic Sample  
Data will be reported outside the CSR (please see Appendix D). 
9.4.4.2 
Ophthalmologic Analysis  
See Section 8.2.5.5. Details will be specified in the SAP. 
9.5 
Interim Analyses  
Two interim analyses for OS are planned. The first OS interim will occur at the primary PFS 
analysis (approximately 40% of target OS events) and the second when approximately 80% of 
the target OS events have occurred. The Lan DeMets approach (Lan and DeMets 1983) that 
approximates the O’Brien and Fleming spending function will be used to maintain an overall 
2-sided type I error across the three planned analyses of OS. If the PFS dual primary analysis 
crosses the efficacy threshold, the 1.0% type I error allocated to the PFS endpoint will be 
reallocated to the OS endpoint for a total 2-sided type I error of 5.0%. Details of the planned 
timing of the two interim and final analyses are provided in Table 11. Note that the actual 
allocation of alpha across the three analysis times will be driven by the actual information 
fraction associated with the analysis. 
The interim analyses will be performed by an IDMC. It is expected that recruitment will have 
completed prior to the results of the interim analyses being available. For the interim analyses, 
the IDMC will review unblinded interim data and inform the sponsor whether the interim 
boundaries specified in Table 11 are met.  
Table 11 
Summary of planned timings of the interim and final OS analyses 
 
Interim Analysis 1 
Interim Analysis 2 
Primary Analysis 
Projected Timing 
21 Months b 
34 Months 
44 Months 
Number of Deaths a 
178 
355 
444 
Information Fraction 
40% 
80% 
100% 
Maturity 
25% 
51% 
63% 
Recommendation 
Continue 
 Reject 
Null 
Hypothesis 
Continue 
 Reject 
Null 
Hypothesis 
Do Not 
Reject Null 
Hypothesis 
Reject 
Null 
Hypothesis 
At 4.0% 2-sided alpha c 
   2-sided nominal p-value 
≥ 0.0005 
< 0.0005 
≥ 0.0184 
< 0.0184 
≥ 0.0345 
< 0.0345 

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Table 11 
Summary of planned timings of the interim and final OS analyses 
 
Interim Analysis 1 
Interim Analysis 2 
Primary Analysis 
   Estimated hazard ratio 
≥ 0.591 
< 0.591 
≥ 0.777 
< 0.777 
≥ 0.817 
< 0.817 
At 5.0% 2-sided alpha c 
   2-sided nominal p-value 
≥ 0.0008 
< 0.0008 
≥ 0.0241 
< 0.0241 
≥ 0.0427 
< 0.0427 
   Estimated hazard ratio 
≥ 0.604 
< 0.604 
≥ 0.786 
< 0.786 
≥ 0.824 
< 0.824 
a  Estimates based on exponential survival where the median OS is 19.0 months for ICC and 25.3 months for 
Dato-DXd. The total proportion of participants randomized at time t [t ≤ 19 months] following the start of the 
study is assumed to be (t/19)1.5. 
b  Timing of first IA based on PFS. Number of deaths is an estimate. 
c  Alpha allocated to OS endpoint (4.0% or 5.0%) dependent on statistical significance of PFS. 
 
The study may continue monitoring participants for OS up to the scheduled final analysis, 
beyond planned interim analyses, to provide more refined estimates of treatment effects for 
survival. 
The first IA for OS will occur at the time of the PFS analysis. If 40% of the target OS events 
(178/444) are available at the time of the first OS IA, then the largest (nominal) 2-sided 
p-value that will cross the efficacy threshold is 0.0008. If the first interim results do not meet 
the criterion for rejecting the null hypothesis in the ITT population, then follow-up will 
continue until at the criteria are met for the second OS IA. The second OS IA is planned when 
approximately 80% of target OS events (355/444) are available. The largest (nominal) 2-sided 
p-value that will cross the efficacy threshold is 0.0241 based on the expected timing of the 
second IA. If the interim results do not meet the criterion for rejecting the null hypothesis in 
the ITT population, then follow-up will continue until the criteria is met for the for OS 
primary analysis. The OS primary analysis will be performed when 444 OS events are 
observed, and the nominal 2-sided p-value will be 0.0427 based on the expected timing of the 
second IA. Note that the p-value boundaries reported in this paragraph presume that 5.0% 
type I error is available for the OS analysis. 
If the PFS primary analysis does not cross the efficacy threshold, the total 2-sided type I error 
allocated to the OS analyses will be 4.0%. For the 2 interim and primary analyses of OS, 
based on the expected number of events at each analysis, the nominal 2-sided p-values 
associated with the three analyses times are 0.0005, 0.0184, and 0.0345, respectively.  
The SAP will describe the planned interim analyses in greater detail. 
9.6 
Data Monitoring Committees  
9.6.1 
Independent Data Monitoring Committee  
An IDMC comprised of independent experts will convene and will meet approximately 
6 months after the study has started. The IDMC will review unblinded safety data and make 

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recommendations on whether the study should continue, be amended, or stopped based on 
safety findings. In addition, the IDMC may be requested to review efficacy data. For the 
interim analyses, the IDMC will review unblinded interim data and inform the Sponsor 
whether the interim boundaries specified in Section 9.5 are crossed. 
Full details of the IDMC communications, procedures, processes, and interim analyses will be 
presented in the IDMC Charter. 
9.6.2 
ILD Adjudication Committee  
An independent ILD Adjudication Committee for the Dato-DXd program is responsible for 
reviewing all cases of potential ILD/pneumonitis. To ensure adequate and relevant 
independent evaluation, systematic additional data collection will be conducted for all cases 
that will be brought for adjudication. These additional data collections will cover a more 
in-depth relevant medical history (eg, smoking, radiation, COPD and other chronic lung 
conditions), diagnostic evaluation, treatment and outcome of the event. This data collection 
will be triggered based on a pre-defined list of PTs eligible for adjudication as described in the 
Event Adjudication Site Manual. Further details can be found in the ILD Adjudication Charter. 
9.6.3 
Ophthalmologic Data Review Committee  
An independent Ophthalmologic Data Review Committee is responsible for reviewing the 
data from baseline, periodic and end of therapy ophthalmologic assessments. This data 
collection will be triggered based on a pre-defined list of PTs eligible for review. Further 
details will be available in the Ophthalmologic Data Review Committee Charter. 
9.7 
Mainland China Cohort  
The global cohort will enrol approximately 1000 participants to randomize approximately 700 
participants. The mainland China cohort will consist of approximately an additional 20 
randomized participants in mainland China. The global cohort will consist of participants 
recruited by the documented date of the last participants randomized of the global cohort. 
Participants randomized in the mainland China cohort prior to the last participants randomized 
of the global cohort enrolment will be included in both the ITT and the mainland China ITT. 
Participants randomized in the mainland China cohort after the last participants randomized of 
the global cohort enrolment will be included only in the mainland China ITT. The mainland 
China ITT will include all participants randomized in the mainland China cohort including 
those who were recruited prior to the closure of the global cohort and are therefore included in 
the analyses of efficacy and safety for the main study. The mainland China safety analysis set 
will consist of all participants included in the mainland China ITT who received at least 1 
dose of study treatment. 
Per NMPA guidance, in addition to the evaluation of the global cohort data for primary, 
secondary and safety objectives, evaluation of consistency in efficacy and safety in Chinese 

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populations is required to facilitate the benefit-risk assessment for mainland Chinese 
participants. Hence, the safety and efficacy data in the mainland China cohort will be analyzed 
separately where the same endpoint definitions and the same analysis methods are applied. 
Details of the mainland China cohort analyses will be specified in the SAP. 

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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  

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Appendix A Regulatory, Ethical, and Study Oversight Considerations  
A 1 
Regulatory and Ethical Considerations  
• 
This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
− Applicable ICH GCP Guidelines 
− Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants. 
• 
AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organization but the accountability remains with AstraZeneca. 
• 
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21CFR 312.120, ICH guidelines, the IRB/IEC, 
and the European Regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
 
Regulatory Reporting Requirements for Serious Adverse Events 
• 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• 
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators. 
• 
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
• 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 

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and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
Regulatory Reporting Requirements for Serious Breaches 
• 
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met. 
− A “serious breach” means a breach likely to affect to a significant degree the safety and 
rights of a participant or the reliability and robustness of the data generated in the 
clinical study. 
• 
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
they become aware of it. 
• 
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches. 
− AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU CT Regulation 536/2014 applies, AstraZeneca is required to enter details of 
serious breaches into the European Medicines Agency CTIS. It is important to note 
that redacted versions of serious breach reports will be available to the public via 
CTIS. 
• 
The investigator should have a process in place to ensure that: 
− The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach. 
− A (potential)_serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca. 
A 2 
Financial Disclosure  
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study. 
A 3 
Informed Consent Process  
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 

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during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study center. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
 
Participants who are rescreened are required to sign a new ICF. The ICF will contain a 
separate section that addresses and documents the collection and use of any mandatory and/or 
optional human biological samples. The investigator or authorized designee will explain to 
each participant the objectives of the analysis to be done on the samples and any potential 
future use. Participants will be told that they are free to refuse to participate in any optional 
samples or the future use and may withdraw their consent at any time and for any reason 
during the retention period. 
A 4 
Data Protection  
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent.  
• 
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
 
Unless previously specified, the biomarker data will have unknown clinical significance and 
AstraZeneca will not provide biomarker assessment results to participants, their family 
members, any insurance company, any employer, a clinical study investigator, a general 
physician, or any other third party, unless required to do so by law; however, AstraZeneca may 
share data and biosamples with research partners, for example Daiichi Sankyo. 
The participant’s samples will not be used for any purpose other than those described in the 

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study protocol. 
A 5 
Committees Structure  
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators. 
For additional details see Section 9.6.1. 
A 6 
Dissemination of Clinical Study Data  
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant. 
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com, http://www.clinicaltrials.gov, and 
https://www.clinicaltrialsregister.eu as will the summary of the main study results when they 
are available. The clinical study and/or summary of main study results may also be available 
on other websites according to the regulations of the countries in which the main study is 
conducted. 
A 7 
Data Quality Assurance  
• 
All participant data relating to the study will be recorded on the CRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents. 
• 
The sponsor or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. 
• 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including clinical reviews of 
study data from a medical perspective, and handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 

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• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca GRAD Schedule. No records 
may be destroyed during the retention period without the written approval of 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca. 
A 8 
Source Documents  
• 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• 
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies). 
A 9 
Study and Site Start and Closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 

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and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• 
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines 
• 
Inadequate recruitment of participants by the investigator 
• 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any Contract Research 
Organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study. 
A 10 
Publication Policy  
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• 
The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement. 
• 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
 

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Appendix B Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
B 1 
Definition of Adverse Events  
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a participant or clinical study participant administered a 
study intervention and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the study 
intervention.  
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
B 2 
Definitions of Serious Adverse Event  
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires in-participant hospitalization or prolongation of existing hospitalization.  
• 
Results in persistent or significant disability or incapacity.  
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above. 
 
AEs for malignant tumors reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the “Important Medical Event” criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 

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The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (ie, it is not the tumor for which entry into the study is a criterion and that is 
being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumor under study). Malignant tumors that – as part 
of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of B cell 
chronic lymphocytic leukemia into diffuse large B cell lymphoma) should not be considered a 
new malignant tumor. 
Life-threatening 
“Life-threatening” means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
participant’s death. “Life-threatening” does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study. 
Important medical event or medical treatment 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
 

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Intensity rating scale: 
The grading scales found in the revised National Cancer Institute CTCAE version 5.0 will be 
utilized for all events with an assigned CTCAE grading. For those events without assigned 
CTCAE grades, the recommendation in the CTCAE criteria that converts mild, moderate and 
severe events into CTCAE grades should be used. A copy of the CTCAE can be downloaded 
from the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly. 
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2. 
B 3 
A Guide to Interpreting the Causality Question  
When making an assessment of causality consider the following factors when deciding if there 
is a “reasonable possibility” that an AE may have been caused by the drug. 
• 
Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug? 
• 
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties? 
• 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
• 
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors. 
• 
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge. 
• 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship. 
 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognized feature of overdose of the drug? 

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• 
Is there a known mechanism? 
 
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as “not related”. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 4 
Medication Error, Drug Abuse, and Drug Misuse  
Medication Error  
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant. 
Medication error includes situations where an error:  
• 
Occurred. 
• 
Was identified and intercepted before the participant received the drug. 
• 
Did not occur, but circumstances were recognized that could have led to an error. 
 
Examples of events to be reported in clinical studies as medication errors: 
• 
Drug name confusion. 
• 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant. 
• 
Drug not administered as indicated, eg, wrong route, dose (error greater than +/- 10%), or 
wrong site of administration. 
• 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet. 
• 
Drug not stored as instructed eg, kept in the refrigerator when it should be at room 
temperature.  

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• 
Wrong participant received the medication (excluding IRT errors). 
• 
Wrong drug administered to participant (excluding IRT errors). 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
• 
Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error.  
• 
Participant accidentally missed drug dose(s) eg, forgot to take medication. 
• 
Accidental overdose (will be captured as an overdose). 
• 
Participant failed to return unused medication or empty packaging. 
 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
Drug Abuse 
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP/study intervention or AstraZeneca NIMP for a perceived 
reward or desired non-therapeutic effect. 
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site using the Drug Abuse Report Form. This form should be used both if the 
drug abuse happened in a study participant or if the drug abuse regards a person not enrolled 
in the study (such as a relative of the study participant). 
Examples of drug abuse include but are not limited to: 
• The drug is used with the intent of getting a perceived reward (by the study participant or a 
person not enrolled in the study) 
• 
The drug in the form of a tablet is crushed and injected or snorted with the intent of getting 
high. 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP/study 
intervention or AstraZeneca NIMP for medicinal purposes outside of the authorized product 
information, or for unauthorized IMPs/study interventions or AstraZeneca NIMPs, outside the 
intended use as specified in the protocol, and includes deliberate administration of the product 
by the wrong route. 
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site using the Drug Misuse Report Form. This form should be used both if the 

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drug misuse happened in a study participant or if the drug misuse regards a person not 
enrolled in the study (such as a relative of the study participant). 
Examples of drug misuse include but are not limited to: 
• The drug is used with the intention to cause an effect in another person 
• The drug is sold to other people for recreational purposes  
• The drug is used to facilitate assault in another person 
• The drug is deliberately administered by the wrong route 
• The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole 
• Only half the dose is taken because the study participant feels that they were feeling 
better when not taking the whole dose 
• Someone who is not enrolled in the study intentionally takes the drug. 
 

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Appendix C Handling of Human Biological Samples  
C 1 
Chain of Custody  
A full chain of custody is maintained for all samples throughout their lifecycle. 
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site. 
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal. 
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers. 
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle. If required, AstraZeneca will ensure that remaining 
biological samples are returned to the site according to local regulations or at the end of the 
retention period, whichever is the sooner. 
C 2 
Withdrawal of Informed Consent for Donated Biological Samples  
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analyzed, AstraZeneca is not obliged to destroy the results of this 
research. The participant will be presented with the option to opt out of the subsequent use of 
the donated samples during the withdrawal process. If the participant decides to opt out, then 
the donated samples will be disposed of. If the participant withdraws consent without opting 
out for the subsequent use of the donated samples, then the samples will be used as per 
protocol. 
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent. 
The investigator: 
• 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 

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• 
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented. 
• 
Ensures that the participant and AstraZeneca are informed about the sample disposal. 
 
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented, and study site notified. 
C 3 
International Airline Transportation Association (IATA) 6.2 
Guidance Document  
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
IATA (https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx ) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt: 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A pathogens are, for example, Ebola, Lassa fever virus. Infectious substances 
meeting these criteria which cause disease in humans or both in humans and animals must be 
assigned to UN 2814. Infectious substances which cause disease only in animals must be 
assigned to UN 2900. 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name: 
• 
UN 3373 – Biological Substance, Category B 
• 
are to be packed in accordance with UN3373 and IATA 650 
 
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class. 
• 
Clinical study samples will fall into Category B or exempt under IATA regulations. 
• 
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging. 
(https://www.iata.org/contentassets/b08040a138dc4442a4f066e6fb99fe2a/dgr-62-en-
pi650.pdf). 

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• 
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content. 

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Appendix D Optional Genomics Initiative Sample  
D 1 
Use/Analysis of DNA  
• 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants. 
• 
This optional genetic research may consist of the analysis of the structure of the 
participant’s DNA, ie, the entire genome.  
• 
The results of genetic analyses may be reported in a separate study summary. 
• 
The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality. 
• 
The samples will be retained while research on Dato-DXd continues but no longer than 
15 years from the end of the study (as defined in the protocol) or other period as per local 
requirements. 
 
D 2 
Genetic Research Plan and Procedures  
Selection of genetic research population 
• 
All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study. 
Inclusion criteria 
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and provide informed consent for the Genomics 
Initiative sampling and analyses. 
Exclusion criteria 
• 
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following: 
− Previous allogeneic bone marrow transplant. 
− Transfusion of non-leukocyte depleted blood or blood component within 120 days of 
genetic sample collection. 

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Withdrawal of consent for genetic research 
Participants may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.2 of the main 
CSP. 
Collection of samples for genetic research 
The blood sample for this genetic research will be obtained from the participants pre-dose at 
the first dosing visit. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an AE. If for any 
reason the sample is not drawn at the first dosing visit, it may be taken at any visit until the 
last study visit. Only one sample should be collected per participant for genetics during the 
study. 
Coding and storage of DNA samples 
• 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples may be stored for a maximum 
of 15 years from the end of the study (as defined in the protocol), after which they will be 
destroyed. DNA is a finite resource that is used up during analyses. Samples will be 
stored and used until no further analyses are possible or the maximum storage time has 
been reached. 
• 
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA). 
• 
The link between the participant enrolment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent. 
Ethical and regulatory requirements 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A. 

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Informed consent 
The genetic component of this study is optional, and the participant may participate in other 
components of the main study without participating in this genetic component. To participate 
in the genetic component of the study the participant must sign and date both the consent form 
for the main study and the addendum for the Genomics Initiative component of the study. 
Copies of both signed and dated consent forms must be given to the participant and the 
original filed at the study center. The principal investigator(s) is responsible for ensuring that 
consent is given freely and that the participant understands that they may freely withdrawal 
from the genetic aspect of the study at any time. 
Participant data protection 
• 
AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician, or any other third party 
unless required to do so by law. 
• 
Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, an AstraZeneca physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate. 
Data management 
• 
Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples. 
• 
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organizations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers.  
• 
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database. 
 
Statistical methods 
The number of participants that will agree to participate in the genetic research is unknown. It 
is therefore not possible to establish whether sufficient data will be collected to allow a formal 

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statistical evaluation or whether only descriptive statistics will be generated. An SAP may be 
prepared where appropriate. 

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Appendix E Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law  
E 1 
Introduction  
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries.  
Specific guidance on managing liver abnormalities can be found in the TMGs (see the Annex 
document to this CSP). 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.  
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events. 
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention.  
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
E 2 
Definitions  
Potential Hy’s Law (PHL) 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point during the study 
following the start of study intervention irrespective of an increase in alkaline phosphatase.  
Hy’s Law (HL) 
AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated alkaline 

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phosphatase indicating cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur. 
E 3 
Identification of Potential Hy’s Law Cases  
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination: 
• 
ALT ≥ 3 × ULN. 
• 
AST ≥ 3 × ULN. 
• 
TBL ≥ 2 × ULN. 
 
Local laboratories being used 
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will: 
• 
Notify the AstraZeneca representative. 
• 
Determine whether the participant meets PHL criteria (see Section E 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits. 
• 
Promptly enter the laboratory data into the laboratory eCRF. 
 
E 4 
Follow-up  
E 4.1 
Potential Hy’s Law Criteria Not Met  
If the participant does not meet PHL criteria the investigator will: 
• 
Inform the AstraZeneca representative that the participant has not met PHL criteria. 
• 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP. 
 
E 4.2 
Potential Hy’s Law Criteria Met  
If the participant does meet PHL criteria the investigator will: 
• 
Notify the AstraZeneca representative who will then inform the central Study Team.  

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• 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criterion “Important medical event” and causality assessment “yes/related” 
according to CSP process for SAE reporting. 
• 
For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition.  
• 
The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participant’s follow-up (including any further laboratory testing) 
and the continuous review of data. 
• 
Subsequent to this contact the investigator will: 
− Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
− Investigate the etiology of the event and perform diagnostic investigations as discussed 
with the study physician.  
− Complete the 3 Liver eCRF Modules as information becomes available.  
 
#A “significant” change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty. 
E 5 
Review and Assessment of Potential Hy’s Law Cases  
The instructions in this Section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study intervention, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria were met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate.  
According to the outcome of the review and assessment, the investigator will follow the 
instructions below. 
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 

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whether the AE meets the criteria for a SAE: 
• 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF. 
• 
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study intervention: 
• 
Send updated SAE (report term “Hy’s Law”) according to AstraZeneca standard 
processes.  
− The “Medically Important” serious criterion should be used if no other serious criteria 
apply. 
− As there is no alternative explanation for the HL case, a causality assessment of 
“related” should be assigned. 
 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
• 
Provide any further update to the previously submitted SAE of PHL, (report term now 
“Hy’s Law case”) ensuring causality assessment is related to study intervention and 
seriousness criterion is medically important, according to CSP process for SAE reporting. 
• 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review, and 
amend the reported term if an alternative explanation for the liver biochemistry elevations 
is determined. 
E 6 
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention  
This section is applicable to participants with liver metastases who meet PHL criteria on study 
intervention, having previously met PHL criteria at a study visit prior to starting study 
intervention. 
At the first on-study intervention occurrence of PHL criteria being met the investigator will 
determine if there has been a significant change in the participant’s condition compared with 

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the last visit where PHL criteria were met. 
• If there is no significant change no action is required. 
• If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2. 
E 7 
Actions Required for Repeat Episodes of Potential Hy’s Law  
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit. 
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence.  
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question: 
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study eg, chronic or progressing malignant disease, severe infection or liver 
disease, or did the participant meet PHL criteria prior to starting study intervention and at their 
first on-study intervention visit as described in Section E 6 of this Appendix? 
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE. 
If Yes: Determine if there has been a significant change in the participant’s condition 
compared with when PHL criteria were previously met. 
• If there is no significant change no action is required. 
• If there is a significant change follow the process described in Section E 4.2 for reporting 
PHL as an SAE. 
E 8 
Laboratory Tests  
The list below represents the standard, comprehensive list of follow-up tests that are 
recommended but not mandatory to further evaluate increases in liver biochemistry and Hy’s 
Law. This list may be modified according to clinical judgment. Any test result must be 
recorded. 

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Tests to Further Evaluate Increases in Liver Biochemistry and Hy’s Law 
Additional standard chemistry and coagulation 
tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA a 
IgM and IgG anti-HCV 
HCV RNA a  
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM & IgG anti-CMV 
IgM & IgG anti-HSV 
IgM & IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate-deficient transferrin b 
Autoimmune hepatitis 
Antinuclear antibody 
Anti-liver/kidney microsomal antibody 
Anti-smooth muscle antibody 
Metabolic diseases 
Alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin b 
Transferrin saturation 
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = gamma glutamyl transferase; 
HAV = hepatitis A virus; HBc = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HEV = hepatitis E virus; HSV = herpes simplex virus; IgG = immuno-globulin G; 
IgM = immuno-globulin M; INR = international normalized ratio; LDH = lactate dehydrogenase; RNA = ribonucleic acid. 
a 
HCV RNA/HBV DNA are only tested when anti-HCV IgG/anti-HBc IgM or IgG are positive or inconclusive. 
b 
Carbohydrate-deficient transferrin and transferrin are not available in mainland China.  
 
E 9 
References  
Aithal et al 2011  
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 
2011;89(6):806-15. 
FDA Guidance 2009  
Food and Drug Administration. Guidance for industry: Drug-induced liver injury: 

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premarketing clinical evaluation. July 2009. Available from: URL: 
https://www.fda.gov/downloads/guidances/UCM174090.pdf. Accessed 08 October 2019. 

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Appendix F Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumors)  
Introduction 
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix. 
Additional special guidance is provided for evaluation of scans collected after a 
RECIST 1.1-defined radiological progression. 
Imaging modalities and acquisition specifications for RECIST 1.1 
A summary of the imaging modalities that can be used for tumor assessment of TLs, NTLs 
and NLs is provided in Table 12. 
Table 12 
Summary of Imaging Modalities for Tumor Assessment 
Target Lesions  
Non-Target Lesions 
New Lesions 
CT 
MRI 
CT 
MRI 
Plain X-ray 
Chest X-ray 
CT 
MRI 
Plain X-ray 
Chest X-ray 
Bone scan (Scintigraphy) 
18F-fluoro-deoxyglucose-PET 
CT = computed tomography; PET/CT = positron emission tomography/CT; MRI = magnetic resonance imaging. 
 
Computed Tomography and Magnetic Resonance Imaging  
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumor 
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumor assessor (eg, radiologist), and 
method of tumor assessment (eg, RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumor assessment schedule as closely 
as possible (refer to the SoA; Table 1), and this on-study imaging schedule MUST be followed 
regardless of any delays in dosing or missed imaging visits. If an unscheduled assessment is 
performed (eg, to investigate clinical signs/symptoms of progression) and the participant has 
not progressed, every attempt should be made to perform the subsequent scan acquisitions at 
the next scheduled imaging visit. 
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 

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scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 
vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases. 
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval. 
a. Anatomic coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen-pelvis. Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
PD, careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumor 
measurements but also identification of new disease. 
Required anatomical regions to be imaged for assessment of tumor burden (TLs and/or NTLs) 
at baseline and follow-up visits vary according to the study, and these time points are specified 
in the SoA (Table 1). Examples include the following: 
• 
IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis). 
• 
Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis). 
• 
IV contrast-enhanced CT or MRI of the head and neck. 
• 
IV contrast-enhanced MRI (preferred) or CT of the brain. 
 
For chest-abdomen-pelvis imaging, the following are scanning options in decreasing order of 
preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to IV contrast or have compromised renal function: 
6 
Chest-abdomen-pelvis CT with IV CT contrast (most preferred). 
7 
Chest CT without IV contrast + abdomen-pelvis MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study. 

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8 
Chest-abdomen-pelvis CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function. 
9 
Chest-abdomen-pelvis MRI with IV MRI contrast, if CT cannot be performed at any time 
during the study. 
 
b. IV contrast administration: Optimal visualization and measurement of metastases in solid 
tumors require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumor 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualize and 
differentiate structures in the abdomen and pelvis. 
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤ 5 mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans. 
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study. 
Chest X-ray 
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs. 
Plain X-ray  
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions. 
Isotopic bone scan  
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray). 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 

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equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a PD assessment at 
that time point. 
18F-Fluoro-deoxyglucose-PET/CT 
18F-fluoro-deoxyglucose positron emission tomography(PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive 18F-Fluoro-deoxyglucose uptake1 not present on baseline or prior 
18F-fluoro-deoxyglucose-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the 18F-fluoro-deoxyglucose-PET scan. The PET portion of 
the PET/CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed. Therefore, if there is no baseline or prior 18F-fluoro-deoxyglucose-PET 
scan available for comparison, and no evidence of NLs on companion CT/MRI scans, then 
follow-up CT/MRI assessments should continue as per the regular imaging schedule to verify 
the unequivocal presence of NLs. 
At present, low-dose or attenuation correction CT portions of a combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated 
diagnostic contrast-enhanced CT scans for tumor measurements by RECIST 1.1. In 
exceptional situations, if a site can document that the CT performed, as part of a PET/CT 
examination, is of identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT 
scan, then the CT portion of the PET/CT can be used for RECIST 1.1 tumor assessments. 
Caution that this is not recommended because the PET portion of the CT introduces additional 
(PET) data that may bias an investigator if it is not routinely or serially performed. 
Ultrasound  
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan. 
Other tumor assessments 
Clinical examination  
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
 
 
1 
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed. 

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not be used for RECIST 1.1 assessments. Tumors identified by clinical examination will need 
to be assessed by correlative CT or MRI anatomical scans. 
Endoscopy and laparoscopy  
Endoscopy and laparoscopy will not be used for tumor assessments as they are not validated 
in the context of tumor assessment. 
Histology and cytology 
Histology or tumor markers on tumor biopsy samples will not be used as part of the tumor 
response assessment as per RECIST 1.1. 
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumor response assessment as per RECIST 1.1. 
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically. 
Measurability of tumor lesions at baseline 
RECIST 1.1 measurable lesions at baseline 
A tumor lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter 
for non-nodal lesions or ≥ 15 mm in short axis1 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. Please 
see additional RECIST 1.1 guidance below on measurability of intrahepatic hepatocellular 
carcinoma lesions and porta hepatis lymph nodes. 
Non-measurable lesions at baseline 
• 
Truly non-measurable lesions include the following: 
− Bone lesions (see exception below for soft tissue component). 
− Leptomeningeal disease. 
− Ascites, pleural effusion, or pericardial effusion. 
− Inflammatory breast disease. 
− Lymphangitic involvement of skin or lung. 
 
 
1 
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• 
All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 mm to < 15 mm short axis diameter at baseline).1 
• 
Previously irradiated lesions.2 
• 
Brain metastasis. 
 
Special considerations regarding lesion measurability at baseline 
• 
Bone lesions: 
− Bone scan, PET scan, or plain X-ray are not considered adequate imaging techniques to 
measure bone lesions; however, these techniques can be used to confirm the presence 
or disappearance of bone lesions. 
− Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability. 
− Blastic lesions are considered non-measurable. 
• 
Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs. 
 
RECIST 1.1 TL selection at baseline 
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected. 
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
 
 
1 
Lymph nodes with < 10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs. 
2 
Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment. 

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organ. 
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
recorded in millimeters. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters. 
Special cases for TL assessment at baseline 
• 
For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter. 
• 
When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter. 
• 
Tumor lesions selected for newly acquired screening biopsy should not be selected as 
TLs, unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing. 
• 
If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan. 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL. 
 
RECIST 1.1 NTL selection at baseline 
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up. 
Evaluation of tumor response and progression 
RECIST 1.1 TL assessment at follow-up 
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimeters. The sum of the diameters for all TLs at each follow-up visit will be 
compared with the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression). 

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Special cases for TL assessment at follow-up: 
• 
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL. 
• 
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded. 
• 
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter. 
• 
If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm. 
• 
If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.  
• 
When a TL has had any intervention (eg, definitive radiotherapy, embolization, surgery, 
transarterial chemoembolization, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 CRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm. 
 
Table 13 
RECIST 1.1 Evaluation of Target Lesions 
CR 
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis diameter to < 10 mm. 
PR 
At least a 30% decrease in the sum of the diameters of TL, taking as reference 
the baseline sum of diameters. 
SD 
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD. 
PD 
At least a 20% increase in the sum of diameters of TLs, taking as reference the 
smallest previous sum of diameters (nadir). This includes the baseline sum if 
that is the smallest on study. In addition to the relative increase of 20%, the 
sum must demonstrate an absolute increase of at least 5 mm from nadir. 
NE 
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, 
missing anatomy) or had a lesion intervention at this visit. Note: If the sum of 
diameters meets the PD criteria, PD overrides NE as a TL response. 
Not applicable 
Only relevant if no TLs present at baseline. 
CR = complete response; NE = not evaluable; PD = progression of disease; PR = partial response; SD = stable disease; 
TL = target lesion. 

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RECIST 1.1 NTL assessment at follow-up 
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator. 
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumor burden has increased sufficiently to merit unequivocal progression by NTLs. 
A modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PD of target disease will therefore be 
extremely rare. 
Table 14 
RECIST 1.1 Evaluation of Non-Target Lesions 
CR 
Disappearance of all NTLs since baseline. All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
Non-CR/non-PD 
Persistence of 1 or more NTLs. 
PD 
Unequivocal progression of existing NTLs. Unequivocal progression may be due 
to an important progression in 1 lesion only or in several lesions. In all cases, the 
progression MUST be clinically significant for the physician to consider 
changing (or stopping) therapy. 
NE 
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit. 
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met. 
Not applicable 
Only relevant if no NTLs present at baseline. 
CR = complete response; NE = not evaluable; NTL = non-target lesion; PD = progression of disease; TL = target lesion. 
 
RECIST 1.1 NL identification at follow-up 
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the CRF. The presence of 1 or more NLs is assessed as progression. The 
finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumor. If a NL is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared. 

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A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD. 
RECIST 1.1 evaluation of overall visit response at follow-up 
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 15. 
Table 15 
RECIST 1.1 Overall Visit Response 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Visit Response 
CR 
CR 
No 
CR 
CR 
NA 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE or NA 
No 
PR 
SD 
Non-PD or NE or NA 
No 
SD 
NE 
Non-PD or NE 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; NTL = non-target lesion; PD = progression of disease; PR = partial 
response; SD = stable disease; TL = target lesion. 
 
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline: 
• 
For participants with TLs (at baseline): CR, PR, SD, PD, or NE. 
Central imaging 
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organization (iCRO) for quality control, 
storage, and for BICR. Digital copies of all original scans should be stored at the investigator 
site as source documents. Electronic image transfer from the sites to the iCRO is strongly 
encouraged. A BICR of images will be performed at the discretion of AstraZeneca. Results of 
these independent reviews will not be communicated to investigators, and results of 
investigator tumor assessments will not be shared with the central reviewers. 
The management of participants will be based in part upon the results of the tumor 
assessments conducted by the investigator. Further details of the BICR will be documented in 
an Independent Review Charter. 

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F 1 
References  
Eisenhauer et al 2009  
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 

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Appendix G Contraception Requirements  
Contraception requirements for this study are as follows. 
G 1 
Female Participants  
Women not of childbearing potential are defined as those who are surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are 
post-menopausal. 
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
• 
Women < 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution, or underwent surgical sterilization (bilateral 
oophorectomy or hysterectomy). 
• 
Women ≥ 50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses > 1 year ago, or had 
chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical 
sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy). 
Women of childbearing potential who are not totally sexually abstinent (ie, refraining from 
heterosexual intercourse during the entire period of risk associated with study interventions) 
and intend to be sexually active with a non-sterilized male partner must use at least 1 highly 
effective method of contraception (Table 16). They should have been stable on their chosen 
method of birth control starting at a minimum of 3 months before C1D1 and continue to use it 
throughout the total duration of the drug treatment and the drug washout period (7 months 
after the last dose of study intervention).  
Non-sterilized male partners of a woman of childbearing potential must use a male condom 
plus spermicide (condom alone in countries where spermicides are not approved) throughout 
this period. Cessation of birth control after this point should be discussed with a responsible 
physician. Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. Total sexual abstinence is an acceptable method 
provided it is the usual lifestyle of the participant. The reliability of sexual abstinence needs to 
be evaluated in relation to the duration of the clinical trial. Female participants should refrain 
from breastfeeding throughout this period. Women must not donate, or retrieve for their own 
use, ova from the time of screening and throughout the study treatment period, and for at least 
7 months after the final study drug administration. Preservation of ova should be considered 
prior to enrolment in this study. 

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G 2 
Male Participants with a Female Partner of Childbearing 
Potential  
Non-sterilized male participants (including males sterilized by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from the time of screening throughout the total duration of the study and the drug washout 
period (ie, at least 4 months after the last dose of study intervention) to prevent pregnancy in a 
partner.  
Not engaging in sexual activity for the duration of the study and drug washout period is an 
acceptable practice. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the participant. Periodic 
abstinence, the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. Male participants should refrain from sperm donation or banking throughout 
the drug washout period. Preservation of sperm should be considered prior to enrolment in this 
study. 
Vasectomized (ie, sterile) males are considered fertile and should still use a male condom plus 
spermicide as indicated above during the clinical study. 
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide (where approved), as indicated above during the clinical study, if there is a concern 
about damaging the developing fetus from drug in ejaculate. 
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 16). 
G 3 
Highly Effective Methods of Contraception  
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 16. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper-containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills). 

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For participants in the ICC (eribulin, capecitabine, vinorelbine, or gemcitabine) group: 
Follow the local Prescribing Information relating to contraception, the time limits for such 
precautions, and any additional restrictions required for the specific ICC agent. 
Table 16 
Highly Effective Methods of Contraception (< 1% Failure Rate) 
Non-Hormonal Methods 
Hormonal Methodsb 
• 
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant) 
• 
Vasectomized sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia) 
• 
Tubal occlusion 
• 
Intrauterine device (provided coils are 
copper-banded) 
• 
Injection: Medroxyprogesterone injection 
(eg, Depo-Provera®) a 
• 
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) a 
• 
Progesterone T intrauterine device 
• 
Implants: Etonogestrel-releasing implants 
(eg, Implanon® or Norplant®) 
• 
Intravaginal devices: 
Ethinylestradiol/etonogestrel-releasing 
intravaginal devices (eg, NuvaRing®)  
• 
Combined pill: Normal and low dose combined 
oral contraceptive pill 
• 
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (eg, Ortho Evra®) 
• 
Mini pill: Progesterone-based oral contraceptive 
pill using desogestrel: Cerazette® is currently the 
only highly effective progesterone-based pill 
a 
Hormonal methods not prone to drug-drug interactions. 
b 
Hormonal methods of contraception must not be used by female patients participating in this study; this 
information is meant for female partners of male participants. 

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Appendix H Patient-reported Outcomes  
H 1 
EORTC QLQ-C30  

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H 2 
EORTC IL116  
 

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H 3 
PRO-CTCAE  
 

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H 4 
EORTC IL117  
 
 

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H 5 
PGI-TT  
 
 

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H 6 
PGIS  
 

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H 7 
PGIC  
 

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H 8 
EQ-5D-5L  
 

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Appendix J 
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis  
Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation. 
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
participant’s safety. If in doubt, please contact the AstraZeneca Study Physician. 
J 1 
Reconsent of Study Participants During Study Interruptions  
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in the sections below. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided.  
J 2 
Rescreening of Participants to Reconfirm Study Eligibility  
An extended rescreening period will be allowed for participants that are affected by study 
disruptions, that have already screen failed and entered rescreening. The investigator should 
confirm this with the designated study physician. 
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Table 1, the participant 
will be allowed to remain in screening until reconfirmation of eligibility before commencing 
study procedures. The procedures detailed in Table 1 must be undertaken to confirm eligibility 
using the same E-code as initially assigned to the participant. 

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J 3 
Home or Remote Visit to Replace On-site Visit (where applicable)  
A qualified HCP from the study site or TPV service will visit the participants home or other 
remote location as per local Standard Operating Procedures, as applicable. Supplies will be 
provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the clinical study protocol (CSP).  
J 4 
Telemedicine Visit to Replace On-site Visit (where applicable)  
In this appendix, the term telemedicine visit refers to remote contact with the participants 
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices. 
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication, and targeted physical 
examination to be reported and documented. Site personnel to also ensure that ePROs are 
being completed by participant as per SoA.  
J 5 
Data Capture During Telemedicine Visits (where applicable)  
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP (or site delegate) from the study site or TPV service in the source documents. 

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Appendix K Protocol Version History  
The Summary of Changes Table for the current revision is located directly before the TOC. 
Amendment 3 (10 October 2022)  
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to provide flexible language for the inclusion of a 
mainland China-specific recruitment tail, if required, for regulatory submission purposes, as 
well as alignment with the latest Dato-DXd program standards. 
Other important administrative and operational clarifications have also been made. 
The rationale for each of these changes is provided in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 1.1, Synopsis, 
Number of 
Participants, 
Statistical Methods 
Section 4.1, Overall 
Design 
Updated to include possibility of a 
mainland China cohort. 
If required for regulatory 
submission purposes, the 
recruitment of participants in 
mainland China may continue 
beyond the close of the global 
cohort. 
Non-Substantial 
Section 1.2, Schema 
Clarified requirement for patient 
to have progressed on and not be 
suitable for endocrine therapy, in 
accordance with existing 
eligibility criteria. 
Typographical correction. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Section 8.2.5.1, 
Echocardiogram/Mult
igated Acquisition 
Scan 
Removed requirement to do an 
ECHO or MUGA scan to assess 
LVEF at EoT visit. Updated 
footnote “i” to clarify that an 
ECHO or MUGA may be done at 
EoT visit, if clinically indicated. 
To align with AstraZeneca 
Dato-DXd program standards, 
the ECHO/MUGA scan is not 
required at EoT visit unless 
clinically indicated. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Section 8.2.4, Table 7 
Removed requirement to do 
coagulation tests at screening. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Added optional bronchoalveolar 
lavage and lung biopsy sample on 
diagnosis of suspected 
ILD/Pneumonitis into SoA. 
Administrative clarification, as 
collection of this sample was 
previously omitted from the 
SoA. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Updated footnote “a” to ensure 
the safety follow-up visit is 
performed 28 (+7) days after the 
last study intervention 
administration regardless of 
participant starting new anticancer 
treatment. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Updated footnote “q” to specify 
prior HIV serology, HBV 
serology, and HCV serology test 
results can still be used if 
performed within 120 days of 
enrolment. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Updated footnote “r” to specify 
that participants must be tested for 
HIV if applicable by local 
regulations or an IRB/EC. 
Administrative clarification. 
Non-substantial 
Section 5.2, 
Exclusion Criteria #5 
Updated text to clarify 
circumstances where patients may 
still be eligible with respect to 
hepatitis B or C. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 5.2, 
Exclusion Criteria #6 
Updated definition of well 
controlled HIV infection. 
Clarified recommendation to 
monitor viral RNA load and 
CD4+ count, and that participants 
must be tested for HIV if 
acceptable by local regulations or 
an IRB/EC. 
To align with AstraZeneca 
Dato-DXd program standards. 
Substantial 
Section 6.5, 
Concomitant Therapy 
Added requirement for all 
concomitant medications 
administered during the study to 
be recorded until the end of the 
safety follow up period and those 
administered for drug-related 
AESIs to be recorded in the eCRF 
as required. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 6.6, Dose 
Modification 
Clarified dose delay allowance.  
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 8.2.4, 
Clinical Safety 
Laboratory 
Assessments 
Section 8.3.6, Hy’s 
Law 
E2 Definitions, E3 
Identification of 
Potential Hy’s Law 
Cases 
Corrected typo in Hy’s Law 
criteria from TBL > 2 ULN to  
TBL ≥ 2 ULN. 
Typographical correction. 
Non-substantial 
Section 8.3.1, Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Added Grade ≥ 2 keratitis events 
to list of AEs to be reported by 
the investigator in eCRF within 
24 hours of awareness. 
To align with AstraZeneca 
Dato-DXd program standards. 
Substantial 
Section 8.3.6, Hy’s 
Law 
Removed reference to Section 
8.3.11 as Hy’s Law event is no 
longer considered an AESI. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 8.3.11, 
Adverse Events of 
Special Interest 
Clarified that all AESIs must be 
followed until either event 
resolution, end of study, trial 
termination, withdrawal of 
consent, or participant death. 
Administrative clarification. 
Non-substantial 
Section 9.3, Table 9, 
Population for 
Analysis 
Updated table to specify that 
participants in the mainland China 
cohort will be excluded from ITT 
population. Additional changes to 
clarify SAS, OAS, and PAS will 
be comprised of participants in 
the ITT population. 
Included as part of flexible 
language to allow for 
mainland China tail, if 
required. 
Non-substantial 
Section 9.4.2.2.9, 
Pharmacokinetics 
Corrected substrate name from 
MAAA-1191a to MAAA-1181a. 
Typographical correction. 
Non-substantial 
Section 9.7, Mainland 
China Cohort 
Summarized details of mainland 
China cohort. 
If required for regulatory 
submission purposes, the 
recruitment of participants in 
mainland China may continue 
beyond the close of the global 
cohort. 
Non-substantial 
Appendix I, Table 19, 
Supportive 
Medications/therapies 
Clarified recommendation for 
usage of prophylactic anti-emetic 
agents. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Throughout CSP 
Clarified that ‘China’ refers to 
mainland China. 
To align with China R&D 
preferred terminology. 
Non-substantial 

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Amendment 2 (19 April 2022)  
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to provide additional guidance for investigators 
after the annual update of the Dato-DXd Investigator’s Brochure v6.0. The Toxicity 
Management Guidelines includes further details on management of ocular surface toxicities, 
and are now located in an Annex document. Adverse Events of Special Interest no longer 
include “combined elevations of aminotransferase and bilirubin”, and stomatitis/mucosal 
inflammation have been separated into “oral mucositis/stomatitis” and “mucosal inflammation 
other than oral mucositis/stomatitis.” 
Other administrative and operational clarifications have also been made. 
The rationale for each of these changes is provided in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 1.1, Synopsis, 
Participant 
Population 
Section 5.1, Inclusion 
Criteria #1 
Removed requirement for 
participants in Japan to be 
≥ 20 years. 
Update to the civil code for 
age of adulthood in Japan. 
Substantial 
Section 1.1, Synopsis, 
Intervention Groups 
and Duration 
Section 4.1, Overall 
Design 
Section 9.4.2.1.5, 
Subgroup Analysis 
Added Canada as a Region 1 
country. 
Administrative clarification. 
Non-Substantial 
Section 1.1, Synopsis, 
Follow-up of 
Participants Post 
Discontinuation of 
Study Intervention 
 
Added that the EoT assessments 
can function as the Safety Follow-
up visit if the date of 
discontinuation is over 35 days 
from the last administration of 
study intervention. 
Administrative clarification. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Added ePRO training and set up. 
Administrative clarification. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Updated footnote “d” so that 
safety assessments do not have to 
be repeated if they have been 
performed within 72 hours prior 
to the day of dosing. 
To allow flexibility in patient 
management without 
compromising safety. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Section 5.1, Inclusion 
Criteria #14 
Updated footnote “p” and added 
clarification that a serum 
pregnancy test should be negative 
at screening and. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Section 6.3, 
Participant Enrolment 
and Randomization 
Updated footnote “q” and 
Section 6.3.1 to be consistent with 
Exclusion Criterion #5. 
Administrative clarification. 
Non-substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Section 8.1.1, 
Imaging Tumor 
Assessments 
Updated footnote “x” and added 
clarification of abdomen imaging. 
To align with AstraZeneca 
program standards. 
Non-substantial 
Section 1.3, Schedule 
of Assessments 
Table 2 added detailing the 
assessments to be performed in 
the event of suspected 
ILD/pneumonitis. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 2.2.1, 
HR-positive, 
HER2-negative, 
inoperable/metastatic 
breast cancer 
Added baseline 
characteristics/factors which 
could be relevant to the target 
study population. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 2.2.2.1, 
TROPION-
PanTumor01 study 
Section 2.3.3, Overall 
Benefit: Risk 
Conclusion 
Updated safety and efficacy data 
from the DS1062-A-J101 study. 
To align with latest Dato-DXd 
Investigator Brochure. 
Non-substantial 
Section 2.3.1.1, 
Dato-DXd, Table 3 
Section 8.3.11, 
Adverse Events of 
Special Interest 
Labeled “stomatitis/oral 
mucositis” as an identified 
risk/AESI and established 
“mucosal inflammation other than 
oral mucositis/stomatitis” as a 
separate identified risk/AESI. 
Removed anaphylaxis in relation 
to IRR. 
To align with latest Dato-DXd 
safety profile information. 
Substantial 
Section 4.3.1, 
Dato-DXd 
Updated to include latest available 
data. 
To align with latest Dato-DXd 
Investigator Brochure. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 5.1, Inclusion 
Criteria #8 
Limit of AST/ALT criteria 
extended to assess adequate organ 
and bone marrow function. 
Removed INR or PT, and either 
PTT or aPTT criteria. 
To allow flexibility in patient 
enrolment without 
compromising safety. 
Substantial 
Section 5.1, Inclusion 
Criteria #10 
Added definition for washout 
period of immunotherapy. 
Administrative clarification. 
Non-substantial 
Section 5.1, Inclusion 
Criteria #15 
Appendix G1, Female 
Participants 
Removed references to HRT in 
relation to female participant 
contraception. 
HRT is contraindicated for 
HR-positive disease. 
Substantial 
Updated contraceptive 
requirement to 3 months before 
C1D1. 
Administrative clarification. 
Substantial 
Section 5.1, Inclusion 
Criteria #16 
Added that female partners of 
male participants are allowed to 
use HRT for contraception. 
Updated that male participants 
should use a highly effective 
method of contraception. 
Clarification following the 
change to Inclusion Criteria 
#15. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 5.2, 
Exclusion Criteria #3 
Removed allowance of study 
physician judgment and added 
examples of permitted toxicities 
related to previous anticancer 
therapy. 
To provide operational 
flexibility without 
compromising safety. 
Substantial 
Section 5.2, 
Exclusion Criteria 
#16 
Clarified to allow concurrent use 
of hormones for non-cancer 
related conditions (eg, insulin for 
diabetes). 
To align with CSP permitted 
medications. 
Non-substantial 
Section 5.2, 
Exclusion Criteria 
#19 
Removed exclusion criteria to 
allow for the enrolment of 
participants using chronic 
systemic corticosteroids. 
To align with AstraZeneca 
Dato-DXd program standards. 
Substantial 
Section 5.3, Lifestyle 
Considerations 
Added recommendation regarding 
consideration to preserve ova 
prior to enrolment. 
Compliance with AstraZeneca 
program standards. 
Non-substantial 
Section 6.2.1.2, 
Administration of 
Dato-DXd 
Added clarification regarding 
mandated pre-medications. 
Added that the IV line will be 
flushed following infusion. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 6.2.1.3, 
Monitoring of Dato-
DXd Administration 
Section to include Dato-DXd 
monitoring added. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 6.5, 
Concomitant Therapy 
Added information regarding 
concomitant use of Dato-DXd and 
CYP3A inhibitors and drugs that 
inhibit OATP1B1, OATP1B3, 
MATE2-K, P-gp, BCRP, and 
MRP1. 
Added information regarding 
concomitant use of Dato-DXd and 
hydroxychloroquine and/or 
chloroquine. 
To align with AstraZeneca and 
Dato-DXd program standards. 
Non-substantial 
Section 6.6, Dose 
Modification 
Added information regarding dose 
delays, interruptions, and 
modifications. 
Consequent to change in 
Section 6.1.1, and to align 
with AstraZeneca Dato-DXd 
program standards. 
Non-substantial 
Section 6.6.4, 
Dato-DXd Dose 
Modification/ 
Toxicity Management 
Guidelines 
Removed Toxicity Management 
Guidelines (TMG) from the body 
of the CSP (including 
Appendix L) and included as an 
Annex. 
To provide operational 
flexibility, as the TMG may be 
updated without CSP 
amendment. 
Non-substantial 
Section 6.7, 
Intervention after the 
End of the Study 
Added text regarding continuation 
of open-label treatment and 
alternative supply options should 
they become available. 
To align with AstraZeneca 
program standards. 
Substantial 
Section 8.1.1 Imaging 
Tumor Assessments 
Added that for participants with 
documented bone lesion at 
baseline, the bone scan must have 
been performed no more than 
28 days before randomization. 
To align with AstraZeneca and 
Dato-DXd program standards. 
Non-substantial 
Section 8.1.1 Imaging 
Tumor Assessments 
Added clarification that CT/MRI 
are to be collected for all 
participants at baseline. 
Removed the text regarding 
treatment continuation regardless 
of study intervention 
discontinuation or start of 
subsequent anticancer therapy. 
Administrative clarification. 
Non-substantial 
Section 8.1.5.9, 
Administration of 
Electronic PRO 
(ePRO) 
Questionnaires 
Added timing of onboarding 
participant onto the ePRO 
application. 
To ensure the correct C1D1 
date is registered in the ePRO 
system. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 8.2.2, Vital 
signs 
Added seated assessment 
position. 
To allow flexibility in patient 
management without 
compromising safety. 
Non-substantial 
Section 8.2.3, 
Electrocardiograms 
Amended the requirement of 
timing of ECGs and ECG 
machine capabilities. 
To provide operational 
flexibility for both timing and 
the ECG machine capabilities; 
without compromising safety. 
Non-substantial 
Section 8.2.4, 
Clinical Safety 
Laboratory 
Assessments 
Added urea and calcium (ionized) 
to the laboratory safety variables. 
To align with AstraZeneca 
Dato-DXd program standards 
and allow for operational 
flexibility without 
compromising safety. 
Non-substantial 
Section 8.2.5.3, 
ILD/Pneumonitis 
Investigation 
Added troponin assessment to the 
ILD/pneumonitis investigations. 
Clarified that bronchoscopy and 
bronchoalveolar lavage are 
options and added optional lung 
biopsy to the ILD/pneumonitis 
investigations. 
To align with AstraZeneca 
Dato-DXd program standards 
to rule out cardiac etiology. 
Substantial 
Section 8.2.5.3, 
ILD/Pneumonitis 
Investigation 
Section 8.5.1, 
Pharmacokinetics 
Removed the requirement for a 
blood sample for PK in the case 
of suspected ILD/pneumonitis. 
No longer within the scope of 
the study. 
Non-substantial 
Section 8.2.5.5, 
Ophthalmologic 
Assessments 
Section 8.3.11, 
Adverse Events of 
Special Interest 
Added that the assessments are to 
be performed by an 
ophthalmologist, or if unavailable, 
another licensed eye care 
provider. 
To align with AstraZeneca 
Dato-DXd program standards. 
Substantial 
Section 8.2.5.5, 
Ophthalmologic 
Assessments 
Added alternative to fluorescein 
staining, ocular symptoms to be 
considered during assessment, 
reporting of assessment results 
and use of additional eye 
medications. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 8.2.5.6, Oral 
Care Plan 
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 18 
Added details of use of 
prophylactic mouthwash and 
cryotherapy. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Section 8.3, Adverse 
Events and Serious 
Adverse Events 
Added requirements for reporting 
Grade ≥ 3 ocular surface toxicity 
events. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 8.3.1, Time 
Period and Frequency 
for Collecting AE and 
SAE Information 
Added specific AEs that should 
be reported within 24 hours of the 
investigator becoming aware. 
To align with AstraZeneca 
program standards. 
Substantial 
Section 8.3.5, 
Adverse Events 
Based on 
Examinations and 
Tests 
Added that ECOG performance 
status and ophthalmologic 
assessments will be summarized 
in the CSR. 
To align with AstraZeneca 
program standards. 
Non-substantial 
Section 8.3.11, 
Adverse Events of 
Special Interest 
Removed combined elevations of 
aminotransferases and bilirubin. 
Added the actions to be taken for 
ILD/pneumonitis cases. 
Clarified dry eye is an identified 
risk and keratitis is a potential risk 
within the ocular surface toxicity 
AESI. 
To align with AstraZeneca 
Dato-DXd program standards. 
Substantial 
Section 8.3.14.1, 
Maternal Exposure 
Added that AstraZeneca must be 
notified of any female participant 
or partner of a male participant 
who becomes pregnant while 
receiving or within 7 months of 
discontinuing Dato-DXd. 
To align with AstraZeneca 
Dato-DXd program standards. 
Substantial 
Section 8.6.3, Other 
Study Related 
Biomarker 
Assessments 
Added reasons for additional 
exploratory analyses. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Section 8.8, Medical 
Resource Utilization 
and Health 
Economics 
Added variables to be captured in 
the HOSPAD eCRF module. 
To align with AstraZeneca 
program standards. 
Non-substantial 
Appendix A7, Data 
Quality Assurance 
Increased the record and 
document retention time to 25 
years. 
To align with updated 
AstraZeneca Global 
Retention and Destruction 
standards. 
Substantial 
Appendix A7, Data 
Quality Assurance 
Added medical oversight 
responsibility. 
To align with AstraZeneca 
program standards. 
Non-substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / Non-
substantial 
Appendix I2, Guidance 
Regarding Potential 
Interactions with 
Concomitant 
Medications 
Added information regarding 
concomitant use of Dato-DXd and 
CYP3A inhibitors and drugs that 
inhibit OATP1B1, OATP1B3, 
MATE2-K, P-gp, BCRP, and 
MRP1. 
 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 17 
Added palliative radiotherapy. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 18 
Added other investigational 
therapeutic agents. 
To align with AstraZeneca 
Dato-DXd program standards. 
Non-substantial 
Appendix I2, Restricted, 
Prohibited, and 
Permitted Concomitant 
Medication/Therapies, 
Table 19 
Added additional supportive 
medications/therapies. 
To align with AstraZeneca 
program standards. 
Non-substantial 
Appendix J, 
Instructions Related 
to COVID-19 
Added requirement if PCR testing 
is not available. 
To align with AstraZeneca 
program standards. 
Non-substantial 
Appendix K2, 
Rescreening of 
Participants to 
Reconfirm Study 
Eligibility 
Rescreening period extended for 
those participants who have 
entered rescreening. 
Updated to allow for participants 
to remain in screening until 
reconfirmation of eligibility. 
To accommodate enrolment of 
participants during periods of 
study disruption, in alignment 
with established study 
processes already in place. 
Substantial 
Throughout 
Minor changes to protocol 
wording, tables and figures, and 
editorial and document formatting 
revisions. 
To align with project standard 
or to provide clarification. 
Non-substantial 
 

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Amendment 1 (27 August 2021)  
Overall Rationale for the Amendment: 
The overall rationale for the amendment is to provide additional guidance for investigators on 
the monitoring and management of ocular surface toxicities potentially associated with 
Dato-DXd, the management of Grade 3 non-hematologic toxicities, as well as clarifying the 
Oral Care Protocol (OCP) to be used on this study. Furthermore, the schedule of assessments 
and inclusion/exclusion criteria were updated. 
The rationale for each of these changes is provided in the table below: 
Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
Title Page 
Added EudraCT number. 
Added EudraCT number as it 
has become available. 
Non-substantial 
Section 1.1, Synopsis, 
Overall Design 
Section 9.2, Sample 
Size Determination 
Updated number of participants to 
be enrolled from 900 to 1000. 
Updated number of participants 
enrolled based on available 
feasibility recruitment data. The 
number of participants to be 
randomized remains 
unchanged. 
Non-substantial 
1.2 Schema 
Removed PARP inhibitors from 
being considered a prior line of 
chemotherapy. 
To ensure that enrolled 
participants have received at 
least one prior line of 
chemotherapy. 
Substantial 
Section 1.3, Schedule 
of Assessments, 
Table 1 
Section 8.2.5.5, 
Ophthalmologic 
Assessments 
Ophthalmological Assessment: 
Updated SoA for ophthalmologic 
assessments to occur every 3 cycles 
from C1D1(within 14 days prior to 
scheduled cycle Day 1 visit), in 
addition to as clinically indicated; 
updated footnote “l” to provide 
additional clarifications around the 
ophthalmologic assessments. 
Section 8.2.5.5 has additional 
details around ophthalmologic 
assessments and care. 
To help prevent ocular surface 
toxicities, and to monitor and 
treat these events should they 
arise. 
 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
Section 1.3, Schedule 
of Assessments, Table 
1 
Section 8.2.5.6, Oral 
Care Plan 
Oral Care Plan: 
Oral Care Plan added to SoA; 
updated footnote “m” and created 
section 8.2.5.6 to provide 
additional details and guidance 
around daily oral care. 
The Oral Care Plan is designed 
to mitigate the risk of oral 
mucositis/stomatitis. This was 
previously listed in section 
6.6.1, Table 5, but has been 
moved to SoA and new section 
created (8.2.5.6) to ensure 
introduction of this plan for 
participants at the appropriate 
time. 
Substantial 
Section 2.3.1.1, Risk 
Assessment – Dato-
DXd 
Section 8.3.11, 
Adverse Events of 
Special Interest 
Ocular surface toxicity was added 
to the list of AESIs, and 
mitigations were added. 
For participant safety, as ocular 
surface toxicity has been noted 
in some participants treated 
with Dato-DXd. Associated 
monitoring by ophthalmologic 
assessments and a dedicated 
safety review will be 
performed. 
Substantial 
Section 5.1, Inclusion 
Criteria #3 
Removed PARP inhibitors from 
being considered a prior line of 
chemotherapy. 
To ensure that enrolled 
participants have received at 
least one prior line of 
chemotherapy. 
Substantial 
Section 5.1, Inclusion 
Criteria #8 
Hemoglobin level unit of 
measurement corrected to g/dL. 
Correction of incorrect unit of 
measurement listed in initial 
version of CSP.  
Non-substantial 
Section 5.2, Exclusion 
Criteria #9 
Additional note added to Exclusion 
Criteria #9 regarding ineligibility 
of participants found to have 
ILD/pneumonitis on baseline 
screening chest CT. 
To ensure participants enrolled 
do not have active ILD. 
Substantial 
Section 6.2.1.2, 
Administration of 
Dato-DXd 
Updated total cumulative time 
from dilution start time until end of 
infusion for Dato-DXd. 
To align with updated handling 
instructions. 
Non-substantial 
Section 6.2.1.2, 
Administration of 
Dato-DXd 
Added guidance around dose re-
calculation if participant’s weight 
changes during the study. 
Original wording is lacking 
information important for 
correct dose re-calculation. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
Section 6.6.1, Table 5: 
Dose Modifications 
for Non-hematologic 
and Hematologic 
Toxicity Related to 
Dato-DXd 
Amended dose reduction 
thresholds and added guidance 
around optimizing use of 
prophylactic and supportive 
medications. 
For participant safety, emphasis 
has been placed on providing 
prophylactic/supportive 
medications (when 
appropriate); in addition, dose 
reductions for Grade 3 
toxicities (regardless of time of 
resolution) have been added for 
most non-hematologic 
toxicities. 
Substantial 
Section 7.1.3, Follow-
up for Survival 
Specified that local death registries 
may be used to obtain survival 
status information. 
To clarify options for gathering 
survival data, in line with AZ 
standards. 
Non-substantial 
Section 8.2.4, Table 7 
Updated list of acceptable values 
for leukocyte differential count to 
now include percentages. 
To accommodate sites only 
able to provide a percentage 
value, as absolute count is not 
key. 
Non-substantial 
Section 9.3, 
Populations for 
Analysis 
Added Ophthalmologic Analysis 
Set (OAS). 
Added analysis for potential 
risk of ocular surface toxicity, 
and terminology clarification. 
Substantial 
Section 9.4.2.1, 
Efficacy, Primary 
Endpoints, Table 10 
Added ‘subsequent anticancer 
therapy’ to list of sensitivity 
analyses. 
Additional sensitivity analysis 
to assess robustness of PFS 
dual primary analysis. 
Substantial 
Section 9.4.2.1.3, PFS 
Sensitivity Analyses 
Added language regarding 
subsequent anticancer therapy. 
Additional sensitivity analysis 
to assess robustness of PFS 
dual primary analysis. 
Substantial 
Section 9.4.2.1.5, 
Subgroup Analysis 
Added two additional subgroups: 
prior use of taxanes and/or 
anthracyclines, and pre-selected 
choice of chemotherapy. 
Clarified that forest plot of the PFS 
hazard ratios will be produced for 
each level of the subgroups. 
More detailed subgroup 
analysis to provide additional 
data, and terminology 
clarification. 
Substantial 
Section 9.4.2.2.8, 
Clinical Outcome 
Assessments 
Updated analysis language. 
To clarify that clinically 
meaningful change thresholds 
will be based on pooled data, 
not the actual TTD endpoint 
analyses. 
Non-substantial 
Section 9.6.3, 
Ophthalmologic Data 
Review Committee 
Added details around the 
independent Ophthalmologic Data 
Review Committee. 
Data review of participant 
safety with regard to 
ophthalmologic assessments. 
Substantial 

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Section # and Name 
Description of Change 
Brief Rationale 
Substantial / 
Non-substantial 
Appendix I, Table 19, 
Supportive 
Medications/Therapies 
Updated details around 
prophylactic/supportive 
stomatitis/oral mucositis agents. 
To mitigate risk of stomatitis 
for participant safety. 
Non-substantial 
Throughout 
Minor changes to protocol 
wording, tables and figures. 
To align with project standard 
or to provide clarification. 
Non-substantial 
Throughout 
Minor editorial and document 
formatting revisions. 
To further clarify. 
Non-substantial 
 

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Appendix L Country-Specific Addendums to the Protocol  
L 1 
Country-specific Requirements for Brazil  
Table L20 
Country-specific Requirements for Brazil (Effective 15 September 2022) 
Section # and Name 
Description of Change with Reason 
▪ Table 1: Informed consent: genetic sample and 
analysis (optional) 
▪ Item 5.1 – Inclusion Criteria #16: “Provision of 
signed and dated written Optional Genetic Research 
Information informed consent prior to collection of 
sample for optional genetic research that supports 
Genomic Initiative”  
▪ Item 6.3.1 – Participant Enrolment (“Obtain 
signed informed consent for the optional Genomics 
Initiative”)  
▪ Item 8.7 – Optional Genomics Initiative Sample 
▪ Item 9.4.4.1 - Optional Exploratory Genetic 
Sample 
▪ Appendix D – Optional Genomics Initiative 
Sample 
AZ clarifies that the information related to the 
Optional Genetic Research described in the 
items/appendix is not applicable for the Brazilian 
Research Participants since Brazil will not take part 
in the Optional Genetic Research (Genomic 
Initiative). 
▪ 
Item 5.1 – Inclusion Criteria - #13: “  
(…) Contraceptive use by men or women 
should be consistent with local regulations 
(…)”. 
▪ 
Item 5.1 – Inclusion Criteria – #15: “(…) 
Female participants must be post-menopausal 
for at least 1 year, surgically sterile, or using one 
highly effective form of birth control (…)”  
▪ 
Item 5.1 – Inclusion Criteria – #16: “Male 
participants who intend to be sexually active 
with a female partner of childbearing potential 
must be surgically sterile or using an acceptable 
method of contraception (…)” 
▪ 
Item 
5.3 
– 
Lifestyle 
Considerations: 
“Participants must follow the contraception 
requirements outlined in Appendix G.” 
AZ clarifies that the research participant will receive 
the contraceptive method chosen in common 
agreement with the Study Doctor, with no costs for 
her/his health insurance and public health system. 
 
Additionally, AZ clarifies that, according to Brazilian 
Resolution 466/12, item III.2.t, if the research 
participant has sexual relationship only with 
partner(s) with the same gender, there is no need to 
use contraceptive methods to participate in this study. 
 
 

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Section # and Name 
Description of Change with Reason 
▪ 
Appendix G- Contraception Requirements 
▪ 
Item 5.2 - Exclusion Criteria - #21: 
“Participation in another clinical study with a 
study intervention or investigational medicinal 
device administered in the last 4 weeks prior to 
first dosing (…)” 
AZ clarifies that, according to Brazilian Resolution 
CNS/MS 251/97, item III.2.j, the study doctor should 
recommend that no individual be selected as research 
participant before a year has passed from her 
participation in another research, unless that 
individual were to directly benefit from it. 
▪ 
Item 1.1 – Synopsis - Intervention Groups 
and Duration: “Continued treatment with the 
same study drug post-progression may be 
allowed, based on prior discussion with study 
physician on case-by-case basis” 
 
▪ 
Item 4.1 – Overall Design  
 
▪ 
Item 6.1.1.1 – Duration of Treatment 
 
 
AZ clarifies that after the end of the research 
participant participation in the study, in accordance 
with the Resolutions of Health National Council, 
AstraZeneca is committed to guarantee the free and 
indefinite access to the study medication, if it has 
been shown effective (for example, until disease 
progression – worsening of your cancer – or toxicity) 
and indicated by the Doctor. 
▪ 
Item 8.5 – Human Biological Samples – This 
item states the following: 
“Samples may be stored for a maximum of 15 
years from the end of the study (as defined in 
Section 4.4) in line with consent and local 
requirements, 
after 
which 
they 
will 
be 
destroyed/repatriated. 
        PK and ADA samples will be disposed of after 
the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report 
(whichever is earlier), unless consented for 
future analyses. Samples may be disposed of or 
anonymized by pooling. Additional analyses 
may be conducted on the anonymized, pooled 
samples to further evaluate and validate the 
analytical method. Any results from such 
analyses may be reported separately from the 
CSR. 
        Remaining sample aliquots will be retained at 
AstraZeneca or its designee for a maximum of 
15 years from the end of the study (as defined in 
Section 4.4). Additional use includes, but is not 
limited to, further characterization of any ADAs, 
evaluation of novel and emerging biomarkers, 
confirmation and/or requalification of the assay, 
AZ clarifies that the information described on these 
items are not applicable for the samples collected 
from Brazilian research participants. For Brazil, the 
biological samples (tumor and blood) will be used as 
stated in the attached document “Sample Receipt and 
Storage Process”. We confirm that there will be no 
future additional analysis different from those 
detailed on this document. After processing the 
biological samples and receiving the results, the 
remaining biological samples will be stored only 
during the execution of this specific project for 
repetition and/or confirmation of the tests previously 
performed when needed and, after that, discarded.  
AZ also clarifies that from CSP v2.0 and CSP v3.0 
implementation, Brazil will no longer participate in 
the exploratory analyses. The samples collected 
under CSP v1.0 will be analyzed and destroyed after 
the end of the study.  
For tumor samples (biopsies), the remaining samples 
will be repatriated (sent back to the hospital 
department who provided it) immediately after all 
study analysis has been completed. 

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Section # and Name 
Description of Change with Reason 
and/or diagnostic assay development. The results 
from future analysis will not be reported in the 
CSR.” 
▪ 
Item 8.6 - Human Biological Sample 
Biomarkers: “(…) Samples may be retained in 
all regions to allow for potential diagnostic 
development (…)” 
▪ Appendix A – Item A3 - Informed consent 
process: “(…) The investigator or authorized 
designee will explain to each participant the 
objectives of the analysis to be done on the samples 
and any potential future use. (..)” 
▪ Appendix C – Item C1 – Chain of custody of 
biological samples (“Samples retained for further 
use will be stored in the AstraZeneca-assigned 
biobanks or other sample archive facilities and will 
be tracked by the appropriate AstraZeneca Team 
during for the remainder of the sample life cycle”).  
 
▪ 
Appendix J - Instructions Related to SARS-
COV-2 (COVID-19) - If the participant 
consents, the remaining serum samples will 
also be stored for future analysis. 
▪ Item 8.5 – Human Biological Samples; 
▪ Items 8.5.1 – Pharmacokinetics;  
▪ Item 8.5.2 – Immunogenicity Assessments;  
▪ Item 
8.6 
– 
Human 
Biological 
Sample 
Biomarkers; 
▪  Item 8.6.1 – Collection of Mandatory Samples 
for Biomarker analysis;  
▪ Item 8.6.2 – Collection of Optional Biomarker 
Samples;  
▪ Item 8.6.3 – Other Study-related Biomarker 
Assessments 
Related to the tests described on these items, AZ 
clarifies that all tests which may be done with 
biological samples during the study (tumor and 
blood) are listed on the attached document “Sample 
Receipt and Storage Process”. No additional tests 
will be performed with the samples provided by 
Brazilian research participants. 
AZ clarifies that from CSP v2.0 and CSP v3.0 
implementation, the information related to 
Exploratory Analysis described in the items/appendix 
listed are also not applicable for the Brazilian 
Research Participants since Brazil will no longer 
participate in the any exploratory analysis (biomarker 
and genetic). The samples collected under CSP v1.0 
will be analyzed and destroyed after the end of the 
study.  
▪ Appendix A – Item A3 - Informed consent 
process 
This item points that a copy of the signed ICF is 
given to each patient or his/her legal representative. 
We clarify that, according to the Brazilian Resolution 

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Section # and Name 
Description of Change with Reason 
 
CNS/MS 466/12, item IV.3.f, the principal 
investigator must ensure that another original of the 
signed ICF is given to each research participant. 
 
Moreover, the FDA has mandated that for additional study participant safety, dose reductions by 1 level for Grade 
3 toxicities (regardless of time to resolution) be added for most non-hematologic toxicities. 
 
Section # and Name 
Description of Change with Reason 
▪ Section 6.6.1, Table 5: Dose 
Modifications for Non-hematologic 
and Hematologic Toxicity Related 
to Dato-DXd 
The following sections do not specify dose reduction by 1 level for 
Grade 3 toxicities: 
 
The text should read as follows: 
 
 
 

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L 2 
Country-specific Requirements for Canada  
Table L21 
Country-specific Requirements for Canada (Effective 13 December 2022) 
Section # and Name 
Description of Change with Reason 
A7 – Data Quality 
Assurance 
Prior text: 
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the end of the study 
(as defined in the protocol) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the 
sponsor. 
 
Modified text: 
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years from the end of the study 
(as defined in the protocol) unless local regulations or institutional policies 
require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the 
sponsor. 
 
Rationale: Health Canada reduced the retention period for clinical trial records 
for drugs and natural health products from 25 years to 15 years under the Food 
and Drug Regulations and Natural Health Products Regulations. 
 
 
 
 

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L 3 
Country-specific Requirements for France  
Table L22 
Country-specific Requirements for France (Effective 10 November 2022) 
Section # and 
Name 
Description of Change with Reason 
Section 1.3, 
Schedule of 
Activities: 
Table 1 
Change: 
 
Addition of Footnote ‘cc’ to clarify that Clinical Outcome Assessments are not 
applicable to date to participants in France. 
 
Reason: 
 
Electronic Patient Reported Outcomes (ePROs) will not be collected from participants 
in France at this time until further notice. This is due to ePRO vendor (Medable) non-
compliance to date with French CNIL regulations which require processing of directly 
identifying data and health data by the same vendor to remain excluded. 
Section 8.1.5, 
Clinical 
Outcome 
Assessments 
(COA) 
Change: 
 
Addition of note to clarify that PROs will not be collected to date from participants in 
France. 
 

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Reason: 
 
Electronic Patient Reported Outcomes (ePROs) will not be collected from participants 
in France at this time until further notice. This is due to ePRO vendor (Medable) non-
compliance with French CNIL regulations which require processing of directly 
identifying data and health data by the same vendor to remain excluded. 
 
 

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Table L23 
Country-specific Requirements for France (Effective 21 January 2022) 
Section # and Name 
Description of Change with Reason 
Section 5.1, Inclusion 
Criteria: Criterion #3  
Change: 
 
Progressed on or not suitable for endocrine therapy per investigator 
assessment, and treated with 1 to 2 lines of prior standard of care 
chemotherapy in the inoperable/metastatic setting. Participant must have 
documented progression on their most recent line of chemotherapy. 
Note:  
• 
If a chemotherapy drug is changed within 28 days of use to another 
drug in the same class (ie, antimetabolite to antimetabolite) for any 
reason, the first drug is not counted as a line (Flatiron 2019). 
Targeted agents (such as mTOR inhibitors, PD-1/PD-L1 inhibitors, 
PARP inhibitors), endocrine therapies, and CDK4/6 inhibitors on 
their own do not contribute to the count of prior lines of 
chemotherapy; however, regimens with such agents in 
combination with metastatic chemotherapy should be classified as 
one line of chemotherapy. 
• 
Patients must have been treated with (neo)adjuvant 
anthracycline and/or taxane, if they received systemic 
treatment in the (neo)adjuvant setting, unless anthracycline 
and/or taxane was contraindicated or not considered the best 
treatment option for the subject in the opinion of the treating 
physician. 
 
Reason: 
 
The French Regulatory Authority (ANSM) request to precise the standard 
of care chemotherapy that patients should have received prior to 
ennrolment. According to the ESMO guidelines, in the absence of 
medical contraindications or patient concerns, anthracycline- or taxane-
based regimens, preferably as single agents, would usually be considered 
as first-line chemotherapy for HER2-negative advanced breast cancer in 
those patients who have not received these regimens as (neo)adjuvant 
treatment. Moreover, capecitabine, vinorelbine or eribulin (and 
gemcitabine as additional choice) are recommended for patients pre-
treated with an anthracycline and a taxane. Thus, the sponsor should 
ensure that patients have had the opportunity to receive taxanes and 
anthracyclines (if not contraindicated) along the course of their disease. 
This request is in line with the EMA scientific advice 
EMA/SA/0000060979 (22/07/2021).  
Section: 6.6.1, Dato-
Change: 

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DXd Dose 
Modification/Toxicity 
Management 
Guidelines: Table 5 
 
Anemia  
Grade 3  
(Hemoglobin < 8.0 g/dL; 
transfusion indicated) 
Delay dose until resolved to 
≤ Grade 2, then maintain dose. 
Grade 4  
Life-threatening consequences; 
urgent intervention indicated 
Delay dose until resolved to ≤ 
Grade 2, then reduce dose by 1 
level. 
Permanently discontinue Dato-
DXd, if recurrent grade 4/life-
threatening anemia occurs after 
dose reduction by 1 level. 
 
Reason: 
 
The French Regulatory Authority (ANSM) request to modify the protocol 
so as to permanently discontinue Dato-DXd in case of recurrent life-
threatening Grade 4 anemia after one level dose reduction. 
Section 6.4, 
Concomitant Therapy 
Change: 
 
Any concomitant treatment, procedure, vaccine, or other medication 
considered necessary by the investigator for the participant’s safety and 
wellbeing (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) or other specific categories of 
interest, that the participant is receiving from the time of screening or 
receives during the study, including the 28 (+7) day safety follow-up 
period following the last dose of study intervention must be recorded in 
the eCRF along with: 
 
− Reason for use. 
− Dates of administration including start and end dates. 
− Dosage information including dose and frequency. 
 
The Study Clinical Lead should be contacted if there are any questions 
regarding concomitant or prior therapy. 
 
If any concomitant therapy is administered due to new or unresolved AE, 
it should be recorded. 
 
Participants must be instructed not to take any medications, including 
over-the-counter products, without first consulting with the investigator. 

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Restricted, prohibited, and permitted concomitant medications/therapies 
are described in more detail in Appendix I2. 
For participants randomized to receive ICC, refer to the local Prescribing 
Information with regard to warnings, precautions, and contraindications.  
Guidance regarding potential interactions with concomitant medications 
is provided in Appendix I1. 
 
For management of patients receiving capecitabine, gemcitabine, 
eribulin mesylate and vinorelbine, investigators must refer to local 
prescribing information and to the SmPC website (https://base-
donnees-publique.medicaments.gouv.fr/), especially for information 
concerning contraindications, special warnings and precautions, 
posology adaptation in case of toxicity, monitoring, as well as 
medications that are contraindicated or that must be used with 
caution. 
 
Reason: 
 
The French Regulatory Authority (ANSM) request to modify the protocol 
in order to inform the investigators that they must refer to the SmPC of 
capecitabine, gemcitabine, eribulin mesylate and vinorelbine for the 
management of patients, especially concerning contraindications, special 
warnings and precautions, posology adaptation in case of toxicity, 
monitoring, as well as medications that are contraindicated or that must 
be used with caution, and, enclose the SmPC or refer to the website: 
http://base-donnees-publique.medicaments.gouv.fr which presents the 
updated version of the SmPCs of medications. 
Section 1.3, Schedule 
of Activities: Table 1, 
Footnote ‘P’ 
Change: 
 
Within 72 hours before randomization for all female subjects of 
childbearing potential; a positive urine pregnancy test result must 
immediately be confirmed using a serum test. Perform repeat pregnancy 
tests (urine or serum test per institutional guideline) within 72 hours 
before each cycle of study intervention and at end of treatment. 
Pregnancy testing is to be repeated monthly during 7 months after 
treatment discontinuation. 
 
Reason: 
 
The French Regulatory Authority (ANSM) request to modify the Table 1 
Schedule of Activities and correspondent sections so as to extend the 
duration for monthly pregnancy testing to 7 months after treatment 

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discontinuation, in order to align with post-treatment contraception 
duration. 
Section 8.2.4, Clinical 
Safety Laboratory 
Assessments 
Change: 
 
A negative result from a serum pregnancy test (which must have a 
sensitivity of at least 25 mIU/mL) must be available at the screening visit. 
Pregnancy tests should be conducted within 72 hours prior to 
randomization for all female participants of childbearing potential. 
Repeat pregnancy tests (urine beta-human chorionic gonadotropin or 
serum test per institutional guideline) should be performed 72 hours 
before infusion of each cycle and at the EoT visit. Pregnancy testing is 
to be repeated monthly during 7 months after treatment 
discontinuation. If a positive urine pregnancy test result is confirmed 
using a serum test in a female participant of childbearing potential, then 
the participant should not be treated. 
 
Reason: 
 
The French Regulatory Authority (ANSM) request to modify the Table 1 
Schedule of Activities and correspondent sections so as to extend the 
duration for monthly pregnancy testing to 7 months after treatment 
discontinuation, in order to align with post-treatment contraception 
duration. 
 
 
 
 
 

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L 4 
Country-specific Requirements for Germany  
Table L24 
Country-specific 
Requirements 
for 
Germany 
(Effective 
15 November 2022) 
Section # and Name 
Description of Change with Reason 
N/A 
Editorial change: adaption of the referenced CSP version  
N/A 
According to AstraZeneca’s procedures the Clinical Study Protocol (CSP) 
version 4.0 from 10 October 2022 was signed by the sponsor electronically 
only. 
This Addendum to the CSP contains the signature of the National Coordinating 
Investigator as requested by local regulatory authority. 
The protocol version 4.0 has no further impact on the German addendum and 
therefore no additional changes were made. 
N/A 
According to AstraZeneca’s procedures the Clinical Study Protocol (CSP) 
version 3.0 from 19 April 2022 was signed by the sponsor electronically only. 
 
Overall study conduct, 
tumor sampling 
 
 
 
 
 
2.3.2 Benefit assessment 
 
 
 
 
 
8.6.2 Collection of 
Optional Biomarker 
Samples 
 
 
 
 
 
 
 
 
 
 
No invasive sampling for fresh tumor specimen for the purpose of testing with 
companion diagnostics will be done for study participants. Therefore, no fresh 
biopsies will be taken during the study and only archived residual tumor 
material will be used at Screening. No optional paired tumor biopsy and no 
optional fresh tumor biopsy at progression will be conducted. Study participants 
will be informed in ICF accordingly.  
 
“Additionally, at the time of disease progression, participants will be offered an 
optional tumor biopsy, which will provide real-time next-generation sequencing 
results from the FoundationOne®CDx, that may help guide next treatment 
options.” 
 
Is deleted from section 2.3.2 
 
“Optional tumor tissue samples for exploratory biomarker research 
• 
Paired tumor biopsy: A baseline biopsy will be taken (where the 
participant has provided informed consent) before initial dosing of study 
intervention (at screening or pre-dose on C1D1), and a paired (second) 
biopsy will be taken on-treatment. The paired on-treatment biopsy can be 
collected C2D1 and C2D7. On-treatment sample may also be collected 
outside of this specified timepoint with prior agreement from the Sponsor. 
Paired preclinical treatment and on-treatment tumor samples must be 
obtained from the same lesion where clinically feasible to maximize the 
utility for assessment of pharmacodynamic changes. 
These optional paired tumor samples will be mandatory at select sites. 
• 
Tumor biopsy on disease progression: An additional tumor biopsy sample 
should be obtained at termination of treatment/documented RECIST 1.1 
disease progression in participants that have signed the additional optional 

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Section # and Name 
Description of Change with Reason 
 
 
 
 
 
 
 
 
 
 
Table 1 
consent. These samples will be used to explore mechanisms of resistance. 
The on-study provision of tumor tissue is encouraged only if clinically 
appropriate and not considered detrimental to participant care. 
Biopsies at study entry, on treatment, and progression are optional for the 
majority of participants in this study, and participants will not be excluded from 
the study if these samples are not collected. These optional biopsy samples will 
be mandatory at select sites.” 
 
Is deleted from Section 8.6.2 
 
“Optional tumor biopsy (FFPE/FF) at Progression” and “Optional paired tumor 
biopsy (FFPE/FF)” is deleted from Table 1 
Section 7.1 
Discontinuation of Study 
Intervention 
The wording in this section is changed from  
Participants may be discontinued from study intervention in the following 
situations:  
to 
Participants must be discontinued from study intervention in the following 
situations:  
• 
RECIST 1.1-defined radiological progression (refer to Section 8.1.1 and 
Appendix F).  
• 
An AE that, in the opinion of the investigator or AstraZeneca, 
contraindicates further dosing.  
• 
Any AE that meets criteria for discontinuation defined in the TMGs (see 
the Annex document to this CSP), or as defined in the local Prescribing 
Information for the ICC agents. 
• 
Participant decision. The participant is at any time free to discontinue 
treatment, without prejudice to further treatment. A participant who 
discontinues treatment is normally expected to continue to participate in 
the study (eg, for safety and survival follow-up) unless they specifically 
withdraw their consent to all further participation in any study procedures 
and assessments (see Section 7.2). 
• 
Severe non-compliance with the CSP as judged by the investigator or 
AstraZeneca. 
• 
Pregnancy or intent to become pregnant (refer to Appendix G and Section 
8.3.14). 
• 
Initiation of subsequent anticancer therapy, including another 
investigational agent. 
Note that discontinuation from study intervention is NOT the same thing as a 
withdrawal from the study. 
Crossover within the study is not permitted. 
Appendix G Contraception 
Requirements 
Women of childbearing potential who are not totally sexually abstinent (ie, 
refraining from heterosexual intercourse during the entire period of risk 

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Section # and Name 
Description of Change with Reason 
G1 Female participants 
associated with study interventions) and intend to be sexually active with a non-
sterilized male partner must use at least 1 highly effective method of 
contraception (Table 16). 
 
Is changed to: 
Women of childbearing potential who are not totally sexually abstinent (ie, 
refraining from heterosexual intercourse during the entire period of risk 
associated with study interventions) and intend to be sexually active with a non-
sterilized male partner must use at least 1 highly effective non-hormonal 
method of contraception (Table 16). Hormonal methods of contraception must 
not be used by female patients participating in this study.  
 
 
 
 

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L 5 
Country-specific Requirements for India  
Table L25 
Country-specific Requirements for India (Effective 02 November 2021) 
Section # and Name Description of Change with Reason 
Section 6.6.1, Table 5: 
Dose Modifications for 
Non-hematologic and 
Hematologic Toxicity 
Related to Dato-DXd 
The following sections do not specify dose reduction by 1 level for Grade 3 
toxicities: 
 
The text should read as follows: 
 
 
The global clinical study protocol and its amendments (as applicable) for the study is to 
be read as follows: 
Section # and Name Description of Change with Reason 
8.3.5 Adverse Events 
Based on Examinations 
and Tests 
Previous Text: 
The results from the CSP-mandated laboratory tests, vital signs, physical 
examinations, ECGs, and echocardiogram/MUGA scans will be summarized in 
the CSR.  
Deterioration as compared with baseline in protocol-mandated laboratory values, 
vital signs, ECGs, and ECHO/MUGA scans should therefore only be reported as 
AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of 
treatment with the study intervention or are considered to be clinically relevant as 
judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, e.g., dose adjustment or study intervention 
interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs 
and symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information. Wherever 
possible the reporting investigator uses the clinical, rather than the laboratory 
term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs 

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Section # and Name Description of Change with Reason 
or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to PD, should not 
be reported as an AE/SAE. Any new or aggravated clinically relevant abnormal 
medical finding at a physical examination as compared with the baseline 
assessment will be reported as an AE unless unequivocally related to the disease 
under study. 
 
Revised Text: 
The results from the CSP-mandated laboratory tests, vital signs, physical 
examinations, ECGs, and echocardiogram/MUGA scans will be summarized in 
the CSR.  
Deterioration as compared with baseline in protocol-mandated laboratory values, 
vital signs, ECGs, and ECHO/MUGA scans should therefore only be reported as 
AEs if they fulfil any of the SAE criteria, are the reason for discontinuation of 
treatment with the study intervention or are considered to be clinically relevant as 
judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, e.g., dose adjustment or study intervention 
interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs 
and symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information. Wherever 
possible the reporting investigator uses the clinical, rather than the laboratory 
term (e.g., anemia versus low hemoglobin value). In the absence of clinical signs 
or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s). 
Deterioration of a laboratory value, which is unequivocally due to PD, should not 
be reported as an AE/SAE. Any new or aggravated clinically relevant abnormal 
medical finding at a physical examination as compared with the baseline 
assessment will be reported as an AE unless unequivocally related to the disease 
under study. 
However, all the events occurring at the Indian sites (the reason whatsoever) that 
meet the criteria for seriousness (SAEs) from the time of signing the ICF, 
throughout the treatment period, including the safety follow up period (28 [+7] 
days after the discontinuation of study intervention) and if an event that starts 
after the defined safety follow-up period noted above and is considered to be due 
to a late onset toxicity to the study intervention, should be reported as an SAE per 
local regulatory requirements to the Sponsor (appropriate AstraZeneca 
representatives), Indian regulatory authority and the concerned Ethics 
Committees in accordance with New Drugs and Clinical Trials Rules, 2019. 
 

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Section # and Name Description of Change with Reason 
Reason for change: 
Per Indian regulatory requirements, all the events that meet criteria for 
seriousness have to be reported expeditiously to the Sponsor, Indian regulatory 
authority and the concerned Ethics Committees. 
8.3.7 Disease 
Progression 
Previous Text: 
Disease progression can be considered as a worsening of a participant’s condition 
attributable to the disease for which the study intervention is being studied. It may 
be an increase in the severity of the disease under study and/or increases in the 
symptoms of the disease. The development of new metastases or progression of 
existing metastasis to the primary cancer under study should be considered as PD 
and not an AE. Events, which are unequivocally due to PD, should not be 
reported as an AE during the study. Death due to disease progression should be 
recorded on the Death eCRF. 
 
Revised Text: 
Disease progression can be considered as a worsening of a participant’s condition 
attributable to the disease for which the study intervention is being studied. It may 
be an increase in the severity of the disease under study and/or increases in the 
symptoms of the disease. The development of new metastases or progression of 
existing metastasis to the primary cancer under study should be considered as PD 
and not an AE. Events, which are unequivocally due to PD, should not be 
reported as an AE during the study. Death due to disease progression should be 
recorded on the Death eCRF. 
However, all the events occurring at the Indian sites (the reason whatsoever) that 
meet the criteria for seriousness (SAEs) from the time of signing the ICF, 
throughout the treatment period, including the safety follow up period (28 [+7] 
days after the discontinuation of study intervention) and if an event that starts 
after the defined safety follow-up period noted above and is considered to be due 
to a late onset toxicity to the study intervention, should be reported as an SAE per 
local regulatory requirements to the Sponsor (appropriate AstraZeneca 
representatives), Indian regulatory authority and the concerned Ethics 
Committees in accordance with New Drugs and Clinical Trials Rules, 2019. 
 
Reason for change: 
Per Indian regulatory requirements, all the events that meet criteria for 
seriousness have to be reported expeditiously to the Sponsor, Indian regulatory 
authority and the concerned Ethics Committees. 
8.3.10 Deaths 
Previous Texts: 
All deaths that occur during the study intervention period, or within the protocol-
defined follow-up period after the administration of the last dose of study 
intervention, must be reported as follows: 
• 
Death clearly resulting from PD should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE. 

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Section # and Name Description of Change with Reason 
• 
Where death is not due (or not clearly due) to PD under study, the AE 
causing the death must be reported as an SAE within 24 hours. It should 
also be documented in the Statement of Death page in the eCRF. The 
report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign the main and contributory causes of 
death. 
• 
Deaths with an unknown cause should always be reported as an SAE and 
documented in the Statement of Death page in the eCRF, but every effort 
should be made to determine a cause of death. A post-mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy 
of the post-mortem results should be forwarded to AstraZeneca Patient 
Safety or its representative within the usual time frames. 
Deaths occurring after the protocol-defined follow-up period after the 
administration of the last dose of study intervention should be documented in the 
Statement of Death page. If the death occurred as a result of an event that started 
after the defined follow-up period and the event is considered to be due to a late-
onset toxicity to study intervention, then it should also be reported as an SAE. 
 
Revised Text: 
All deaths that occur during the study intervention period, or within the protocol-
defined follow-up period after the administration of the last dose of study 
intervention, must be reported as follows: 
• 
Death clearly resulting from PD should be documented in the eCRF in 
the Statement of Death page. It should not be reported as an SAE. 
• 
Where death is not due (or not clearly due) to PD under study, the AE 
causing the death must be reported as an SAE within 24 hours. It should 
also be documented in the Statement of Death page in the eCRF. The 
report should contain a comment regarding the co-involvement of PD, if 
appropriate, and should assign the main and contributory causes of 
death. 
• 
Deaths with an unknown cause should always be reported as an SAE and 
documented in the Statement of Death page in the eCRF, but every effort 
should be made to determine a cause of death. A post-mortem may be 
helpful in the assessment of the cause of death, and if performed, a copy 
of the post-mortem results should be forwarded to AstraZeneca Patient 
Safety or its representative within the usual time frames. 
Deaths occurring after the protocol-defined follow-up period after the 
administration of the last dose of study intervention should be documented in the 
Statement of Death page. If the death occurred as a result of an event that started 
after the defined follow-up period and the event is considered to be due to a late-
onset toxicity to study intervention, then it should also be reported as an SAE. 
However, all the events occurring at the Indian sites (the reason whatsoever) that 
meet the criteria for seriousness (SAEs) from the time of signing the ICF, 
throughout the treatment period, including the safety follow up period (28 [+7] 
days after the discontinuation of study intervention) and if an event that starts 

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Section # and Name Description of Change with Reason 
after the defined safety follow-up period noted above and is considered to be due 
to a late onset toxicity to the study intervention, should be reported as an SAE per 
local regulatory requirements to the Sponsor (appropriate AstraZeneca 
representatives), Indian regulatory authority and the concerned Ethics 
Committees in accordance with New Drugs and Clinical Trials Rules, 2019. 
 
Reason for change: 
Per Indian regulatory requirements, all the events that meet criteria for 
seriousness have to be reported expeditiously to the Sponsor, Indian regulatory 
authority and the concerned Ethics Committees. 
Study sites affected by this addendum: 
This Clinical Study Protocol - Addendum affects all the study sites in India and will prevail 
if in conflict with any other section in the Clinical Study Protocol (CSP) (including its 
appendices). 
 

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L 6 
Country-specific Requirements for United Kingdom  
Table L26 
Country-specific 
Requirements 
for 
United 
Kingdom 
(Effective 
19 May 2022) 
Section # and Name 
Description of Change with Reason 
Section 5.1 Inclusion 
Criteria #16 
Inclusion #16 states - “Male participants who intend to be sexually active 
with a female partner of childbearing potential must be surgically sterile or 
using an acceptable method of contraception (see Appendix G) from the 
time of screening throughout the total duration of the study and the drug 
washout period (at least 4 months after the last dose of study intervention) 
to prevent pregnancy in a partner. Male participants must not donate or 
bank sperm during this same time period. Not engaging in heterosexual 
activity (sexual abstinence) for the duration of the study and drug washout 
period is an acceptable practice if this is the preferred usual lifestyle of the 
participant; however, periodic or occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of 
contraception.” 
 
To clarify for the UK: If administered with either Gemcitabine or 
Vinorelbine, non-sterilized male participants must use an acceptable 
method of contraception and refrain from donating or banking sperm from 
the time of screening throughout the total duration of the study and the 
drug washout period (i.e., at least 6 months after the last dose of study 
intervention). 
Section 8.3.14.2 
Paternal 
Exposure 
To clarify specifically for non-sterilized male participants administered 
either Gemcitabine or Vinorelbine who intend to be sexually active with a 
female partner of childbearing potential, that they must use an acceptable 
method of contraception and refrain from donating or banking sperm from 
the time of screening throughout the duration of the study and the drug 
washout period (i.e., at least 6 months after the last dose of study 
intervention). 
Appendix G, G2 
Male Participants 
with a Female 
Partner of 
Childbearing 
Potential 
To clarify specifically for non-sterilized male participants administered 
either Gemcitabine or Vinorelbine who intend to be sexually active with a 
female partner of childbearing potential, that they must use an acceptable 
method of contraception and refrain from donating or banking sperm from 
the time of screening throughout the duration of the study and the drug 
washout period (i.e., at least 6 months after the last dose of study 
intervention). 
 

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11 
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Si g nat ure Pa ge f or V V- RI M- 0 5 7 9 4 0 7 3 v 2. 0
Si g nat ure Pa ge f or V V- RI M- 0 5 7 9 4 0 7 3 v 2. 0
A p pr o ve: D oc u me nt Le vel Tas k
Ver dict: A p pr o ve d 
C o nte nt A p pr o val
2 4- A pr- 2 0 2 4 1 4: 1 4: 0 8 G M T + 0 0 0 0
A p pr o ve: D oc u me nt Le vel Tas k
Ver dict: A p pr o ve d 
C o nte nt A p pr o val
2 9- A pr- 2 0 2 4 1 1: 3 4: 1 7 G M T + 0 0 0 0
A p pr o ve: D oc u me nt Le vel Tas k
Ver dict: A p pr o ve d 
C o nte nt A p pr o val
2 9- A pr- 2 0 2 4 1 2: 2 7: 0 0 G M T + 0 0 0 0
P P D
P P D
P P D