An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients With or Without Baseline Brain Metastasis With Previously Treated Advanced/Metastatic HER2-Positive Breast Cancer (DESTINY-Breast12)
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol - Amendment 2
Trastuzumab deruxtecan (T-DXd, AZD4552) - D9673C00007
AstraZeneca

Clinical Study Protocol - Amendment 2
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Trastuzumab deruxtecan (T-DXd, AZD4552) - D9673C00007
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Clinical Study Protocol
Study Intervention
Trastuzumab deruxtecan 
(T-DXd, AZD4552)
Study Code
D9673C00007
Version
Amendment 2
Date
07Jun2022
An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of 
Trastuzumab Deruxtecan in Patients With or Without Baseline 
Brain Metastasis With Previously-Treated Advanced/Metastatic 
HER2-Positive Breast Cancer (DESTINY-Breast12)
Sponsor Name:
AstraZeneca AB, 151 85 Södertälje, Sweden
Daiichi Sankyo Co., Ltd., 3-5-1, Nihonbashi-honcho, Chuo-ku, Tokyo, Japan 
(Local sponsor for Japan)
Regulatory Agency Identifier Numbers:
US IND number: 146,111
EudraCT number: 2020-005048-46
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: D9673C00007
Amendment Number: Amendment 2
Study Intervention: Trastuzumab deruxtecan (T-DXd). The non-proprietary name of T-DXd is 
trastuzumab deruxtecan except in the US where it is fam-trastuzumab deruxtecan-nxki.
Study Phase: Phase 3b/4
Short Title: A Study of T-DXd in Patients With or Without Brain Metastasis Who Have 
Previously-Treated Advanced or Metastatic HER2 Positive Breast Cancer
Acronym: DESTINY-Breast12
Study Physician name and contact information will be provided separately.
International Coordinating Investigators:
Nadia Harbeck, MD, PhD
Head, Breast Center, 
Ludwig-Maximilians-University of Munich 
Department of Obstetrics and Gynecology 
Marchioninistr. 15, 81377 
Munich, Germany
Nancy U. Lin, MD
Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women's Cancers
Director, Metastatic Breast Cancer Program
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date of issue
Amendment 2
07-Jun-2022
Amendment 1
08-Apr-2021
Original protocol
06-Nov-2020
Amendment 2 07 Jun 2022
This amendment is considered 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 European Union.
Overall Rationale for the Amendment:
This amendment was prepared to allow for more patients in earlier lines in Cohort 1 versus 
later lines, as a result of published results from DESTINY-BREAST 03. The protocol was also 
updated to provide further emphasis on prophylaxis of nausea and vomiting as well as to 
correct minor inconsistencies.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1 Synopsis;
Section 4.1 Overall 
Design
Restriction of 25% added for 
the number of third-line 
patients enrolled in Cohort 1
To maximise the number of 
patients on 1L/2L within 
this cohort
Substantial
Section 1.3 Schedule of 
Activities
Requirement for HIV antibody 
test updated from “if required” 
to “if allowed by local 
regulations or IRB/EC)
For clarification
Non-substantial
 
 
 
 
For clarification
Non-substantial
Section 1.3 Schedule of 
Activities; Section 3 
Objectives and 
Endpoints; Section 8.6.1 
Collection of Mandatory 
Samples for 
 
Analysis
 sampling updated to 
be subject to local laws and 
regulations
To allow for these samples 
not to be collected in 
countries where it is against 
local regulations
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.3 Synopsis;
Section 3 Objectives and 
Endpoints;
Section 8.5 Human 
Biological Samples
Section 8.5.2 
Immunogenicity 
Assessments;
Section 9.4.4.3 
Immunogenicity 
Assessments
ADA sampling and analysis 
removed from the protocol
ADA analysis is not a 
requirement for a Phase 
IIIb/IV study given the 
significant evidence already 
generated in the T-DXd 
study programme
Non-substantial
Section 1.3 Schedule of 
Activities
Section 6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding
Central laboratory acceptance 
of HER2 tumor sample 
removed
For clarification
Non-substantial
Section 1.3 Schedule of 
Activities
Section 6.3 Measures to 
Minimize Bias: 
Randomization and 
Blinding;
Section 8.3.1 Time 
Period and Frequency 
for Collecting AE and 
SAE Information; 
Appendix A3 Informed 
Consent Process
Pre-screening updated to be 
mandatory for all participants
For clarification
Substantial
Section 1.3 Schedule of 
Activities;
Section 6.6.1 Specific 
Toxicity Management 
and Dose Modification 
Information – T DXd
Clarification added for 
Troponin-T
Based on ESC advice
Non-substantial
Section 1.3 Schedule of 
Activities
Section 8.2.5.2 
Pulmonary Assessments
Section 8.2.5.3 
ILD/Pneumonitis 
Investigation
HRCT for screening and 
ILD/pneumonitis investigation 
updated to non-contrast
The injection of contrast has 
the potential for subtly (and 
unpredictably) increasing 
lung density, thereby 
increasing the difficulty in 
distinguishing between a 
reaction to the study 
treatment and the 
(temporary) impact of 
contrast on the lung
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 3 Objectives and 
Endpoints
New 
 endpoint 
added 
 
 
 
 
 
Substantial
Section 3 Objectives and 
Endpoints; Section 
9.4.2.3.2 
 
 
 
 
 
 
 
 
Substantial
Section 5.1 Inclusion 
Criteria
Inclusion criterion 1 updated 
to remove Japan-specific age 
of consent
Change in Japanese 
regulations; age of consent 
is now 18 years
Substantial
Inclusion criterion 3b(ii) 
updated to clarify eligibility of 
participants with CNS lesions 
≤2 cm
For clarification
Non-substantial
Inclusion criterion 3c(i) 
updated to clarify completion 
of treatment
Non-substantial
Inclusion criterion 4a updated 
to clarify dexamethasone 
treatment
Non-substantial
Inclusion criterion 4b updated 
to clarify relation between 
anticonvulsants and start of 
T-DXd dosing
Non-substantial
Inclusion criterion 8a updated 
to add evidence of disease 
progression on or within 
6 months after HER2 targeted 
therapy
In order to include all 
approved SoC therapies in 
the study countries
Substantial
Inclusion criterion 10 updated 
to clarify organ and bone 
marrow function parameters 
For clarification
Non-substantial
Section 5.1 Inclusion 
Criteria;
Section 5.2 Exclusion 
Criteria
Dexamethasone daily dose 
updated
For suitability of the steroid 
dose for participants with 
BMs
Substantial
Section 5.2 Exclusion 
Criteria
Exclusion criterion 6 removed
To remove duplicated 
information
Non-substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Exclusion criterion 20a 
updated to allow for 
denosumab treatment for bone 
lesions
For clarification
Non-substantial
Exclusion criterion 20(c) 
removed
For clarification as TKIs 
approved for non-small cell 
lung cancer are not 
applicable in this study
Substantial
Minor updates to exclusion 
criteria 8, 11, and 13 made; 
new exclusion criterion 20 
added
For consistency with the 
clinical development 
programme
Non-substantial
Section 5.3.1 Caffeine, 
Alcohol and Tobacco
Abuse of caffeine and use of 
psychoactive drugs added; 
section name updated
For clarification
Non-substantial
Section 5.4 Screen 
Failures
Disposition wording updated 
for subjects that fail screening
Correction
Non-substantial
Section 6.2.1 
Trastuzumab Deruxtecan 
Preparation, 
Administration, and 
Storage
Observation period added for 
first infusion of T-DXd
For clarification
Non-substantial
Window added to infusion 
period added for subsequent 
cycles of T-DXd
Section 6.5 Concomitant 
Therapy
Follow-up for ILD 
concomitant therapy updated
For clarification
Non-substantial
Section 6.6.1 Specific 
Toxicity Management 
and Dose Modification 
Information – T DXd
ILD Advisory Committee 
remit and ILD guidance 
references updated
For clarification
Non-substantial
Section 6.6.2 Dose 
Reductions, 
Interruptions, and 
Modifications; Appendix 
O Toxicity Management 
Guidelines
Dose delay time period from 
last infusion date updated
For consistency with the 
drug development 
programme
Non-substantial
Section 8.1.5.3 SRGQ-I
SRGQ-I updated to SRGQ in 
the first sentence
To correct an error
Non-substantial
Section 8.1.5.4 At-home 
Pulse Oximetry
Purpose of the walking 
assessment added
For clarification
Non-substantial
Section 8.1.5.5 
Administration of ePRO 
Questionnaires
Clarification added in case of 
handheld device failure
For clarification
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 8.2.2 Vital Signs
Number of blood pressure 
measurements required 
reduced from 3 to 1
To reduce patient burden
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Variables
Absolute neutrophil count and 
absolute lymphocyte count
removed from Laboratory 
Safety Variables table
To remove duplication
Non-substantial
Section 8.2.5 Other 
Safety Assessments
Diffusion capacity of the lungs 
for carbon monoxide updated 
to be mandatory for 
participants with prior severe 
and/or clinically significant 
pulmonary disorders only and 
“if feasible” for all other 
participants
To reduce patient burden
Non-substantial
For pulmonary assessments, it 
was clarified that non-contrast 
HRCT is to be performed at 
Screening, but CT is 
acceptable if HRCT is not 
feasible. It was also clarified 
that non-contrast HRCT is 
mandatory for suspected 
ILD/pneumonitis
Section 8.3.11 Adverse 
Events of Special 
Interest
ILD Advisory Committee title 
updated
To correct typo
Non-substantial
Section 9.2 Sample Size 
Determination
Final analysis of Cohort 2 
updated to clarify receipt of 
first dose by the last 
participant in the cohort and 
length of time in the study
For clarification
Non-substantial
Section 9.3 Populations 
for Analysis
Provision added to allow 
additional analysis sets to be 
included in the SAP
To allow for existing 
analysis sets to be 
constructed as needed
Non-substantial
Section 9.4.2.1.4 
Subgroup Analyses
“(White vs non-White)”
removed from race subgroup 
analyses
In line with Australian
Health Authority request
Substantial
Appendix I 1 Female 
Participants
Definition of menopause
removed
For consistency with the 
clinical development 
programme
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix O Toxicity 
Management Guidelines
Minor updates made to 
Toxicity management 
guidelines for T-DXd
For consistency with the 
clinical development 
programme
Non-substantial
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not 
been summarized
Non-substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE .....................................3
TABLE OF CONTENTS ......................................................................................................9
LIST OF FIGURES ............................................................................................................ 12
LIST OF TABLES .............................................................................................................. 12
1
PROTOCOL SUMMARY ................................................................................ 14
1.1
Synopsis ........................................................................................................... 14
1.2
Schema............................................................................................................. 20
1.3
Schedule of Activities ....................................................................................... 20
2
INTRODUCTION............................................................................................ 31
2.1
Study Rationale ................................................................................................ 31
2.2
Background ...................................................................................................... 31
2.2.1
Background Information on the Disease to Be Treated...................................... 31
2.2.2
Background Information on T-DXd................................................................... 33
2.3
Benefit/Risk Assessment................................................................................... 34
2.3.1
Risk Assessment ............................................................................................... 34
2.3.1.1
Risks of T-DXd................................................................................................. 34
2.3.1.2
Risks of HER2-targeted Agents......................................................................... 34
2.3.1.3
Risks of Topoisomerase I Inhibitors.................................................................. 36
2.3.2
Benefits of T-DXd............................................................................................. 36
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 38
3
OBJECTIVES AND ENDPOINTS................................................................... 40
4
STUDY DESIGN ............................................................................................. 43
4.1
Overall Design.................................................................................................. 43
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 43
4.2
Scientific Rationale for Study Design ............................................................... 44
4.2.1
Rationale for Study Design ............................................................................... 44
4.2.2
Rationale for T-DXd in MBC............................................................................ 44
4.2.3
Rationale for Study Endpoints .......................................................................... 45
4.3
Justification for T-DXd Dose ............................................................................ 45
4.4
End of Study Definition.................................................................................... 46
5
STUDY POPULATION.................................................................................... 47
5.1
Inclusion Criteria .............................................................................................. 47
5.2
Exclusion Criteria ............................................................................................. 51
5.3
Lifestyle Considerations ................................................................................... 55
5.3.1
Tobacco, Alcohol, Psychoactive Drugs and Caffeine......................................... 55

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5.4
Screen Failures ................................................................................................. 55
6
STUDY INTERVENTION ............................................................................... 57
6.1
Study Intervention Administered....................................................................... 57
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 57
6.2.1
Trastuzumab Deruxtecan Preparation, Administration, and Storage................... 58
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 59
6.4
Study Intervention Compliance......................................................................... 61
6.5
Concomitant Therapy........................................................................................ 62
6.5.1
Other Protocol Restrictions or Supportive Treatments....................................... 63
6.6
Dose Modification ............................................................................................ 63
6.6.1
Specific Toxicity Management and Dose Modification Information – T-DXd.... 63
6.6.2
Dose Reductions, Interruptions, and Modifications ........................................... 65
6.7
Intervention After the End of the Study............................................................. 66
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 67
7.1
Discontinuation of Study Intervention............................................................... 67
7.1.1
Temporary Discontinuation............................................................................... 68
7.1.2
Follow-up of Participants Post Discontinuation of Study Intervention............... 69
7.1.3
Follow-up of Participants to PFS2..................................................................... 69
7.1.4
Follow-up for Survival...................................................................................... 69
7.2
Participant Withdrawal From the Study............................................................. 70
7.3
Lost to Follow-up ............................................................................................. 70
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 72
8.1
Efficacy Assessments........................................................................................ 72
8.1.1
Imaging Tumor Assessments............................................................................. 72
8.1.2
Central Reading of Scans.................................................................................. 73
8.1.3
Time to Second Progression or Death................................................................ 73
8.1.4
Overall Survival................................................................................................ 74
8.1.5
Clinical Outcome Assessments.......................................................................... 74
8.1.5.1
EORTC QLQ-C30 ............................................................................................ 74
8.1.5.2
MDASI Symptom Diary................................................................................... 75
8.1.5.3
SGRQ-I ............................................................................................................ 75
8.1.5.4
Other COAs...................................................................................................... 75
8.1.5.5
Administration of ePRO Questionnaires............................................................ 76
8.2
Safety Assessments........................................................................................... 78
8.2.1
Physical Examinations...................................................................................... 78
8.2.2
Vital Signs ........................................................................................................ 79
8.2.3
Electrocardiograms........................................................................................... 79
8.2.4
Clinical Safety Laboratory Assessments............................................................ 80
8.2.5
Other Safety Assessments ................................................................................. 81
8.2.5.1
Echocardiogram/Multigated Acquisition Scan................................................... 81
8.2.5.2
Pulmonary Assessments.................................................................................... 82
8.2.5.3
ILD/Pneumonitis Investigation ......................................................................... 83

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8.2.5.4
ECOG Performance Status................................................................................ 84
8.2.5.5
Ophthalmologic Assessments............................................................................ 84
8.3
Adverse Events and Serious Adverse Events..................................................... 84
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 85
8.3.2
Follow-up of AEs and SAEs ............................................................................. 86
8.3.3
Causality Collection.......................................................................................... 87
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 87
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 87
8.3.6
Hy’s Law.......................................................................................................... 88
8.3.7
Disease Progression.......................................................................................... 88
8.3.8
Disease Under Study......................................................................................... 88
8.3.9
New Cancers..................................................................................................... 88
8.3.10
Deaths .............................................................................................................. 89
8.3.11
Adverse Events of Special Interest.................................................................... 89
8.3.12
Safety Data to be Collected Following the Final Data Cutoff of the Study......... 90
8.3.13
Reporting of Serious Adverse Events................................................................ 91
8.3.14
Pregnancy......................................................................................................... 91
8.3.14.1
Maternal Exposure............................................................................................ 91
8.3.14.2
Paternal Exposure............................................................................................. 92
8.3.15
Medication Error............................................................................................... 92
8.3.16
Medical Device Deficiencies............................................................................. 93
8.4
Overdose .......................................................................................................... 93
8.5
Human Biological Samples............................................................................... 93
8.5.1
Pharmacokinetics.............................................................................................. 94
8.6
Human Biological Sample Biomarkers ............................................................. 94
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 94
8.6.2
Collection of Optional 
 Samples ....................................................... 96
8.6.3
..................................................... 97
8.7
................................................................ 97
8.8
........................................ 97
9
STATISTICAL CONSIDERATIONS................................................................ 99
9.1
Statistical Hypotheses....................................................................................... 99
9.2
Sample Size Determination............................................................................... 99
9.3
Populations for Analyses................................................................................. 100
9.4
Statistical Analyses ......................................................................................... 100
9.4.1
General Considerations................................................................................... 101
9.4.2
Efficacy .......................................................................................................... 101
9.4.2.1
Primary Endpoints .......................................................................................... 101
9.4.2.2
Secondary Endpoints ...................................................................................... 104
9.4.2.3
Exploratory Endpoints .................................................................................... 106
9.4.3
Safety ............................................................................................................. 108
9.4.4
Other Analyses................................................................................................ 110
9.4.4.1
..................................................................................................... 110
9.4.4.2
............................................................. 110
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9.5
Interim Analyses............................................................................................. 110
9.6
Data Monitoring Committees.......................................................................... 110
9.6.1
IDMC ............................................................................................................. 110
9.6.2
Steering Committee .........................................................................................111
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 112
11
REFERENCES............................................................................................... 203
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 20
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 22
Table 2
Objectives and Endpoints......................................................................... 40
Table 3
Parameters for Adequate Organ and Bone Marrow Function.................... 49
Table 4
Study Treatment ...................................................................................... 57
Table 5
Dose Reduction Levels of T-DXd............................................................ 65
Table 6
Laboratory Safety Variables..................................................................... 81
Table 7
Spirometry Components .......................................................................... 82
Table 8
.................. 99
Table 9
..... 100
Table 10
Populations for Analysis ........................................................................ 100
Table 11
Summary of Guideline Recommendations ............................................. 134
Table 12
Reporting Elements for IHC (Local HER2 Test).................................... 136
Table 13
Reporting Elements for FISH (Local HER2 Test) .................................. 137
Table 14
Summary of Imaging Modalities for Tumor Assessment........................ 138
Table 15
RECIST 1.1 Evaluation of Target Lesions ............................................. 145
Table 16
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 146
Table 17
RECIST 1.1 Overall Visit Response ...................................................... 147
Table 18
Response Criteria for CNS Metastases per 
.......................... 150
Table 19
Highly Effective Methods of Contraception (<1% Failure Rate) ............ 153
Table 20
Restricted Medications/Therapies .......................................................... 164
Table 21
Prohibited Medications/Therapies.......................................................... 165
Table 22
Supportive Medications/Therapies......................................................... 166
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Table 23
NCCN Guidelines for the prevention of acute and delayed emesis by 
moderate emetic risk parenteral anticancer agents.................................. 167
Table 24
COVID-19 Dose Modification Criteria .................................................. 171
Table 25
Toxicity Management Guidelines for T-DXd......................................... 177
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 113
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 119
Appendix C
Handling of Human Biological Samples ................................................ 124
Appendix D
..................................................... 126
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 129
Appendix F
ASCO/CAP Guidelines on HER2 Testing in Breast Cancer ................... 134
Appendix G
Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria............................................................................................. 138
Appendix H
 
................................................................................ 149
Appendix I
Contraception Requirements.................................................................. 151
Appendix J
Patient-reported Outcomes..................................................................... 154
Appendix K
Guidance Regarding Restricted, Prohibited, and Permitted Concomitant 
Medications ........................................................................................... 164
Appendix L
Instructions Related to COVID-19......................................................... 170
Appendix M
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 173
Appendix N
Guidance for Management of Participants with Drug-Induced 
ILD/Pneumonitis ................................................................................... 175
Appendix O
Toxicity Management Guidelines .......................................................... 177
Appendix P
Family History and Exposure History for Interstitial Lung Disease........ 185
Appendix Q
Abbreviations ........................................................................................ 188
Appendix R
Protocol Amendment History................................................................. 193
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in 
Patients With or Without Baseline Brain Metastasis with Previously-Treated 
Advanced/Metastatic HER2-Positive Breast Cancer (DESTINY-Breast12)
Short Title:
A Study of T-DXd in Patients With or Without Brain Metastasis Who Have Previously-Treated 
Advanced or Metastatic HER2-Positive Breast Cancer
Rationale:
Several agents have been studied in patients with HER2-positive breast cancer with BMs. 
However, due to the decreased QoL and poor prognosis in this patient population, there is still 
a significant unmet need, particularly for later lines of treatment.
In DESTINY-Breast01, 184 patients with heavily pretreated breast cancer were treated with
T-DXd at the recommended dose of 5.4 mg/kg. This study population included 24 patients 
who had CNS metastases at baseline. Within this small cohort, the efficacy response for 
T-DXd was encouraging, supporting a more extensive evaluation of T-DXd in these patients.
The current study is designed to evaluate the efficacy and safety of T-DXd in a real-world 
setting. Overall, this study will look to provide a much more robust and detailed 
understanding of T-DXd that will complement studies that are ongoing or already completed. 
This study will be conducted in participants with advanced/metastatic breast cancer, including 
participants with previously-treated, stable BM and participants with active BM, either 
previously untreated or progressing (but not requiring immediate local therapy), to evaluate 
their response to T-DXd treatment. Therefore, this study may provide additional treatment 
options for patients.
Objectives and Endpoints
Objectives
Endpoints
Primary
To describe the overall treatment effect of T-DXd in 
HER2-positive MBC patients with or without 
baseline BM
Participants without BM at baseline (Cohort 1):
!
ORR by RECIST 1.1 per ICR
Participants with BM at baseline (Cohort 2):
!
PFS by RECIST 1.1 per ICR

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Objectives
Endpoints
Secondary
To describe the treatment effect on the development 
and progression of BM in patients with or without 
baseline BM using additional efficacy measurements
Participants in both cohorts:
!
OS
!
DoR by RECIST per ICR
!
Time to progression by RECIST per ICR
!
DoT on subsequent lines of therapy
!
PFS2
Participants without BM at baseline (Cohort 1):
!
Incidence of new symptomatic CNS metastasis 
during treatment
In patients who develop isolated CNS progression, 
receive local therapy, and continue on protocol 
therapy:
!
Time to next progression (CNS or extracranial) 
or death
!
Site (CNS vs extracranial vs both) of next 
progression
To describe efficacy in patients with stable or 
untreated BM
Participants with BM at baseline (Cohort 2):
!
ORR by RECIST 1.1 per ICR
!
CNS PFS by CNS RECIST 1.1 per ICR
!
Time to new CNS lesions
!
CNS ORR by CNS RECIST 1.1 per ICR
!
CNS DoR by CNS RECIST 1.1 per ICR
To describe the effect of T-DXd on symptoms, 
functioning, and HRQoL in HER2-positive MBC 
patients with or without baseline BM
Changes in symptoms, functioning, and HRQoL as 
measured by
!
All patients: EORTC QLQ-C30, NANO scale, 
cognitive tests
!
BM patients: MDASI brain tumor-specific items
!
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Objectives
Endpoints
Safety
To describe the safety profile of T-DXd
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, clinical laboratory results, and 
ECGs. 
Assessments related to AEs will also include:
!
Rate of investigator-assessed ILD/pneumonitis
∀
PTs will be matched with most commonly
reported terms within ILD cluster terms
∀
Rate of ILD clinical symptom resolution 
among ILD patients who have been treated 
with high-dose steroid (total daily dose 
> 2 mg dexamethasone or equivalent)
!
Rate of AEs among patients with baseline BM 
who are treated with concurrent high-dose 
steroid (total daily dose > 2 mg dexamethasone 
or equivalent)
AE = adverse event; BM = brain metastasis; CNS = central nervous system; DoR = duration of response; 
CR = complete response; DoT = duration of treatment; ECG = electrocardiogram; EORTC = European 
Organization for the Research and Treatment of Cancer; HER2 = human epidermal growth factor receptor 2; 
HRQoL = health-related quality of life; ICR = independent central review; ILD = interstitial lung disease; 
MDASI = MD Anderson Symptom Inventory; NANO = Neurologic Assessment in Neuro-oncology; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = time to second 
progression or death; PT = preferred term; QLQ-C30 = 30 item core quality of life questionnaire; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 1.1; SGRQ-I = St. George's Respiratory 
Questionnaire – idiopathic pulmonary fibrosis version; T-DXd = trastuzumab deruxtecan.
For exploratory objectives, see Section 3 of the protocol.
Overall Design
This is a Phase 3b/4, open-label, multicenter, international study assessing the efficacy and 
safety of T-DXd in participants with or without BM, with previously-treated 
advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior anti-
HER2-based regimens and who received no more than 2 lines/regimens of therapy in the 
metastatic setting (excluding tucatinib). Participants will be enrolled into 1 of 2 cohorts 
according to the presence or absence of BMs at baseline. 
Approximately 500 eligible participants will be treated in this study with 5.4 mg/kg T-DXd 
q3w until RECIST 1.1-defined radiological progression outside CNS, unless there is 
unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met. 
To ensure adequate representation of participants with BM at baseline, the maximum number 
of participants without BM at baseline will be limited to 250. Cohort 1 will additionally be 
limited to include no more than 25% third-line participants. The study will evaluate ORR by 
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other measures of efficacy, and further characterize the safety and tolerability profile of 
T-DXd. 
This study will be conducted in Europe, the US, Australia, and Japan.
Disclosure Statement: This is a Phase 3b/4, parallel cohorts, open-label, single-arm,
multicenter, international study assessing the efficacy and safety of T-DXd in participants with 
or without BM, with previously-treated advanced/metastatic HER2-positive breast cancer.
Participant Population:
The target population of interest in this study is adults with previously-treated 
advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior 
anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the 
metastatic setting (excluding tucatinib). This study will include participants with 
previously-treated stable BM and participants with active BM, either previously untreated or 
progressing (but not requiring immediate local therapy). At the time of enrollment, 
participants must have an ECOG score of 0-1 and must not have LMD.
Number of Participants:
Approximately 500 eligible participants will be treated in the study. Of these, approximately 
250 eligible participants without BM at baseline (Cohort 1) and 250 eligible participants with 
BM at baseline (Cohort 2) will be treated.
Intervention Groups and Duration:
All participants will receive IV T-DXd, 5.4 mg/kg, every 3 weeks (21-day cycle) until 
RECIST 1.1-defined radiological progression outside CNS. Participants may continue to 
receive T-DXd beyond progression, as long as they are continuing to show clinical benefit, as 
judged by the investigator, and in the absence of other discontinuation criteria.
Temporary interruption is allowed for local therapy of CNS-only progression. Dose delays, 
dose reductions to 4.4 mg/kg and further dose reductions to 3.2 mg/kg are allowed for the 
management of toxicities.
Follow-up of Participants Post Discontinuation of Study Intervention:
After study intervention discontinuation, all participants will undergo an EOT visit (within 
7 days of discontinuation) and will be followed up for safety assessments 40 (+ up to 7) days 
after their last dose of study intervention (ie, the safety follow-up visit).
Participants who have discontinued study intervention prior to RECIST 1.1-defined 
radiological progression will be followed up with tumor assessments according to the SoA
until RECIST 1.1-defined PD or death regardless of whether or not the participant started a 

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subsequent anticancer therapy, unless they have withdrawn all consent to study-related 
assessments.
In addition, all participants will be followed up for survival status and DoT on subsequent 
therapies after intervention discontinuation every 3 months (± 14 days) from the date of the 
safety follow-up until death, withdrawal of consent, or the end of the study, as per the SoA.
No intervention is planned 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.
Independent Data Monitoring Committee:
An IDMC composed of independent experts will be convened to review safety data and make 
recommendations to continue, amend, or stop the study based on safety findings.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
Statistical Methods
The primary objective of this study is to describe the overall treatment effect of T-DXd in 
HER2-positive MBC patients with or without baseline BM:
!
In participants without BM at baseline (Cohort 1), this objective will be evaluated upon 
completion of the study by the ORR. The ORR is defined as the proportion of participants 
who have a confirmed CR or confirmed PR, as determined by ICR per RECIST 1.1, and 
will be assessed for all dosed participants in Cohort 1.
 
 
 
 
 
The ORR will be assessed as a secondary 
endpoint for participants in Cohort 2.
!
In participants with BM at baseline (Cohort 2), the primary objective will be evaluated by 
PFS as assessed by RECIST 1.1. 
 
 
 
 
 
 
 The PFS will be defined as the time from the date of the first dose of 
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study intervention until the date of objective PD per RECIST 1.1 as assessed by ICR or 
death and will be assessed for all dosed participants in Cohort 2. PFS will be analyzed by 
the Kaplan-Meier method. 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. The proportion of participants alive and progression-free at 
12-monthly intervals from the first date of dosing will be summarized.
For each study visit, participants will be programmatically assessed for RECIST 1.1 response 
of CR, PR, SD, PD, or NE based on an ICR of imaging scans and depending on the status of 
their disease compared with baseline and previous assessments. The imaging scans will be 
reviewed by 2 independent radiologists using RECIST 1.1 and will be adjudicated, if required. 
The tumor response endpoints (ORR, PFS, time to progression, and DoR) will be derived 
from the scan dates and overall visit responses.
No formal hypothesis testing will be done for this single-arm, open-label study.
Safety data will be summarized descriptively and will not be formally analyzed unless 
otherwise specified.

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1.2
Schema
The study design is summarized in Figure 1.
Figure 1
Study Design
ASCO/CAP = American Society of Clinical Oncology/College of American Pathologists; BM = brain metastasis; 
CNS = central nervous system; DoR = duration of response; DoT = duration of treatment; ECOG = Eastern 
Cooperative Oncology Group; HER2 = human epidermal growth factor receptor 2; HRQoL = health-related 
quality of life; IV = intravenous; MBC = metastatic breast cancer; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PFS2 = time to second progression or death; q3w = every 3 weeks; 
RECIST = Response Evaluation Criteria in Solid Tumors; T-DM 1 = trastuzumab emtansine; T-DXd = 
trastuzumab deruxtecan.
1.3
Schedule of Activities
The procedures for this study are presented in Table 1.
Unless all eligibility criteria have been met, participants must not be treated. When 
participants do not receive study intervention, participants should undergo a physical 
examination and vital signs assessment with additional assessments at the discretion of the 
investigator. All samples are collected before infusion unless otherwise indicated.
Participants will be enrolled into the study after signing the main ICF and will begin 
screening/baseline procedures. Screening will take place for up to 28 days from the date of 
enrollment. At the end of screening/baseline procedures, participants who pass the eligibility 
criteria will be assigned to treatment. Every effort should be made to minimize the time 
between treatment assignment and dosing. Dosing should occur no more than 3 days after 
treatment assignment. If it is anticipated that dosing cannot occur within 3 days, a discussion 

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with the AstraZeneca study physician is required. Participants who fail to meet the eligibility 
criteria will be termed “screen failures”.
A pre-screen ICF must be signed by patients to permit tumor tissue sample collection for 
HER2 status testing prior to the 28-day screening window. At the time of signing the 
pre-screen ICF, Investigators should ensure that there is a reasonable possibility that the 
patient would be a candidate for this study based on available information (e.g., medical 
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
Informed consent b
X
Section 5.1
and Appendix 
A 3
 
X
Section 5.1
and Appendix 
A 3
Study Procedures and Assessments
Inclusion and exclusion criteria
X
Sections 5.1, 
5.2, and 5.3
Demography
X
Section 5.1
Full physical examination
X
Section 8.2.1
Targeted physical examination
X c
X c
X c
X c
X
X
Section 8.2.1
Height
X
Section 8.2.1
Weight
X
X c
X c
X c
X c
X
X
Section 8.2.1
Medical history (includes 
substance use and prior cancer 
treatment) 
X
X d
Sections 5.1
and 5.2
Subsequent anticancer therapy 
(including surgery and radiation 
therapy)
X
X
Section 7.1.1
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
ECOG performance status
X
X c
X c
X c
X c
X
X
Section 
8.2.5.4
12-lead ECG
X
X c
X (C4 and 
every 
4 cycles) c e
X
Section 8.2.3
Vital signs e
X
X c
X
X
X c
X c
X c
X
X
Section 8.2.2
ECHO or MUGA (LVEF)
X
X (C5 and 
every 
4 cycles 
[±7 days])
X
Section 
8.2.5.1
Pulmonary function tests
X
If ILD/pneumonitis is suspected
Section 
8.2.5.2
SpO2
X
X c
X
X
X c
X c
X c
X
X
Section 
8.2.5.2
Non-contrast HRCT
X
If ILD/pneumonitis is suspected
Section 
8.2.5.2 and 
8.2.5.3
Ophthalmologic assessments
X
As clinically indicated
X
Section 
8.2.5.5
ILD/pneumonitis investigation
If ILD/pneumonitis is suspected
Section 
8.2.5.3
AE f
At every visit and may be conducted by phone if not tied to a visit
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
Concomitant therapy 
At every visit and may be conducted by phone if not tied to a visit
Section 6.5
Laboratory Assessments 
Serum/urine pregnancy test 
(WOCBP only)
X
X c
X c
X c
X c
X
X
Sections 5.1, 
5.2, and 8.2.4, 
Hepatitis B/C serology
X
Sections 5.2
and 8.2.4
HIV antibody test (if allowed
by local regulations or IRB/EC)
X
Sections 5.2
and 8.2.4
Clinical safety laboratory 
assessments (clinical chemistry, 
hematology)
X g
X c
X
X
X c
X c
X c
X
X
Section 8.2.4
Coagulation
X
As clinically indicated
Section 8.2.4
Urinalysis
X
As clinically indicated
Section 8.2.4
Troponin h
X
If at any time a participant reports signs or symptoms suggesting 
CHF, myocardial infarction, or other causes of myocyte necrosis
X
Sections 
6.6.1, 8.2.4,
and 8.2.5.1
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
Mandatory (if available) 
archival FFPE (preferred) tumor 
tissue sample for confirmation 
of HER2 status and 
 
X
Sections 6.3
and 8.6.1
Mandatory blood sample for 
 
 
X
X
X
X
X (C4 then 
aligned 
with 
RECIST 
assessments
)i
X 
(progress
ion only)
Section 8.6.1
Mandatory newly acquired 
biopsy (if archival tumor tissue 
not available)
 
 
X
Sections 6.3, 
8.6.1, and 
8.6.2
 
X
(± 1 
week)
Section 8.6.2
X 
(progress
ion only)
Section 8.6.2
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
Blood sample for 
 
 
X
X
X
X (C4 then 
aligned 
with 
RECIST 
assessments
)i
X 
(progress
ion only)
Section 8.6.1
Blood sample for 
 
 
X
X
X
X (C4 then 
aligned 
with 
RECIST 
assessments
) i
X 
(progress
ion only)
Section 8.6.1  
Blood samples for PK and 
 
 
At the time of ILD onset, if ILD/pneumonitis is suspected
Sections 
8.2.5.3 and 
8.6.1
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
Whole blood sample for gene 
expression analysis (RNA)
X
X
X
X (C4 then 
aligned 
with 
RECIST 
assessments
)i and on 
suspected/ 
diagnosis of 
ILD
X 
(progress
ion only)
Section 8.6.1
 
 
 
X
Section 8.7
and 
Appendix D
 
 
If ILD/pneumonitis is suspected
Section 8.6.2
If ILD/pneumonitis is suspected
Section 8.6.2
Study intervention administration
T-DXd
T-DXd at 5.4 mg/kg will be administered via IV infusion on Day 1 
of each 3-week cycle
Sections 6
and 7
Efficacy measurements
Tumor imaging (RECIST 1.1)
X
Every 6 weeks (± 1 week) from Cycle 1 Day 1 for 48 weeks, and 
then every 9 weeks (± 1 week, starting at Week 57) until 
RECIST 1.1-defined radiological PD
X
Section 8.1.1, 
Appendix G
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
Brain MRI (preferred)/CT 
imaging (CNS RECIST 1.1 and 
)
X j
Every 6 weeks (± 1 week) from Cycle 1 Day 1 for 48 weeks, and 
then every 9 weeks (± 1 week, starting at Week 57) k until 
RECIST 1.1-defined radiological PD
X j
Section 8.1.1, 
Appendix G, 
Appendix H
Isotopic bone scan 
(scintigraphy)
X
As clinically indicated until RECIST 1.1-defined radiological PD
Section 8.1.1, 
Appendix G
Survival status
X
X
Sections 7.1.4
and 8.1.3
PFS2
X
X
Sections 7.1.3
and 8.1.3
Other assessments and procedures
ePRO device allocation (ePRO 
device allocated only if 
participant does not have own 
compatible device) and training
X
Section 
8.1.5.5
EORTC QLQ-C30, MDASI 
brain tumor-specific items l
Every 3 weeks from Cycle 1 Day 1, (or coinciding with the next cycle if not exactly 3 weeks gap), at the EOT 
Visit, and for up to 24 weeks post EOT or second progression, whichever occurs earlier
Section 
8.1.5.1
Cognitive tests l
Every 12 weeks from Cycle 1 Day 1
X
Section 
8.1.5.4
NANO scale l
X
X
X
X
X
Section 
8.1.5.4
SGRQ-I
After diagnosis of ILD/pneumonitis and q1w thereafter until EOT
X
X
Section 
8.1.5.1
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Table 1
Schedule of Activities
Procedure
Screening 
-28 days
Cycle 1
Cycle 
2
Cycle 3
Cycle 4 
and 
subsequent 
cycles until 
PD
Post-intervention follow-up period
Details in CSP 
section or 
appendix
Day 1
Day 8
(± 1 
day)
Day 15
(± 1 
day)
Day 1 
(± 2 
days)
Day 1
(± 2 
days)
Day 1 
(± 2 days)
EOT a
or E/D
Safety 
F/U 
(40 + 7 
days after 
last dose)
Progressi
on/
survival 
F/U q3 
months 
± 14 days)
MDASI lung cancer (ILD 
symptom-specific items)
Cycle 1 Day 1 before dosing and, after diagnosis of ILD/pneumonitis, daily until safety F/U visit
Section 
8.1.5.2
At-home pulse oximetry
Resting: Cycle 1 Day 1 before dosing and, after diagnosis of ILD/pneumonitis, daily until safety F/U visit
Walking:  Cycle 1 Day 1 before dosing and, after diagnosis of ILD/pneumonitis, q1w until safety F/U visit
Section 
8.1.5.4
At each scheduled visit, the site should review clinical notes for any non-study-related hospital admissions 
and visits that have occurred
Section 8.8
a
EOT is the date the investigator decides to permanently discontinue a participant from study intervention; the visit should occur within 7 days of the decision.
b
Written informed consent and any locally required privacy act document authorization must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations. A pre-screen ICF must be signed for participants to permit for tumor tissue sample collection (HER2 status) and testing prior to the 28-day 
screening window.
c
Within 3 days before administration.
d
If screening assessments have been performed within 3 days prior to starting study intervention, they do not have to be repeated at Cycle 1 Day 1 if the participant’s 
condition has not changed. Medical history should include substance use (drugs, alcohol, caffeine, type and frequency of tobacco use, e-cigarette use, vaping [including 
dates]).
e
If ECG is abnormal, follow institutional guidelines. 
f
During the pre-screening period, only SAEs directly related to tissue screening procedure (ie, if a participant undergoes a tumor biopsy) will be reported.
g
Laboratory tests must be performed within 14 days of randomization/enrollment, and include hematology (red blood cell count, hemoglobin, hematocrit, platelet count, white 
blood cell count, differential white blood cell count [neutrophils, lymphocytes, monocytes, eosinophils, basophils]) and chemistry (total protein, albumin, alkaline 
phosphatase, ALT, AST, TBL, blood urea nitrogen, calcium, chloride, serum creatinine, lactate dehydrogenase, potassium, sodium and magnesium).
h
Troponin-T (preferably high-sensitivity troponin-T) will be measured at screening and at EOT, and as needed based on participant-reported cardiac signs or symptoms 
suggesting CHF, myocardial infarction, or other causes of cardiac myocyte necrosis. If ECG is abnormal, follow institutional guidelines. Qualitative testing for Troponin-T 
or Troponin-I instead of Troponin-T may be acceptable to perform, if in accordance with local practice and if quantitative method or Troponin-T is not available. Positive 
results must be followed up with a quantitative measurement along with other institutional guidance (refer to Appendix O for additional management guidelines)
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i
Samples to be collected on Day 1 of Cycle 4, then every 6 weeks (± 1 week) until Week 48 and every 9 weeks ( ± 1 week) after Week 57.
j
 
k
Brain imaging by IV contrast-enhanced MRI (preferred, unless contraindicated) or IV contrast-enhanced CT is required for all patients at screening/baseline and EOT visit.
l
 
m
Note: All assessments on treatment days are to be performed prior to study intervention administration, unless otherwise indicated. Data collection following study analysis until 
the end of the study is described in Section 8.
AE = adverse event; ALT = alanine aminotransferase ; AST = aspartate aminotransferase ; BM = brain metastasis; C = cycle; CHF = congestive heart failure; CNS = central 
nervous system; CSP = clinical study protocol; CT = computed tomography; 
 EC = ethics committee; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; E/D = Early Study Intervention/Discontinuation; EORTC = European Organization for Research and Treatment 
of Cancer; EOT = end-of-treatment; ePRO = electronic patient-reported outcome; FFPE = formalin-fixed and paraffin-embedded; F/U = follow-up; HER2 = human epidermal 
growth factor receptor 2; HIV = human immunodeficiency virus; 
 HRCT = high-resolution computed tomography; ICF = informed consent 
form; ILD = interstitial lung disease; IRB = institutional review board; IV = intravenous; LVEF = left ventricular ejection fraction; MDASI = MD Anderson Symptom Inventory; 
MRI = magnetic resonance imaging; MUGA = multigated acquisition; NANO = Neurologic Assessment in Neuro-oncology; PD = progression of disease; PFS2 = time to second 
progression or death; q1w = every 1 week; q3 months = every 3 months; QLQ-C30 = 30 item core quality of life questionnaire; 
; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, Version 1.1; RNA = ribonucleic acid; SAE = serious adverse event; SGRQ-I = St. George’s Respiratory 
Questionnaire – idiopathic pulmonary fibrosis-specific version; SpO2 = peripheral capillary oxygen saturation ; TBL = total bilirubin; T-DXd = trastuzumab deruxtecan; WOCBP 
= women of childbearing potential.
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2
INTRODUCTION
Trastuzumab deruxtecan is an ADC that targets HER2. The non-proprietary name for T-DXd 
is trastuzumab deruxtecan except in the US where it is fam-trastuzumab deruxtecan-nxki.
2.1
Study Rationale
Several agents have been studied in patients with HER2-positive breast cancer with BMs. 
Specifically, the HER2CLIMB study showed that tucatinib is effective in active/stable treated 
or asymptomatic untreated BMs (Murthy et al, 2020). However, due to the decreased QoL and 
poor prognosis in this patient population, there is still a significant unmet need particularly in 
later lines of treatment.
Within the clinical development program for T-DXd, there is some data supporting the use of 
T-DXd in patients with BMs. In DESTINY-Breast01, 184 patients with heavily pretreated
breast cancer were treated with T-DXd at the recommended dose of 5.4 mg/kg. This study 
population included 24 patients who had CNS metastases at baseline (Jerusalem et al, 2020). 
Within this small cohort, the efficacy response for T-DXd was encouraging, supporting a more 
extensive evaluation of T-DXd in this patient population.
The current study is designed to evaluate the efficacy and safety of T-DXd in a real-world 
setting. Overall, this study will look to provide a much more robust and detailed 
understanding of T-DXd that will complement studies that are ongoing or already completed. 
This study will be conducted in participants with advanced/metastatic breast cancer, including 
participants with previously-treated stable BM and participants with active BM, either 
previously untreated or progressing (but not requiring immediate local therapy), to evaluate 
their response to T-DXd treatment. Therefore, this study may provide additional treatment 
options for patients.
2.2
Background
A detailed description of the chemistry and pharmacology of T-DXd and the nonclinical and 
clinical efficacy and safety results of T-DXd are provided in the IB.
2.2.1
Background Information on the Disease to Be Treated
Despite advances in diagnosis and treatment, 10 to 15% of women diagnosed with MBC have 
cancer that has metastasized to the brain; this number can be as high as approximately 50% in 
women with HER2-positive breast cancer (Pestalozzi et al, 2013). Previously, having cancer 
that metastasized to the brain was associated with low life expectancy (~6 months), decreased 
QoL and a poor prognosis. With new therapies (eg, radiation, systemic therapy), life 
expectancy has increased to a median of 3.03 years (95% CI, 1.94-NE) (Anders, 2016). 
Although treatable, MBC remains largely an incurable disease with an estimated 5-year OS of 
only 25% (Cardoso et al, 2020).

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Breast cancer treatment paradigms in the metastatic setting are defined by the expression of 
the HER2 and the ER and PgR, which are collectively referred to as HR. In women with 
HER2-positive breast cancer, there is overexpression and/or overamplification of HER2. 
Several HER2 targeted therapies such as HERCEPTIN® (trastuzumab), PERJETA®
(pertuzumab), KADCYLA® (T-DM1), and TYKERB® (lapatinib) are used in breast cancer 
patients who have HER2 overexpression/overamplification.
Guidelines such as those from ASCO, ESMO, and National Comprehensive Cancer Network
recommend patients with symptomatic BMs receive local therapy and continue the same anti-
HER2 therapy if the patients continue to derive clinical benefit systemically. Recent studies 
have specifically included patients with HER2-positive breast cancer with BMs with positive 
results.  
HER2CLIMB was a Phase 2, global, randomized, double-blind, placebo-controlled study in 
adults with locally advanced unresectable or metastatic HER2-positive breast cancer who 
previously received trastuzumab, pertuzumab, and T-DM1 separately or in combination
(Murthy et al, 2020). At the time of the study, it included the largest number of patients with 
BMs (48% of the study population) studied in a registrational trial for HER2-positive MBC. 
The HER2CLIMB study evaluated tucatinib versus placebo in combination with trastuzumab 
and capecitabine. It met all primary and secondary endpoints demonstrating a 46% reduction 
in the risk of disease progression or death and an improvement in OS by a median of 
4.5 months. Specifically, in patients with BMs, a 52% lower risk of disease progression or 
death was observed (Lin et al, 2020).
DESTINY-Breast01 (NCT03248492) was a Phase 2, open-label, single-group, multicenter 
study conducted in 2 parts (Modi et al, 2020). In Part 1 of the study, 3 doses were evaluated,
and in Part 2, the selected dose of 5.4 mg/kg was used to evaluate the efficacy and safety of 
T-DXd in adult patients with pathologically documented HER2-positive MBC who had 
received previous treatment with T-DM1. A total of 253 patients were treated with T-DXd in 
both parts of this study, including 184 patients who received T-DXd at the recommended dose 
of 5.4 mg/kg. This study population included 24 patients who had CNS metastases at baseline. 
The ORR in this subset of patients was 58%, similar to the ORR of 61% in patients without 
CNS metastases (Jerusalem et al, 2020; Modi et al, 2020). The subset of patients with baseline 
CNS metastases also had a similar estimated mPFS (18.1 months) compared with the mPFS 
for the overall study population (16.4 months). However, clinical experience of T-DXd in this 
patient population is limited due to the small sample size and the inclusion and exclusion 
criteria for the study.
Improving the quality of MBC clinical research through the adoption and incorporation of 
clinically meaningful trial endpoints that measure both QoL and survival is important. To that 
end, there is a need to assess the efficacy of T-DXd in delaying the development of 

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symptomatic BM.
2.2.2
Background Information on T-DXd
As of 28 March 2019, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) 
entered into a joint global development and collaboration agreement for T-DXd, a 
HER2-targeting ADC.
Trastuzumab deruxtecan consists of an anti-HER2 antibody, MAAL-9001, covalently linked 
to ~8 molecules of MAAA-1162a (GGFG tetrapeptide cleavable linker and a TOPO-1
inhibitor payload [MAAA-1181a]). The antibody MAAL-9001 has the same amino acid 
sequence as trastuzumab, and thus T-DXd is similarly targeted to HER2-expressing tumors. 
The drug MAAA-1181a (DXd), a derivative of exatecan, is released after internalization and 
leads to apoptosis of the target tumor cells via the inhibition of TOPO-1.
Due to incorporation of a novel linker, T-DXd achieves a higher DAR of approximately 8 with 
homogeneous conjugation of DXd, compared with other approved ADCs, which have a DAR 
of 3 to 4 (Ogitani et al, 2016). In addition, the cleavable linker in T-DXd is stable in plasma, 
conferring a favorable safety profile as observed in nonclinical toxicology rat and monkey 
studies.
Trastuzumab deruxtecan exhibits HER2-specific anti-tumor activity via a mechanism of action 
that combines the mAb specificity with the broad cytotoxicity of the released drug. After 
binding to HER2 and internalization, the T-DXd linker is selectively cleaved by lysosomal 
enzymes preferentially expressed in tumor cells and releases the drug DXd in the cytoplasm.
The drug DXd is an exatecan derivative with greater potency than SN-38, the active 
metabolite of irinotecan (Ogitani et al, 2016). The TOPO-1 inhibitor payload of T-DXd is 
released into the cytoplasm of the target cell where it enters the nucleus, inhibits TOPO-1, and 
arrests DNA synthesis, leading to apoptosis of target cells.
There are completed and ongoing clinical trials with T-DXd, either alone or in combination, 
across multiple HER2-expressing tumor types including breast cancer, gastric cancer, non-
small cell lung cancer, and colorectal cancer (please refer to the T-DXd IB for a list of 
completed and ongoing trials and most recent patient exposure data).
For details on the schematic structures, molecular formula, finished product of T-DXd and the 
overall safety and clinical efficacy data from different studies that involved T-DXd, refer to 
the most recent IB.
T-DXd is approved in the US and Japan for the treatment of adult patients who have received 
prior treatments for HER2-positive breast cancer that is unresectable or metastatic 
(US)/recurrent (Japan). In the European Union, T-DXd received a conditional marketing 
authorization for the treatment of adult patients with unresectable or metastatic HER2-positive

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breast cancer, who have received 2 or more prior anti-HER2 based regimens.
2.3
Benefit/Risk Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, and applicable regulatory 
requirements.
More detailed information about the known expected benefits and risks and the overall 
efficacy and safety profiles of T-DXd are found below and in the IB.
2.3.1
Risk Assessment
The risks of T-DXd, HER2-targeted agents, and TOPO-1 inhibitors are summarised below. 
Toxicity management guidelines for T-DXd are provided in Appendix O.
2.3.1.1
Risks of T-DXd
Based on data from clinical trials that involved T-DXd, toxicities considered to be associated 
with administration of T-DXd include the important identified risks of ILD/pneumonitis and
neutropenia (including febrile neutropenia). Other identified risks for T-DXd are 
infusion-related reactions, hematological AEs (anemia, leukopenia, lymphopenia, 
thrombocytopenia), pulmonary/respiratory AEs (cough, dyspnea, upper respiratory tract 
infection, epistaxis), gastrointestinal AEs (abdominal pain, constipation, diarrhea, dyspepsia, 
nausea, stomatitis, vomiting), hepatic AEs (hepatic function abnormality, ALT, AST, and
alkaline phosphatase increased), skin AEs (alopecia, rash, pruritis), blood bilirubin increased, 
pneumonia, dry eye, dehydration, hypokalemia, decreased appetite, dizziness, fatigue,
peripheral edema, pyrexia, and headache.
Based on the available preclinical data, review of the cumulative literature, and reported 
toxicities for the same class of agents, the important potential risks for T-DXd are embryofetal 
toxicity and LVEF decrease (re-labelled as ‘LV dysfunction’ as the undesirable clinical 
outcome of LVEF reductions, in accordance with the Revision 2 of the European Medicines 
Agency guidelines on Good Pharmacovigilance Practice. This re-labelling of the risk does not 
affect the nature or monitoring methods of the LVEF decrease as a potential risk associated 
with T-DXd). Keratitis is considered a potential risk for T-DXd.
Interstitial lung disease/pneumonitis and LVEF decrease are considered AESIs.
Trastuzumab deruxtecan has not been studied in subjects with severe/moderate hepatic 
impairment or severe renal impairment.
2.3.1.2
Risks of HER2-targeted Agents
Several agents that target HER2 and prevent its activation or heterodimerization have been 

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developed and marketed for the treatment of HER2-positive cancers. These include the mAbs 
trastuzumab and pertuzumab, the ADC T-DM1, and HER1- and HER2-associated TKIs, 
lapatinib, and neratinib. The safety profile of these HER2-targeted agents has been well 
described. The main safety risks identified in patients receiving HER2-targeted products are 
described below; these could potentially be expected to occur in patients receiving T-DXd.
Cardiotoxicity: Patients treated with trastuzumab are at increased risk for developing CHF 
(NYHA class IIIV) or asymptomatic cardiac dysfunction, including LVEF decrease. Cardiac 
dysfunction, mainly asymptomatic LVEF decrease, has also been observed with pertuzumab 
in combination with trastuzumab. Similarly, cardiac dysfunction has been observed in patients 
receiving T-DM1, at a lower incidence than in trastuzumab treated patients. Majority of cases 
have been asymptomatic decreases in LVEF. Cardiac dysfunction with lapatinib has occurred 
mainly in patients receiving the combination of trastuzumab and lapatinib and has consisted of 
predominantly asymptomatic LVEF decrease.
Pulmonary Toxicity: Cases of pulmonary toxicity, including ILD and pneumonitis, have been 
observed in patients receiving trastuzumab, T-DM1, and lapatinib. Occasionally these cases 
have been severe in nature and have resulted in fatal outcomes. Risk factors associated with 
ILD/pneumonitis include prior or concomitant therapy with other anti-neoplastic therapies 
known to be associated with it such as taxanes, gemcitabine, vinorelbine, and radiation 
therapy.
Hypersensitivity/Infusion-Related Reactions: The administration of therapeutic proteins is 
associated with a risk of hypersensitivity and/or infusion reactions. 
Hypersensitivity/infusion-related reactions have been reported with trastuzumab, pertuzumab 
and T-DM1. These can range from mild reactions to severe anaphylactic shock with fatal 
outcome as has been the case for trastuzumab.
Hepatic Toxicity: Cases of hepatic toxicity have occurred with T-DM1, lapatinib, and 
trastuzumab. In patients receiving T-DM1, hepatic toxicity has manifested mainly as transient 
asymptomatic liver transaminase elevations, although serious cases of drug-induced liver 
failure and nodular regenerative hyperplasia have also been reported. Lapatinib has also been 
associated with serious cases of DILI.
Hematological Toxicity: Hematological toxicity has been observed with all HER2-targeted 
therapies. Neutropenia, febrile neutropenia, leukopenia, and anemia have occurred commonly 
with trastuzumab, pertuzumab, and T-DM1. Thrombocytopenia, including Grade 3 and 4, is a 
common occurrence in T-DM1-treated patients. Although rare, serious hemorrhagic events 
have been reported in the setting of thrombocytopenia. Lower rates of thrombocytopenia have 
also occurred with trastuzumab and pertuzumab when used in combination with 
chemotherapy.

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2.3.1.3
Risks of Topoisomerase I Inhibitors
The drug DXd is a derivative of exatecan (DX-8951f), a TOPO-1 inhibitor. Other products of 
the same class include irinotecan and topotecan. Exatecan is a camptothecin derivative which 
has previously been developed by the former Daiichi Pharmaceuticals Co., Ltd. as an 
anticancer therapy.
The main risks associated with the use of TOPO-1 inhibitors include hematological toxicities 
and gastrointestinal toxicities. Hematological toxicities, manifesting as neutropenia, febrile 
neutropenia, anemia, thrombocytopenia, and pancytopenia are commonly observed. An 
increased risk of infections, including neutropenic colitis and neutropenic sepsis, has been 
reported with these agents.
Diarrhea and delayed onset diarrhea, which can be severe and lead to dehydration, have been 
associated with TOPO-1 inhibitors. Other significant risks include ILD/pneumonitis, liver 
impairment, immune system disorders, and alopecia. Acute cholinergic syndrome, manifesting 
as diarrhea and other cholinergic symptoms, has been reported with irinotecan.
The safety profile of exatecan is broadly similar to the safety profile of other TOPO-1
inhibitors, with hematological toxicities and gastrointestinal toxicities being the most 
significant groups of events.
2.3.2
Benefits of T-DXd
Trastuzumab deruxtecan is under development for the treatment of HER2-expressing cancers 
and HER2-mutant tumors. Based on preliminary clinical observations in a Phase 1 study 
(Study DS8201-AJ101 [Phase 1; NCT02564900]), Study DS8201-A-U201 
(DESTINY-Breast01, Phase 2; NCT03248492), and the DESTINY-Gastric01 Phase 2 study 
(NCT03329690), T-DXd demonstrated anti-tumor activity in HER2-expressing cancers, 
including gastric cancer and breast cancer, and a generally acceptable safety profile in these 
populations. Data from the Phase 2 DS8201-A-U204 (DESTINY-Lung01; [NCT03505710]) 
study also provides encouraging preliminary evidence of anti-tumor activity of T-DXd in 
tumors with HER2 mutations.
Human epidermal growth factor receptor 2-positive breast cancer is associated with a 
relatively high incidence of BM (up to ~50%; Freedman et al, 2019; Lin and Winer, 2007) and 
therefore therapies are needed that can address this patient population. DESTINY-Breast01 
was a Phase 2, open-label, single-group, multicenter study in 253 patients with heavily 
pretreated breast cancer, including 24 patients with CNS metastases at baseline (13%). The 
demographic characteristics were consistent for patients with HER2-positive breast cancer 
with and without BM, including having a median of 6 prior lines of therapy (range, 3 to 16).
For all efficacy measures, T-DXd demonstrated similar results in the CNS subgroup compared 
to the overall study population. Among the 184 patients who received T-DXd at the 

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recommended dose of 5.4 mg per kilogram, the confirmed ORR on ICR was 60.9% (95% CI, 
53.4 to 68.0) and 58.3% (95% CI, 36.6% to 77.9%) in the CNS subgroup. Median PFS in the 
CNS subgroup was 18.1 months (95% CI 6.7 to 18.1 months) compared to the overall study 
population (16.4 months [95% CI 12.7 months to NE]). Disease progression in the CNS 
among patients with non-CNS disease at baseline was 8% (Jerusalem et al, 2020). The median 
DoR and median time until response was consistent among the overall study population and 
the CNS subgroup.
These results from the DESTINY-Breast01 study demonstrated a positive response rate for 
T-DXd treatment in patients with HER2-positive MBC who had been previously treated with 
multiple therapies. However, there remains a need to generate more clinical data with T-DXd 
to evaluate its effects on delaying the development of symptomatic BM.
DESTINY-Breast03 was a Phase 3, multicenter, randomized, open-label, 2-arm, 
active-controlled head-to-head study of T-DXd versus trastuzumab emtansine (T-DM1) in 
patients with HER2-positive MBC previously treated with trastuzumab and taxane
(Cortés et al, 2022). Patients in the T-DXd and control arms had median follow-up of 16.2 and 
15.3 months, respectively. At the time point of the DCO, the number of patients remaining on 
treatment were 132/261(50.6%) in the T-DXd arm and 47/263 (17.9%) in the T-DM1 arm. 
T-DXd demonstrated a 72% reduction in the risk of disease progression or death compared to 
T-DM1 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.22-0.37; p = 7.8 × 10-22). 
The median PFS for patients treated with T-DXd was not reached (95% CI 18.5-NE) 
compared to 6.8 months for T-DM1 (95% CI 5.6 to 8.2) as assessed by blinded independent 
central review (BICR). In the key secondary endpoint of PFS assessed by investigators, 
patients treated with T-DXd experienced a three-fold improvement in median PFS of 
25.1 months versus 7.2 months for T-DM1 (HR 0.26; 95% CI 0.20-0.35; p = 6.5×10-24). A 
consistent PFS benefit was observed in key subgroups of patients treated with T-DXd, 
including hormone receptor status positive vs. HR-negative), prior pertuzumab treatment (yes 
vs no), visceral disease (yes vs no), prior lines of metastatic therapy (0-1 vs ≥2), and history 
of stable brain metastases (yes vs. no). There was a trend towards improved overall survival 
(OS) with T-DXd (HR 0.56; 95% CI 0.36-0.86; nominal p = 0.007172), however this analysis 
is not yet mature and did not cross the pre-defined threshold for statistical significance based 
on the number of observed events. At 12 months, 94.1% of patients treated with T-DXd were 
alive compared to 85.9% of patients treated with T-DM1. The confirmed objective response 
rate (ORR) more than doubled in the T-DXd arm versus the T-DM1 arm (79.7% vs. 34.2%). 
Forty-two (16.1%) complete responses (CR), and 166 (63.6%) partial responses (PR) were 
observed in patients treated with T-DXd compared to 23 (8.7%) CRs and 67 (25.5%) PRs in 
patients treated with T-DM1. Additionally, in DESTINY-Breast03, T-DXd monotherapy 
treatment resulted in greater efficacy compared to T-DM1 in patients with brain metastasis 
with a mPFS of 15.0 months with T-DXd (N = 43) vs 3.0 months with T-DM1 (N = 39) 
(Hurvitz et al, 2021).

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In addition, several other studies report promising intracranial efficacy for T-DXd. 
TUXEDO-1 study, a Phase 1 study of previously treated HER2+ MBC patients with active 
brain metastases, T-DXd monotherapy demonstrated an intracranial response in 83.3% (5/6) 
patients enrolled in the first stage of the trial ungating full enrolment (N = 15) in the study 
(Bartsch et al, 2021); active brain metastases were defined as newly diagnosed brain 
metastases or brain metastases with radiological progression after prior local therapy. 
Similarly in DEBBRAH, a Phase 2 study of previously treated HER2+ or HER2-low patients 
MBC with a history of brain metastases and/or leptomeningeal carcinomatosis, T-DXd 
monotherapy demonstrated preliminary efficacy and a manageable toxicity profile in the 
34 patients enrolled as of the 15 September 2021 data cut-off with the most frequent adverse 
events being fatigue (52.9% [18/34]), nausea (41.2% [14/34]), vomiting (32.4% [11/34]), 
neutropenia (26.5% [9/34]), diarrhoea (26.5% [9/34]), and anaemia (26.5% [9/34]); enrolment 
is completed in cohort 1 (N = 8) and cohort 3 (N = 9), and efficacy data were reported (Batista 
et al, 2021). In DEBBRAH cohort 1, HER2+ MBC patients with non-progressing brain 
metastases after radiotherapy and/or surgery were enrolled; 87.5% (7/8) patients were alive 
without disease progression at 16 weeks meeting the primary endpoint with a median follow-
up time of 8.5 months. While in DEBBRAH cohort 3, HER2+ MBC with progressing brain 
metastases after local treatment were enrolled; CNS ORR was 44.4% (4/9) meeting the 
primary endpoint with a median follow-up time of 8.8 months. 
Finally, in a retrospective multi-institutional cohort of patients with HER2+ breast cancer and 
brain metastases treated with T-DXd monotherapy, the CNS ORR in patients with measurable 
brain metastases at baseline was 73% (11/15), and in the subset of patients with untreated or 
progressive brain metastases the CNS ORR was 70% (7/10) as of the 1 June 2021 data cut-off 
(Kabraji et al, 2021).
2.3.3 Overall Benefit/Risk Conclusion
There is an unmet medical need for better therapies in treatment of HER2-positive MBC in 
order to improve clinical outcomes. There are multiple treatment options for HER2-positive
breast cancer patients in the adjuvant and neoadjuvant settings; however, once resistance 
develops against HER2-targeting therapy, limited effective treatment options are available. 
Rechallenge with previously administered therapies can be attempted, but their efficacy may 
be compromised, usually depending on the disease-free interval between the last adjuvant 
therapy and metastatic disease (Metzger-Filho et al, 2016). New treatments may provide 
prolongation of survival and improvement of QoL.
Results from the DESTINY-Breast01 study demonstrated that T-DXd was beneficial in 
patients with HER2-positive MBC who had been previously treated with multiple therapies. 
Improved anti-tumor activity against BMs was seen in patients who had stable, treated CNS 
metastases at baseline and was similar to the efficacy results in the overall study population. 

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The safety profile of T-DXd in the CNS subgroup was consistent with the non-CNS subgroup 
and with that seen in the overall patient population. Treatment-emergent AEs in the CNS 
subgroup were generally consistent with the overall patient population and were 
predominantly gastrointestinal or hematologic in nature.
The recent read-out of the DESTINY-Breast03 trial demonstrated a highly statistically 
significant and clinically meaningful improvement in PFS over the T-DM1 in second-line 
HER2-positive MBC, and the totality of the data show compelling superiority of treatment 
benefit from T-DXd over T-DM1. These data provide strong confirmation of the single-arm, 
open label, Phase 2 DESTINY-Breast01 study data in patients with unresectable or metastatic 
late-line HER2-positive breast cancer. Overall, the available data suggest that T-DXd has the 
potential to offer a positive benefit risk profile in patients in earlier lines of HER2-positive 
breast cancer.
The important identified risks associated with administration of T-DXd are ILD/pneumonitis 
and neutropenia, including febrile neutropenia; LVEF decrease and embryofetal toxicity are 
considered important potential risks. To specifically mitigate the incidence of pulmonary 
toxicities, strict inclusion/exclusion criteria have been included in this CSP, prohibiting most 
participants with pre-existing pulmonary comorbidities from entering the study. In addition, 
baseline pulmonary function tests will be performed for all participants. For hematological 
toxicities, the use of growth factors is allowed at the discretion of the investigator. Participants 
will be monitored closely throughout the study and clinical and laboratory assessments will be 
performed before every cycle. The TMGs (Appendix O) are also provided to assist with the 
management of the most commonly seen AEs.
The emergence of COVID-19 presents a potential safety risk for participants; therefore, 
several risk mitigation factors are included in this study. Details regarding instructions related 
to COVID-19 and a more detailed description of benefit/risk considerations relevant to 
COVID-19 are provided in Appendix L. Note that no vaccine against COVID-19 has been 
tested when given alongside T-DXd. Therefore, it is not known what effect (if any) T-DXd has 
on the effectiveness and safety of COVID-19 vaccines.
Trastuzumab deruxtecan has the potential to provide meaningful clinical benefit. Considering 
the measures to minimize risks to participants, the benefit/risk assessment supports the 
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3
OBJECTIVES AND ENDPOINTS
Table 2
Objectives and Endpoints
Objectives
Endpoints
Primary
To describe the overall treatment effect of T-DXd in 
HER2-positive MBC patients with or without 
baseline BM
Participants without BM at baseline (Cohort 1):
!
ORR by RECIST 1.1 per ICR
Participants with BM at baseline (Cohort 2):
!
PFS by RECIST 1.1 per ICR
Secondary
To describe the treatment effect on the development 
and progression of BM in patients with or without 
baseline BM using additional efficacy measurements
Participants in both cohorts:
!
OS
!
DoR by RECIST 1.1 per ICR
!
Time to progression by RECIST 1.1 per ICR
!
DoT on subsequent lines of therapy
!
PFS2
Participants without BM at baseline (Cohort 1):
!
Incidence of new symptomatic CNS metastasis 
during treatment
In patients who develop isolated CNS progression, 
receive local therapy, and continue on protocol 
therapy:
!
Time to next progression (CNS or extracranial) 
or death
!
Site (CNS vs extracranial vs both) of next 
progression
To describe efficacy in patients with stable or 
untreated BM
Participants with BM at baseline (Cohort 2):
!
ORR by RECIST 1.1 per ICR
!
CNS PFS by CNS RECIST 1.1 per ICR
!
Time to new CNS lesions
!
CNS ORR by CNS RECIST 1.1 per ICR
!
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Table 2
Objectives and Endpoints
Objectives
Endpoints
To describe the effect of T-DXd on symptoms, 
functioning, and HRQoL in HER2-positive MBC 
patients with or without baseline BM
Changes in symptoms, functioning, and HRQoL as 
measured by:
!
All patients: EORTC QLQ-C30, NANO scale, 
cognitive tests
!
BM patients: MDASI brain tumor-specific items
!
ILD/pneumonitis patients: SGRQ-I
Safety
To describe the safety profile of T-DXd
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, clinical laboratory results, and 
ECGs. 
Assessments related to AEs will also include:
!
Rate of investigator-assessed ILD/pneumonitis
∀
PTs will be matched with most commonly
reported terms within ILD cluster terms
∀
Rate of ILD clinical symptom resolution 
among ILD patients who have been treated 
with high-dose steroid (total daily dose 
> 2 mg dexamethasone or equivalent)
!
Rate of AEs among patients with baseline BM 
who are treated with concurrent high-dose 
steroid (total daily dose > 2 mg dexamethasone 
or equivalent)
Exploratory
 
!
!
 
!
 
!
!
!
 
 
 
 
 
 
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Table 2
Objectives and Endpoints
Objectives
Endpoints
 
 
 
 
 
 
 
 
AE = adverse event; BM = brain metastasis; 
; CNS = central nervous 
system; 
 DoR = duration of response; DoT = duration of treatment; 
ECG = electrocardiogram; EORTC = European Organization for the Research and Treatment of Cancer; 
HER2 = human epidermal growth factor receptor 2;
HRQoL = health-related quality of life; ICR = independent central review; ILD = interstitial lung disease; 
MDASI = MD Anderson Symptom Inventory; NANO = Neurologic Assessment in Neuro-oncology; 
ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = time to second 
progression or death; PT = preferred term; QLQ-C30 = 30 item core quality of life questionnaire; 
; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors Version 1.1; SGRQ-I = St. George's Respiratory Questionnaire – idiopathic pulmonary fibrosis 
version; T-DXd = trastuzumab deruxtecan; 
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 3b/4, open-label, multicenter, international study assessing the efficacy and 
safety of T-DXd in participants with or without BM, with previously-treated 
advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior 
anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the 
metastatic setting (excluding tucatinib). (Figure 1). Participants will be enrolled into 1 of 
2 cohorts according to the presence or absence of BMs at baseline.
Approximately 500 eligible participants will be treated in this study with 5.4 mg/kg T-DXd 
q3w until RECIST 1.1-defined radiological progression outside CNS, unless there is 
unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met. 
To ensure adequate representation of participants with BM at baseline, the maximum number 
of participants without BM at baseline will be limited to 250. Cohort 1 (participants without 
BM at baseline) will additionally be limited to include no more than 25% third-line 
participants. In DESTINY-Breast 03, T-DXd demonstrated statistically significant progression 
free survival benefit over T-DM1, irrespective of number of prior lines on treatment, resulting 
in international guidelines establishing T-DXd as the standard of care for 2L HER2+ mBC, 
replacing T-DM1. Limiting recruitment in Cohort 1 to 25% third line participants reflects the 
change in clinical practice. The study will evaluate ORR by RECIST 1.1, PFS by RECIST 1.1, 
the incidence of new symptomatic CNS metastasis, and other measures of efficacy, and further 
characterize the safety and tolerability profile of T-DXd. For details on what is included in the 
efficacy and safety endpoints, see Section 3 Objectives and Endpoints.
For an overview of the study design see Figure 1, Section 1.2. For details on treatments given 
during the study, see Section 6.1.
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. In case access to the study site is restricted for vendors, 
remote monitoring may be conducted by CRO-appointed staff, as permitted by local 
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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 for the mitigation procedures (note, in the case of verbal consent, the 
ICF should be signed at the participant’s next contact with the study site).
!
Rescreening: Additional rescreening for screen failure and 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 HCP or HCP provided by a 
third-party vendor.
!
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
!
At-home study intervention administration: Performed by a site qualified HCP, HCP 
provided by a third-party vendor, or by the participants or the participant’s caregiver, if 
possible. Additional information related to the visit can be obtained via telemedicine.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix M.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design
The current study is designed to evaluate the efficacy and safety of T-DXd in a real-world 
setting. Overall, this study will look to provide real-world data and a detailed understanding of 
T-DXd that will complement studies that are ongoing or already completed. This study will 
include participants who have been previously treated for their breast cancer, including those 
who also have BMs to evaluate their response to T-DXd treatment. Therefore, this study may 
provide additional treatment options for patients.
4.2.2
Rationale for T-DXd in MBC
Several agents have been studied in patients with HER2-positive breast cancer with BMs. 
Specifically, the HER2CLIMB study showed that tucatinib is effective in active/stable treated 
or asymptomatic untreated BMs (Murthy et al, 2020). However, HER2-positive breast cancer 
with BMs remains an incurable disease. Due to the decreased QoL and poor prognosis in this 
patient population, there is still a significant unmet need particularly in later lines of treatment.
Within the clinical development program for T-DXd, there is some data supporting the use of 

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T-DXd in patients with BMs. In DESTINY-Breast01, 184 patients with heavily pretreated
breast cancer were treated with T-DXd at the recommended dose of 5.4 mg/kg. This study 
population included 24 patients who also had BMs (Jerusalem et al, 2020). Within this small 
cohort, the efficacy response was encouraging, supporting a more extensive evaluation of 
T-DXd in this patient population.
4.2.3
Rationale for Study Endpoints
The primary objective for this study is to describe the overall treatment effect of T-DXd in 
HER2-positive MBC patients with or without baseline BM. The primary endpoint for 
Cohort 1 (participants with no BM at baseline) is ORR by ICR according to RECIST 1.1, and 
the primary endpoint for Cohort 2 (participants with BM at baseline) is PFS by ICR according 
to RECIST 1.1.
For patients without BMs, the ORR is an early indication of treatment effect. The use of ORR 
will allow an early assessment on whether T-DXd is providing benefit to patients in a 
real-world setting that is similar to other studies where this has been analyzed. The use of 
ORR in patients with BM is not found to provide a good indication of response, as it is often 
uninterpretable in a population with recent CNS-directed therapy such as radiation therapy. 
Additionally, interlesional variability of response to treatment can render the evaluation of
response in multiple metastases problematic. As a result, PFS has been chosen as the primary 
endpoint in the BM cohort.
The secondary endpoints (Section 3) are in line with the recommendations outlined in the NCI
Breast Cancer Steering Committee Working Group Report, where for HR-positive/
HER2-positive breast cancer in the first line setting it is appropriate to have the following 
secondary endpoints: OS, duration of disease control, time to treatment failure, and PROs 
(Seidman et al, 2018).
The secondary symptoms, functioning, and overall HRQoL endpoints will show the overall 
influence of the benefits and toxicity of the treatment from the patient’s perspective and will 
aid in understanding the benefit/risk evaluation. These clinical outcomes assessments are 
well-established instruments that have been previously included in cancer clinical studies.
Biological samples will be used to 
 
 
4.3
Justification for T-DXd Dose
For this study, a T-DXd dose of 5.4 mg/kg given as an IV infusion once every 3 weeks (21-day 
cycle) will be used. This is the approved dose for adult patients with unresectable or 
metastatic HER2-positive breast cancer (ENHERTU, 2019). For information on dose 
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modifications for T-DXd, see Section 6.6.
For additional details on the nonclinical and clinical data on T-DXd, see the T-DXd IB.
4.4
End of Study Definition
A participant is considered to have completed the study when he/she has completed all phases 
of the study including the last visit (Section 1.3).
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings. 
The end of the study is defined as completing the last expected visit/contact of the last 
participant undergoing the study. The DCO for final analysis is defined Section 9.2. See 
Section 6.7 for details on participant management following the final DCO as well as 
following study completion.

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5
STUDY POPULATION
The target population of interest in this study is adults with previously-treated
advanced/metastatic HER2-positive breast cancer whose disease has progressed on prior 
anti-HER2-based regimens and who received no more than 2 lines/regimens of therapy in the 
metastatic setting (excluding tucatinib). This study will include participants with 
previously-treated stable BM and participants with active BM, either previously untreated or 
progressing (but not requiring immediate local therapy). At the time of enrollment, 
participants must have an ECOG score of 0-1 and must not have LMD.
Prospective approval of protocol deviations to recruitment and enrollment 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.
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
Pathologically documented breast cancer that:
(a) Is unresectable/advanced or metastatic, and
(b) Has confirmed HER2-positive status as determined according to ASCO/CAP
guidelines (Wolff et al, 2018) evaluated at a local laboratory
3
Participant must have either:
(a) No evidence of BM, or
(b) Untreated BM on screening contrast brain MRI / CT scan
(i)
not needing immediate local therapy, or
(ii) For participants with untreated CNS lesions:
If lesion ≤2 cm, no discussion with study physician is required prior to 
enrollment
If lesion is > 2.0 cm, discussion with and approval from the study physician 
is required prior to enrollment, or
(c) Previously-treated stable or progressing BM
(i)
Previously-treated BM with local therapy may either be radiographically stable 
for ≥4 weeks since completion of treatment or may have progressed since prior 

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local CNS therapy, provided that there is no clinical indication for immediate 
re-treatment with local therapy
(ii) Patients treated with CNS local therapy for newly identified lesions found on 
contrast brain MRI / CT scan performed during screening for this study who also 
have other sites of disease assessable by RECIST 1.1
4
Participants with BMs must be neurologically stable and:
(a) Be receiving the equivalent of dexamethasone ≤3 mg/day if treatment is required
(b) If receiving an anticonvulsant regimen, the regimen must have been stable for 
≥14 days before first day of dosing
(c) Relevant records of any CNS treatment must be available to allow for classification 
of TLs and NTLs
5
For participants requiring radiotherapy due to BMs, there should be an adequate washout 
period before day of first dosing:
(a) ≥ 7 days since stereotactic radiosurgery or gamma knife
(b) ≥ 21 days since whole brain radiotherapy
6
ECOG performance status 0-1 with no deterioration over the previous 2 weeks prior to 
baseline or day of first dosing.
7
All participants must provide a FFPE tumor sample that meets the tissue requirements 
specified in Section 8.6.1 for tissue-based analysis (including but not restricted/limited to 
IHC staining to determine HER2 expression and 
 
. If an archival tumor tissue sample is not available, a newly 
acquired sample from a biopsiable tumor must be collected at study entry.
8
Previous breast cancer treatment:
(a) Radiologic or objective evidence of disease progression on or after HER2 targeted 
therapies.
Note: Disease progression within 6 months after adjuvant treatment with HER2 
targeted therapies is also acceptable.
(b) No more than 2 lines/regimens of therapy in the metastatic setting.
Note: A line/regimen of treatment should be counted based on a progression event.
9
Participant with the following measurable or non-measurable disease:
(a) At least 1 lesion that 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 and is suitable for accurate repeated measurements.
(b) Or the following non-measurable diseases:
(i)
Non-measurable, bone-only disease that can be assessed by CT or MRI or 
X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or 
X-ray in the absence of measurable disease as defined above is acceptable; 
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patients with sclerotic/osteoblastic bone lesions only in the absence of 
measurable disease are not eligible.
(ii) Non-measurable CNS disease (Cohort 2 only).
10 Adequate organ and bone marrow function within 14 days before the day of first dosing 
as described in Table 3 below. All parameters must meet the inclusion criteria on the 
same day and must be the most recent results available.:
Table 3
Parameters for Adequate Organ and Bone Marrow Function
Adequate bone marrow function
Platelet count
≥ 100,000/mm3. (Platelet transfusion is not allowed within 1 week prior to 
screening assessment)
Hemoglobin
≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth 
factor support to maintain hemoglobin ≥9.0 g/dL are not eligible. (Red blood 
cell transfusion is not allowed within 1 week prior to screening assessment.)
Absolute neutrophil count
≥ 1500/mm3 (granulocyte-colony stimulating factor administration is not 
allowed within 1 week prior to screening assessment)
Adequate hepatic function
ALT and AST
≤ 3 × ULN (< 5 × ULN in participants with liver metastases)
TBL
≤ 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
Serum albumin
≥ 2.5 g/dL
Adequate renal function
CrCL
≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight) or 
modified Cockcroft Gault
Males:
CrCL = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
CrCL = 
Weight (kg) × (140 - Age) × 0.85
(mL/min)
72 × serum creatinine (mg/dL)
Adequate blood clotting function
International normalized ratio or 
Prothrombin time and either 
partial thromboplastin or 
activated partial thromboplastin 
time
≤ 1.5 × ULN
CrCL = calculated creatinine clearance; ULN = upper limit of normal.
11 LVEF ≥ 50% within 28 days before day of first dosing
12 Minimum life expectancy of 12 weeks at screening

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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.
Reproduction
14 Negative pregnancy test (serum) for women of childbearing potential who are sexually 
active with a non-sterilized male partner
Female participants must be 1 year post-menopausal, 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). 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 for a 
minimum of 3 months before entering the study to 7 months after the last dose (see
Appendix I for complete list of highly effective birth control methods). 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. Not engaging in sexual activity for the duration of the study and drug washout 
period (7 months after the last dose of study intervention) is an acceptable method 
provided it is the usual lifestyle of the participant (consideration must be made to the 
duration of the clinical trial); however, periodic or occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 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 T-DXd
administration. They should refrain from breastfeeding throughout this time. Preservation 
of ova may be considered prior to starting the study treatment.
15 Non-sterilized 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 I) from the time of screening throughout the total duration of 
the study and the drug washout period (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 (4 months after the last dose of study intervention) is an 
acceptable method provided it is the usual lifestyle of the participant (consideration must 
be made to the duration of the clinical trial); however, periodic, or occasional abstinence, 
the rhythm method, and the withdrawal method are not acceptable methods of 
contraception. Male participants must not donate or bank sperm during this same time 
period. Preservation of sperm should be considered prior to starting the study treatment.

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Informed Consent
16 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.
17 Provision of signed and dated written Optional 
 
 
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Known or suspected LMD. If LMD has been reported radiographically on baseline MRI 
but is not suspected clinically by the investigator, the participant must be free of 
neurological symptoms of LMD1
2
Prior exposure to tucatinib treatment
3
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled 
systemic diseases, including ongoing or active infection, uncontrolled hypertension, renal 
transplant, active bleeding diseases, or serious chronic gastrointestinal conditions 
associated with diarrhea) substantially increase risk of incurring AEs, which, in the 
investigator’s opinion, makes it undesirable for the participant to participate in the study 
or would jeopardize compliance with the protocol
4
Refractory nausea and vomiting, chronic gastrointestinal disease, or previous significant 
bowel resection that would preclude adequate absorption, distribution, metabolism, or 
excretion of T-DXd
5
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, 
other solid tumors curatively treated, or contralateral breast cancer.
                                               
1 LMD is a clinical diagnosis, defined as positive CSF cytology and/or unequivocal radiologic or clinical 
evidence of leptomeningeal involvement. Patients with leptomeningeal symptoms in the setting of 
leptomeningeal enhancement would be considered to have LMD even in the absence of positive CSF cytology, 
unless a parenchymal lesion can adequately explain the neurologic deficit. In contrast, asymptomatic or 
minimally symptomatic patients with mild or nonspecific leptomeningeal enhancement would not be considered 
to have LMD. In such patients, CSF sampling is not required to formally exclude LMD but can be performed at 
the investigator’s discretion on the basis of level of clinical suspicion.
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6
Based on screening contrast brain MRI / CT scan, participants must not have any of the
following:
(a) Any untreated brain lesions > 2.0 cm in size, unless discussed with the study 
physician and approval is given
(b) Ongoing use of systemic corticosteroids for control of symptoms of BMs at a total 
daily dose of > 3 mg of dexamethasone (or equivalent). However, participants on a 
chronic stable dose of ≤ 3 mg total daily of dexamethasone (or equivalent) may be 
eligible with discussion and approval by the study physician.
(c) Any brain lesion thought to require immediate local therapy, including (but not 
limited to) a lesion in an anatomic site where increase in size or possible treatment-
related edema may pose risk to participant (eg, brain stem lesions). Participants who 
undergo local treatment for such lesions identified by screening contrast brain MRI / 
CT scan may still be eligible for the study based on criteria described under CNS 
inclusion criteria 3 and 5.
(d) Have poorly controlled (> 1/week) generalized or complex partial seizures, or 
manifest neurologic progression due to BMs notwithstanding CNS-directed therapy
7
Has spinal cord compression
8
Known active hepatitis B or C infection, such as those with serologic evidence of viral 
infection within 28 days of Cycle 1 Day 1. Participants with past or resolved HBV 
infection are eligible, if negative for HBsAg and positive for anti-HBc. Participants 
positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
9
Active primary immunodeficiency, known to have tested positive for HIV
10 Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
11 Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines 
are not considered attenuated live vaccines) within 30 days prior to the first dose of 
T-DXd.
Note: Patients, if enrolled, should not receive live vaccine during the study and up to 
30 days after the last dose of T-DXd.
12 Has substance abuse or any other medical conditions such as clinically significant cardiac 
or psychological conditions, that may, in the opinion of the investigator, interfere with 
participation in the clinical study or evaluation of the clinical study results
13 Participants with a medical history of myocardial infarction (MI) within 6 months before 
screening, symptomatic CHF (NYHA Class II to IV), unstable angina pectoris, or a recent 
(< 6 months) cardiovascular event including stroke. Participants with troponin levels 
above ULN at screening (as defined by the manufacturer), and without any myocardial 
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14 Investigator judgment of 1 or more of the following:
(a) Mean resting corrected QTcF interval > 470 ms (females) or > 450 msec (males),
obtained from triplicate ECGs performed at screening
(b) 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
(c) Congenital long QT syndrome, family history of long QT syndrome, or unexplained 
sudden death under 40 years of age in first-degree relatives
15 History of arrhythmia (multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE 
Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or 
asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation 
controlled by medication or arrhythmias controlled by pacemakers may be permitted upon 
discussion with the study physician.
16 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.
17 Lung criteria:
(a) Lung-specific intercurrent clinically significant illnesses including, but not limited to, 
any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of study 
enrollment, severe asthma, severe COPD, restrictive lung disease, pleural effusion,
etc)
(b) Any autoimmune, connective tissue or inflammatory disorders (ie, rheumatoid 
arthritis, Sjogren’s, sarcoidosis, etc.) where there is documented, or a suspicion of 
pulmonary involvement at the time of screening. Full details of the disorder should 
be recorded in the eCRF for participants who are included in the study.
(c) Prior pneumonectomy
Prior/Concomitant Therapy
18 Prior exposure, without adequate treatment washout period before the day of first dosing,
to chloroquine/hydroxychloroquine: < 14 days
19 Anticancer chemotherapy
(a) Immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy: 
< 3 weeks (< 2 weeks or 5 half-lives, whichever is longer, for small-molecule 
targeted agents such as 5-fluorouracil-based agents, folinate agents, and weekly 
paclitaxel)
(b)
< 6 weeks for nitrosoureas or mitomycin C
(c) Antibody-based anticancer therapy: < 4 weeks. Denosumab for the treatment of bone 
lesions will be permitted.

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(d) Any concurrent anticancer treatment. Concurrent use of hormonal therapy for 
non-cancer-related conditions (eg, hormone replacement therapy) is allowed.
20 Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Subjects may be enrolled with 
chronic, stable Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 
3 months prior to randomization/enrolment and managed with standard of care treatment) 
that the investigator deems related to previous anticancer therapy, such as:
(a) Chemotherapy-induced neuropathy
(b) Fatigue
(c) Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies 
which may include:
o
Hypothyroidism/hyperthyroidism
o
Type 1 diabetes
o
Hyperglycemia
o
Adrenal insufficiency
o
Adrenalitis
o
Skin hypopigmentation (vitiligo)
21 Palliative radiotherapy with a limited field of radiation within 2 weeks (palliative 
stereotactic radiation therapy to other areas within 1 week) or with wide field of radiation, 
radiation to the chest, or to more than 30% of the bone marrow within 4 weeks before the 
first dose of study intervention.
22 Major surgical procedure (excluding placement of vascular access) or significant 
traumatic injury within 4 weeks of the first dose of study intervention or an anticipated 
need for major surgery during the study.
23 Participants with prior exposure to immunosuppressive medication within 14 days prior to 
first study dose, except for intranasal and inhaled corticosteroids or systemic 
corticosteroids at doses less than 3 mg/day of dexamethasone or equivalent are to be 
excluded. Steroids as premedication for hypersensitivity reactions due to radiographic 
contrast agents are allowed. Prophylactic or supportive treatment of study drug-induced 
AEs will be otherwise as per investigator’s discretion and institutional guidelines. Any 
concurrent chemotherapy, anticancer investigational product or biologic, radiotherapy 
(except palliative radiotherapy to areas other than chest, after consultation with the study 
physician), or hormonal therapy for cancer treatment are considered exclusionary during 
the study. Note, local therapy is allowed for participants with BM while on study 
treatment.
Prior/Concurrent Clinical Study Experience
24 Previous treatment in the present study

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25 Participation in another clinical study with a study intervention or investigational 
medicinal device administered in the last 30 days or 5 half-lives, whichever is longer, 
prior to first dose of study intervention, randomization into a prior T-DXd study 
regardless of treatment assignment, or concurrent enrollment in another clinical study, 
unless it is an observational (noninterventional) clinical study or during the follow-up 
period of an interventional study
26 Participants with a known hypersensitivity to study intervention or any of the excipients 
of the product or other monoclonal antibodies
Other Exclusions
27 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca / 
Daiichi Sankyo staff and/or staff at the study site)
28 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
29 Currently pregnant or breastfeeding
5.3
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:
1
Participants must follow the contraception requirements outlined in Appendix I.
2
Participants should not donate blood or blood components while participating in this 
study and up to and including the safety follow-up period.
Restrictions relating to concomitant therapies are described in Appendix K.
5.3.1
Tobacco, Alcohol, Psychoactive Drugs and Caffeine
1
Use of tobacco products, e-cigarettes and vaping is strongly discouraged but not 
prohibited. Any prior or current use of these products as well as prior or current use of 
alcohol and psychoactive drugs, should be recorded in the eCRF. Prior or current abuse of 
caffeine must be documented in the eCRF as well.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. 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, 

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eligibility criteria, and any SAE for screen failures including patients who are identified in the 
pre-screening phase as not eligible.
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 its effect on study results, if any, can be assessed.
All assessments must be repeated for rescreening unless they are within 28 days of inclusion 
in the study or as applicable as some screening assessments could be valid for more than 
28 days.
These participants should have the reason for study withdrawal recorded in the eCRF as 
“screen failure” (ie, participant does not meet the required inclusion/exclusion criteria). This 
reason for study withdrawal is only valid for screen failures (ie, participants who are not 
entered in the study).
Participant enrollment is described in Section 6.3.

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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the CSP. Study intervention in this study refers to T-DXd.
6.1
Study Intervention Administered
The study treatment to be administered in this study is shown in Table 4.
Table 4
Study Treatment
Study 
treatment 
name
Dosage 
presentatio
n
Unit dose 
strength
Dosage 
level
Route of 
administrati
on
Packaging 
and labeling
Use
Sourcing
T-DXd 
(DS-8201a) 
a
Vial
Powder for 
concentrate 
for solution 
for infusion 
100 mg/vial
5.4
mg/kg
IV
T-DXd will 
be provided in 
a vial in a 
carton. Each 
vial and 
carton will be 
labeled in 
accordance 
with GMP 
Annex 13 and 
per country 
regulatory 
requirements a
Experimental
Provided 
centrally by 
AstraZeneca
a
Label text for T-DXd (DS-8201a) will show “DS-8201a” depending on the agreed product name used in the 
respective approved study master label document. All naming conventions for these compounds are correct 
during this transitional period.
GMP = Good Manufacturing Practice; IV = intravenous; T-DXd = trastruzumab deruxtecan.
Duration of Treatment
All participants will receive T-DXd, 5.4 mg/kg, IV, every 3 weeks until RECIST 1.1-defined 
radiological progression outside CNS. Participants may continue to receive T-DXd beyond 
progression, as long as they are continuing to show clinical benefit, as judged by the 
investigator, and in the absence of other discontinuation criteria.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee (eg, pharmacist) must confirm appropriate temperature 
conditions have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2
Only participants enrolled in the study and who meet eligibility requirements may receive 
study intervention and only authorized site staff may supply or administer study 
intervention. All study intervention must be stored in a secure, environmentally 

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controlled, and monitored (manual or automated) area in accordance with the labeled
storage conditions with access limited to the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy Manual.
6.2.1
Trastuzumab Deruxtecan Preparation, Administration, and Storage
Trastuzumab deruxtecan will be supplied by AstraZeneca as a 100 mg/vial lyophilized powder 
for concentrate for solution for infusion. Following reconstitution with sterile water for 
injection the solution contains 20 mg/mL T-DXd in 25 mM histidine/histidine HCl, 90 mg/mL 
sucrose, 0.03% (w/v) polysorbate 80; it has a pH of 5.5. The post-reconstitution label-claim 
volume is 5 mL.
The reconstituted product is a clear to opalescent, colorless to yellow liquid, and practically 
free from visible particles.
Preparation of T-DXd
The dose of T-DXd for administration must be prepared by the investigator’s or site’s 
designated study intervention manager using aseptic technique. Total time from needle 
puncture of the T-DXd vial to the start of administration must not exceed:
!
24 hours at 2°C to 8°C (36° F to 46° F)
!
4 hours at room temperature
If the final product is stored at both refrigerated and ambient temperature, the total time must 
not exceed 24 hours.
After preparation and during administration, the prepared IV bag must be covered by light 
protection cover.
Administration of T-DXd
It is recommended that participants receive prophylactic anti-emetic agents prior to infusion of 
T-DXd and on subsequent days. Antiemetics such as 5-HT3 antagonists or NK1 receptor 
antagonists and/or steroids (eg, dexamethasone) should be administered in accordance with 
the prescribing information or institutional guidelines.
Trastuzumab deruxtecan will be administered using an IV bag containing 5% (w/v) dextrose 
injection infusion solution and delivered through an IV administration set with a 0.2- or 

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0.22-μm filter. The standard infusion time for T-DXd 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 infusion time for subsequent cycles is 
30 minutes ± 10 minutes. However, if there are interruptions during infusion, the total allowed 
time must not exceed 3 hours at room temperature.
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.
Refer to the Pharmacy Instructions for detailed information about preparation and 
administration of T-DXd.
Monitoring of T-DXd Administration
Participants will be monitored during and after infusion of T-DXd. Vital signs will be 
measured according to the SoA (Section 1.3).
Management of study intervention-related toxicities are described in Section 6.6.1. As with 
any biologic product, allergic reactions 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.
A 1-hour observation period is recommended after the first IV infusion of T-DXd. For 
subsequent infusions, the recommended observation period is 30 minutes.
Storage of T-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.
Trastuzumab deruxtecan vials are to be stored at 2 °C to 8 °C (36 °F to 46 °F) and must not be 
frozen. T-DXd must be kept in original packaging until use to prevent prolonged light 
exposure.
6.3
Measures to Minimize Bias: Randomization and Blinding
This is an open-label, single-arm, 2-cohort study. All eligible participants will receive T-DXd.

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Participant Enrollment
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening and/or pre-screening.
At screening/baseline (Days -28 to -1), the investigators or suitably trained delegate will:
!
Obtain signed informed consent before any study-specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 
consent, these can be used for screening purposes with consent of the participant. 
However, all screening laboratory and imaging results must have been obtained within 
28 days of the first dose of study intervention. A pre-screen ICF must be signed by 
patients to permit for tumor tissue sample collection (HER2 status) and testing prior to the 
28-day screening window. At the time of signing pre-screen ICF, investigators should 
ensure that there is a reasonable possibility that the patient would be candidate for this 
study based on available information (eg, medical history, availability of required number 
of slides for study).
!
Participants will be identified to the IRT per country regulations. Obtain a 
 
 through the IRT in the following format: 
 
 
 This number is the participant’s unique identifier and is 
used to identify the participant on the eCRFs. If a participant withdraws from the study, 
his/her enrollment code cannot be reused. Withdrawn participants will not be replaced.
!
Obtain sample and send for HER2 testing. A mandatory FFPE tumor sample from 
archival tumor tissue or fresh biopsy must be provided that meets the tissue requirements 
specified in Section 8.6.1 is required. Obtaining the sample should be given the highest 
priority and, as such, the sample may be obtained and sent for testing prior to the 28-day 
screening window (after obtaining signed pre-screen ICF) in order to permit analysis prior 
to the first dose of study intervention. Tumor lesions used for newly acquired biopsies 
should not be the same lesions used as RECIST 1.1 TLs, unless there are no other lesions 
suitable for biopsy; and in this instance only core needle (not excisional/incisional) biopsy 
is allowed.
!
Determine participant eligibility (see Sections 5.1 and 5.2).
!
Obtain signed informed consent for 
 (optional). Participants who 
decide not to sign the 
 ICF, but the general study ICF, are eligible for 
study enrollment and all other study procedures.
If the participant is ineligible, the IRT should be accessed to terminate the participant in the 
system.
The day participants receive the first dose of study treatment is Cycle 1 Day 1. Every effort 
CCI
CCI
CCI
CCI
CCI
CCI

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should be made to minimize the time between screening/baseline and dosing. Dosing should 
occur no more than 3 days after treatment assignment. If it is anticipated that dosing cannot 
occur within 3 days, a discussion with the AstraZeneca study physician is required. 
Participants must not be treated unless all eligibility criteria have been met.
Participants who fail to meet the eligibility criteria should not, under any circumstances, 
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 started on 
study intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is 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.
Methods for Assigning Treatment Groups
Not applicable; this is a single-treatment group study with 2 cohorts.
Study intervention will be centrally assigned using IRT. Before the study is initiated, 
directions for the IRT will be provided to each site. The site will contact the IRT to confirm 
cohort selection prior to the start of study intervention administration for each participant. 
Once a cohort is fully enrolled, the IRT will be closed for this cohort. When study intervention 
is provided centrally by the sponsor, the IRT will provide the kit identification number to be 
allocated to the participant at each dispensing visit.
6.4
Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff.
Participants are dosed at the site and will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of dose administered in 
the clinic 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 
by a member of the study site staff other than the person administering the study intervention.
Deviation(s) from the prescribed dosage regimen should 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.

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6.5
Concomitant Therapy
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the participant’s safety and wellbeing, or vaccine including over-the-counter 
or prescription medicines, vitamins, and/or herbal supplements that the participant is receiving 
from the time of screening or receives during the study including the 40-day 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 physician 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.
In special cases, such as cases with ILD, documentation of concomitant therapy is required 
even after the safety follow-up period.
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 K.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix K.
Drug-drug Interactions
There is no information to date on drug-drug interactions with T-DXd, either pre-clinically or 
in participants. There may be a hypothetical interaction between T-DXd and 
hydroxychloroquine and/or chloroquine, therefore concomitant treatment with 
hydroxychloroquine or chloroquine is not allowed during the study treatment.
Results from Study DS8201-A-A104 suggested that strong cytochrome P450 3A4 inhibitors 
(eg, boceprevir, clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, 
telaprevir, telithromycin, and voriconazole) or organic anion transporting polypeptide 1B 
inhibitors (eg, lopinavir/ritonavir, cyclosporine, and rifampicin) can be administered without 
T-DXd dose adjustment.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix K.

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6.5.1
Other Protocol Restrictions or Supportive Treatments
Other CSP restrictions or supportive treatments are listed below (refer also to Appendix K):
T-DXd is emetogenic, which includes delayed nausea and/or vomiting. Prior to each dose of 
T-DXd, patients should be premedicated with a combination regimen of 2 or 3 medicinal 
products (eg dexamethasone with either a 5-HT3 receptor antagonist and/or an NK1 receptor 
antagonist, as well as other medicinal products as indicated) for prevention of 
chemotherapy-induced nausea and vomiting.
Hematopoietic growth factors may be used for treatment based on the clinical judgment of the 
investigator.
Concomitant use of dietary supplements, medications not prescribed by the investigator, and 
alternative/complementary treatments is discouraged, but not prohibited.
Prophylactic or supportive treatment of study intervention-induced AEs will otherwise be as 
per investigator’s discretion and institutional guidelines.
6.6
Dose Modification
Dose modification guidelines for T-DXd-related toxicities are shown in Appendix O. 
Appropriate and optimal treatment of the toxicity is assumed prior to considering dose 
modifications. Prior to discontinuation of study intervention due to toxicities, please consult 
with the study physician.
6.6.1
Specific Toxicity Management and Dose Modification Information –
T-DXd
All dose modifications (interruption, re-initiation, reduction and/or discontinuation) should be 
based on the worst preceding toxicity (NCI CTCAE v5.0). Specific criteria for interruption, 
re-initiation, dose reduction and/or discontinuation of T-DXd are listed in Appendix O, which 
is applicable only to TEAEs that are assessed as related to use of T-DXd by the investigator(s).
For non-drug-related TEAEs, follow standard clinical practice. Appropriate clinical experts 
should be consulted as deemed necessary.
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Please 
refer to Appendix L for additional information on dose modification for suspected or 
confirmed COVID-19 infection for participants treated with T-DXd.
ILD/Pneumonitis Management Guidance
Please refer to the ILD/pneumonitis management summary flow chart in Appendix N for the 
management of drug-induced ILD/pneumonitis. All potential ILD/pneumonitis cases should 

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be reported within 24 hours; including both serious and non-serious potential 
ILD/pneumonitis cases (potential ILD/pneumonitis is defined in the current Site Manual List 
of MedDRA Preferred Terms).
ILD/pneumonitis should be ruled out if a participant develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough, or fever. If the 
AE is confirmed to have an etiology other than ILD/pneumonitis, follow the management 
guidance outlined in Appendix O.
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. As soon as ILD/pneumonitis is suspected, corticosteroid treatment should be 
started promptly as per clinical treatment guidelines (See Appendix N and Appendix O for 
further guidance).
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in 
Appendix N and Appendix O. All events of ILD/pneumonitis regardless of severity or 
seriousness will be followed until resolution including after study intervention 
discontinuation.
All cases of potential ILD/pneumonitis will be reviewed internally by medical monitor and 
study safety physician. An ILD Advisory Committee will also be consulted unless the ILD 
Advisory Committee charter is out of scope. To ensure adequate and relevant evaluation, 
systematic additional data collection will be conducted for all cases that will be brought for 
evaluation. This additional data collection 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 for AEs reported 
using selected MedDRA Preferred Terms.
LVEF decrease Management Guidance
Refer to the management guidance outlined in Appendix O.
!
Left ventricular ejection fraction will be measured by either ECHO or MUGA scan. All 
ECHOs/MUGAs will be evaluated by the investigator or delegated physician for 
monitoring cardiac function.
!
Troponin-T (preferably high-sensitivity troponin-T) will be measured at screening and at 
EOT, and as needed based on participant-reported cardiac signs or symptoms suggesting 
CHF, MI, or other causes of cardiac myocyte necrosis. If ECG is abnormal, follow 
institutional guidelines. Qualitative testing for Troponin-T or Troponin-I instead of 
Troponin-T may be acceptable to perform, if in accordance with local practice and if 
quantitative method or Troponin-T is not available. Positive results must be followed up 

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with a quantitative measurement along with other institutional guidance (refer to 
Appendix O for additional management guidelines).
Electrocardiograms will be performed at screening, prior to administration of study 
intervention for every 4th cycle (once) and if an abnormality is detected or if there is a 
troponin increase. Triplicate ECGs will be performed at screening. Subsequent ECGs will be 
performed in triplicate only if abnormalities are noted. Twelve-lead ECGs will be performed, 
and standard ECG parameters will be measured, including RR, PR, QT intervals, and QRS 
duration. All ECGs must be evaluated by investigator or delegated physician for the presence 
of abnormalities prior to the injection of study intervention at every cycle. Whether or not 
measurement is performed, date performed, results, and findings for each parameter is to be 
recorded in the eCRF.
6.6.2
Dose Reductions, Interruptions, and Modifications
Once the dose of T-DXd has been reduced because of toxicity, all subsequent cycles should be 
administered at that lower dose level unless further dose reduction is required (Table 5). More 
than 2 dose reductions are not allowed, and the study intervention will be discontinued if 
further toxicity that meets the requirement for dose reduction occurs.
Table 5
Dose Reduction Levels of T-DXd
Starting dose
Dose level -1
Dose level -2
5.4 mg/kg
4.4 mg/kg 
3.2 mg/kg 
T-DXd = trastuzumab deruxtecan
Dose Interruption and Modification/TMGs
Every effort should be made to limit study drug delay. In circumstances of adverse event 
management or medical intervention, the study drug can be held up to 18 weeks (126 days) 
from the last T-DXd dose, however, two consecutive doses must be administrated at least 
19 days apart. During this time scheduled CT/MRI scans should continue as per protocol, and 
participants should fulfil all of the following criteria:
!
Study drug may be resumed with confirmation of continued benefit per RECIST 1.1. 
Scans should be performed at the frequency defined per protocol, while the drug is being 
held.
!
At minimum 1 restaging scan must be done within 6 weeks prior to restarting the study 
drug.
!
IP(s) is/are restarted within the guidance of the TMGs for T-DXd and any combination 
agents, if appropriate.
!
No prohibited concomitant medications have been administered since the last dose of 
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Treatment cycles for a participant for whom T-DXd dosing is temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last T-DXd dose.
In addition, investigators may consider dose reductions or discontinuations of T-DXd 
according to the participant’s condition and after discussion with the study physician or 
designee. For management of dose delays due to T-DXd related events, the TMGs in 
Appendix O should be followed, as applicable.
In summary, if a participant experiences a clinically significant and/or unacceptable toxicity, 
dosing will be interrupted or permanently discontinued depending on the severity of the 
toxicity, and supportive therapy administered as required.
On improvement of an AE for which T-DXd was temporarily interrupted, T-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, T-DXd may be restarted at a one dose level reduction on improvement of the AE 
or discontinued if the participant is receiving the lowest protocol-specified dose level 
(Appendix O).
In case a dose reduction is necessary, the study intervention will be administered as described 
in Appendix O.
Appropriate and optimal treatment of the toxicity is assumed prior to considering dose 
modifications. Prior to discontinuation of study intervention due to toxicities, please consult 
with the study physician.
6.7
Intervention After the End of the Study
No intervention is planned 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.
After the final DCO for this study, AstraZeneca will continue to supply T-DXd to participants
who received T-DXd until meeting any discontinuation criteria as defined in Section 7.1. 
Where possible, if commercial supply of T-DXd is available in the local market then this route 
should be used.
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 T-DXd may be 
transitioned to such a study, and the current study would reach its end. The roll-over or safety 
extension study would ensure treatment continuation with visits and assessments per its 
protocol. Any participant who would be proposed to move to such a study would be asked to 
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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 survival, either through direct contacts or by collecting 
public records (eg, death certificates) as allowed by local laws. 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. 
Participants may be discontinued from study intervention in the following situations:
!
RECIST 1.1-defined radiological progression outside CNS (refer to Section 8.1.1 and
Appendix F).
!
Those patients who receive local therapy (radiation) for isolated CNS progression, 
providing there is no other systemic progression may be allowed to continue study 
assigned treatment until a second progression (brain or body) is observed. Study treatment 
will be discontinued at the time of second progression (see Section 7.1.1).
!
Investigator determination that the participant is no longer benefiting from study 
intervention.
!
An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing.
!
Any AE that meets criteria for discontinuation defined in the dose modification guidelines 
for management of study intervention-related toxicities (see Section 6.6).
!
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.
!
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Subjective disease progression (global deterioration of health status) without objective 
evidence of PD according to RECIST 1.1.
!
Study terminated by AstraZeneca.
!
Participant lost to follow-up.
!
Death.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
See the SoA (Section 1.3) for data to be collected at the time of intervention discontinuation 
(ie, the EOT visit) and follow-up and for any further evaluations that need to be completed.
7.1.1
Temporary Discontinuation
Temporary discontinuation of T-DXd may be required for the management of drug-induced
ILD/pneumonitis (Appendix N).and other toxicities (Appendix O), 
 
.
 
 
 
 
 
 
 
 
 
 
 
 
 
!
 
 
!
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!
!
!
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7.1.2
Follow-up of Participants Post Discontinuation of Study Intervention
All participants who discontinue the study intervention will be followed up for safety 
assessments 40 (+ up to 7) days after their last dose of study intervention. Additional 
assessments to be performed at the time of the 40-day safety follow-up are detailed in the SoA
(Section 1.3). 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 assessments as indicated in the SoA 
(Section 1.3) until RECIST 1.1-defined PD or death regardless of whether or not the 
participant started a subsequent anticancer therapy, unless they have withdrawn all consent to 
study-related assessments.
7.1.3
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.
7.1.4
Follow-up for Survival
Participants will be followed up for survival status as indicated in the SoA (Section 1.3) 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, or by contact with the 
participant’s current physician. Additional assessments to be performed at the time of survival 
follow-up are detailed in the SoA.
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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.
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 on any ongoing AEs and concomitant medications 
(eg, telephone contact at 40 [+ up to 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 early study intervention 
discontinuation visit should be conducted, as shown in the SoA (Section 1.3). 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 ICF 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.” 

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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 
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 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 lost to 
follow-up and withdrawn 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 enrolled, 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, PFS2, and OS, the survival status of all 
participants in the full analysis and the safety analysis sets should be rechecked; 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.

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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 1.3). Data collection 
following study analysis until the end of the study is described below.
!
Protocol waivers or exemptions are not allowed.
!
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, 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.
8.1
Efficacy 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. When 
assessing whether a progression event has occurred, please ensure that COVID-19 and other 
infective lymphadenopathies have been excluded first.
For the brain, images from MRI (preferred, unless contraindicated) with and without IV 
contrast, or contrast-enhanced CT, will be collected for all participants at baseline, and for
participants with BMs at regular (follow-up) intervals during study intervention.
Participants with active (untreated or progressive) and measurable BMs should have CNS 
lesions included as TL(s) for RECIST 1.1 assessments. The assessment of RECIST endpoints 
could include TLs within and outside the CNS (if possible), while assessment of CNS
RECIST endpoints (eg, CNS ORR, CNS DoR) will only include TLs within the CNS. Both 
endpoints will be analyzed separately and may include overlapping or different TLs.
Any other areas of disease involvement should be additionally imaged at screening based on 
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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 (Table 1). Screening/baseline imaging should be performed no more than 
28 days before start of study intervention and ideally should be performed as close as possible 
to and prior to the start of study intervention. Scanning/tumor assessments continue 
throughout treatment until RECIST 1.1-defined radiological progression. 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 (defined as measurable) 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).
For the evaluation of tumor response, refer to Appendix G for RECIST 1.1 / CNS RECIST 1.1
and Appendix H for 
criteria.
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 ICR. 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. An ICR 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.
Further details of the ICR 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 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.
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8.1.4
Overall Survival
Assessments for survival will be conducted every 3 months ± 14 days following objective PD
or treatment discontinuation. 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.
8.1.5
Clinical Outcome Assessments
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. Clinical outcome 
assessments can be reported by a participant (PRO), a clinician, an observer, 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, functioning, and HRQoL of the participant to aid 
understanding of the risk/benefit profile. In this study, COAs will be used to assess changes in 
disease and treatment-related symptoms, including those related to BM and ILD/pneumonitis, 
functioning including neurological and cognitive functioning for those with BM, and overall 
HRQoL.
A PRO is one type of COA and is a general term referring to all outcomes and symptoms that 
are directly reported by the participant. PROs have become important in evaluating the 
effectiveness 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: EORTC QLQ-C30 (all participants), MDASI brain tumor-specific 
items (participants with BM), and for participants who develop ILD/pneumonitis, the SGRQ-I 
and MDASI lung cancer (ILD symptom-specific items) (see Appendix J).
Additional COAs for all participants include the clinician-completed NANO scale and 
participant-completed cognitive function tests, and for participants who develop 
ILD/pneumonitis, at-home pulse oximetry.
Clinical outcome assessments will be administered according to the SoA (Section 1.3).
8.1.5.1
EORTC QLQ-C30
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group 1993. It consists 
of 30 items 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 and vomiting); a 2-item global QoL scale; 5 single items assessing additional 
symptoms commonly reported by cancer patients (dyspnea, loss of appetite, insomnia, 
constipation, and diarrhea), and 1 item on the financial impact of the disease. The EORTC 
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8.1.5.2
MDASI Symptom Diary
The MDASI symptom diary is a validated, multi-item, cancer-specific PRO questionnaire 
capturing symptom severity and interference (Cleeland et al, 2000). 
MDASI brain tumor-specific items
The MDASI brain tumor module includes 9 symptoms specific to brain tumors (weakness on 
one side of the body, difficulty understanding, difficulty speaking, seizures, difficulty 
concentrating, problems with vision, change in appearance, change in bowel pattern (diarrhea 
or constipation), and irritability). These 9 items will be used to capture symptoms associated 
with BMs for those diagnosed with BM. Each item is rated on an 11-point numeric rating 
scale, with higher scores indicating greater symptom severity.
MDASI lung cancer (ILD symptom-specific items)
Three items from the MDASI lung cancer module will be used to capture the core 
ILD/pneumonitis symptoms of cough, shortness of breath, and chest heaviness/tightness. Each 
item is rated on an 11-point numeric rating scale, with higher scores indicating greater 
symptom severity.
8.1.5.3
SGRQ-I
The original SGRQ is a commonly used, validated instrument capturing HRQoL for patients 
with chronic respiratory disease. The SGRQ-I is an idiopathic pulmonary fibrosis-specific 
version of the instrument developed and validated for use among patients with idiopathic 
pulmonary fibrosis, a type of ILD (Yorke et al, 2010). The SGRQ-I will be used to assess the 
HRQoL among participants who have been diagnosed with ILD/pneumonitis. It includes 34 of 
the original SGRQ items determined to be most reliable for assessing the HRQoL of 
participants with idiopathic pulmonary fibrosis. The instrument yields 3 domain scores 
(symptoms, activity, and impact) as well as a total score, with scores ranging from 0 to 100
(see Appendix J). Higher scores indicate greater impairment in HRQoL.
8.1.5.4
Other COAs
NANO Scale
The NANO scale is a clinician-reported assessment of neurologic functioning in neuro-
oncology patients (Nayak et al, 2017). The instrument captures 9 domains (gait, strength, 
ataxia, sensation, visual fields, facial strength, language, level of consciousness, and behavior) 
and was developed to provide a simple, objective assessment of neurologic function that 
would be combined with radiographic assessment to provide an overall outcome assessment 
for neuro-oncology patients in clinical trials and in daily practice.
Cognitive Tests
Computerized, self-completed cognitive tests will be used to capture cognitive function, 
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Time, Paired Assistance Learning, and Spatial Working Memory and are low-burden, highly 
sensitive, precise measures of cognitive function.
At-home Pulse Oximetry
An electronic, wireless pulse oximetry device will be provided to participants diagnosed with 
ILD/pneumonitis. The research nurse or appointed site staff will train participant on the use of 
the device. All participants will complete a resting and walking assessment at the baseline visit 
before dosing. After diagnosis of ILD/pneumonitis, at-home pulse oximetry testing will be 
performed by the participant once daily while resting (after at least 10 minutes of rest) at 
approximately the same time each day and once weekly while walking, in accordance with the 
SoA (Section 1.3).
For the walking assessment participants will walk in their homes for 3 minutes at their own 
pace on level ground and with any walking aid they would normally use. The walk should be 
discontinued if at any time the participant experiences severe shortness of breath, anterior 
chest pain, or if the participant feels that he or she is unable to continue walking. The 
measurement of pulse oximetry should be taken immediately after the participants have 
completed the 3 minutes of the walking assessment. The lower limit SpO2 value after the 3 
minutes of walking is the value to be recorded.
The research nurse or appointed site staff will check the participant’s adherence to the correct 
use of the pulse oximetry at each site visit.
8.1.5.5
Administration of ePRO Questionnaires
The PRO questionnaires will be self-administered electronically by the participants using a 
provisioned handheld device at the time points indicated in the SoA, if a linguistically 
validated version is available in the language of their country of residence.
Participants should complete the ePROs at home prior to the site visit or at the site visit, if the 
assessment time point coincides with a scheduled site visit.
Participants must be instructed to bring the 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.
In case of handheld device failure, the site should follow the ePRO device failure mitigation 
plan which has been agreed by AstraZeneca.
Approximately 2 to 20 minutes is required for participants to complete the questionnaires, 
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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 patient that these questions are being asked to find out, directly from them, 
how they feel.
!
It is vital that the ePRO reporting is initiated on Cycle 1 Day 1 as specified in the SoA 
to capture the effect of study intervention. The ePRO device must be charged and fully 
functional at the beginning of the baseline visit to ensure that the PROs can be 
completed at the start of the visit.
!
The participant should bring the ePRO device to each site visit so the research nurse or 
appointed site staff can check if there are available PRO questionnaires to be 
completed and that the device is functioning properly.
!
PRO questionnaires completed at sites must be completed prior to treatment 
administration performed at the site and ideally before any discussions of health status 
to avoid biasing the participant’s responses to the questions. As feasible, site staff 
should also ensure PRO questionnaires are completed prior to other study procedures, 
such as collection of laboratory samples, to further minimize bias.
!
PRO questionnaires should be completed by the participant in a quiet and private 
location.
!
The participants 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 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 electronically. 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 participants 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 PRO 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 that requires PRO completion, the 
participant may be exempted from completing the PRO questionnaires at that site visit.
!
Site staff must not read or complete the PRO questionnaires on behalf of the 
participant. If the participant is unable to read the questionnaire (eg, is blind, 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 patient cannot 
complete the PRO questionnaires due to reasons other than being blind, illiterate, or 
not fluent in the language, the AstraZeneca study team must be contacted to determine 
if they can be exempted. Participants exempted in this 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 the participant speaks.
!
If PRO questionnaires are completed at home, 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 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 should 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). A 
solution to enhance/resolve compliance should be discussed with the participant. Discussions 
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 (Section 1.3).
8.2.1
Physical Examinations
!
A complete physical examination will include assessments of the following: head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine 
systems. 
!
Targeted physical examinations are to be used by the investigator on the basis of clinical 
observations and symptomatology. A brief physical examination will include, at a 
minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
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Physical examination, as well as assessment of height and weight, will be performed as 
specified in the SoA; investigators should pay special attention to clinical signs related to 
previous serious illnesses, and new or worsening abnormalities that may qualify as AEs, see 
Section 8.3.5 for details.
8.2.2
Vital Signs
Vital signs will be performed as specified in the SoA (Section 1.3).
Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
Blood pressure and pulse measurements will be assessed with a completely automated device. 
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 consist of 1 pulse and 1 blood pressure measurement. The blood pressure 
readings will be recorded on the eCRF.
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 ECGs will be performed at screening. Subsequent ECGs will be performed in 
triplicate only if abnormalities are noted. ECGs will be taken after the participant has been 
resting semi-supine 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. Refer to Section 7 for QTcF withdrawal criteria and any 
additional QTcF readings that may be necessary.
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. At 
each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. The full set of triplicates should 
preferably be completed within 5 minutes.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
Whenever vital signs and blood draws are scheduled for the same nominal time, the vital signs 
assessments should preferably occur first. Whenever ECGs, vital signs, and blood draws are 
scheduled for the same nominal time, ECG assessments should preferably occur first, then 

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vital signs assessments, and then blood draws; the timing of the first 2 assessments should be 
preferably such that it allows the blood draw to occur at the timepoints indicated in the SoA.
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 (Section 1.3).
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.
The clinical chemistry, hematology, and urinalysis will be performed at a local laboratory at or 
near to the investigator site. Sample tubes and sample sizes may vary depending on laboratory 
method used and routine practice at the site.
Other safety laboratory tests include assessment for pregnancy (serum [at screening] or urine 
[other time points]), hepatitis B and C serology (optional), and HIV antibody test (as required 
by local regulations). Pregnancy tests may be performed at the site using a licensed test (urine 
or serum pregnancy test). Abnormal clinically significant laboratory results should be repeated 
as soon as possible (preferably within 24 to 48 hours).
Pregnancy tests will be conducted within 72 hours before the day of first dosing for all female 
participants 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) 72 hours before infusion of each cycle and at EOT. A negative result 
for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be 
available at the screening visit and urine beta-human chorionic gonadotropin pregnancy test 
prior to each administration of study intervention.
The following laboratory variables will be measured (Table 6).

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Table 6
Laboratory Safety Variables
Hematology/hemostasis (whole blood)
Clinical chemistry (serum or plasma)
Hemoglobin
Creatinine
Leukocyte count
Bilirubin, total
Leukocyte differential count (absolute count; neutrophils, 
lymphocytes, monocytes, eosinophils, basophils)
Alkaline phosphatase
Platelet count
AST
Total white blood cell count
ALT
Total red blood cell count
Albumin
Hematocrit
Potassium
Calcium, total
Urinalysis
Sodium
Hemoglobin/erythrocytes/blood 
Gamma-glutamyl transferase
Protein/albumin 
Lactate dehydrogenase
Glucose 
Protein, total
Urea nitrogen/blood urea nitrogen
Coagulation
Troponin
Coagulation variables (aPTT, PTT, and INR)
Magnesium
Chloride
Serum creatinine 
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; INR = international normalized ratio; PTT = partial thromboplastin time.
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.
In case a participant shows an AST or ALT ≥3 × ULN together with TBL > 2 × ULN please 
refer to Appendix E, “Actions required in cases of increases in liver biochemistry and 
evaluation of HL,” for further instructions.
8.2.5
Other Safety Assessments
8.2.5.1
Echocardiogram/Multigated Acquisition Scan
An ECHO or MUGA scan to assess LVEF will be performed at the visits as shown in SoA 

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(Section 1.3). The modality of the cardiac function assessments must be consistent for a given 
participant (ie, if ECHO is used for the screening assessment for a given participant, then 
ECHO 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 estimated to 5%). All 
ECHOs/MUGAs will be evaluated by the investigator or delegated physician for monitoring 
cardiac function.
Situations in which ECHO or MUGA results should be reported as AEs are described in 
Section 8.3.5.
8.2.5.2
Pulmonary Assessments
Pulse oximetry (SpO2) should be evaluated by investigator or the delegate physician prior to 
the administration of study intervention at each visit after at least 10 minutes of rest.
Pulmonary function tests should include basic spirometry at a minimum with optional 
additional components as mentioned in Table 7.
Table 7
Spirometry Components
Required spirometry components
Optional spirometry components
FVC (L)
PEF
FVC % predicted
FEV6
FEV1 (L)
TLC
FEV1 % predicted
RV
FEV1/FVC %
DLCO
DLCO = diffusion capacity of the lungs for carbon monoxide; FEV = forced expiratory volume; FEV1 = 
FEV-1 second; FEV6 = FEV-6 seconds; FVC = forced vital capacity; L = liters; PEF = peak expiratory flow; 
RV = residual volume; TLC = total lung capacity.
The DLCO will be performed/encouraged if feasible, but for participants with prior severe 
and/or clinically significant pulmonary disorders, DLCO is a requirement.
A non-contrast HRCT scan of the chest will be performed at screening. If HRCT is not 
feasible, a non-contrast CT is acceptable. A non-contrast HRCT is mandatory if 
ILD/pneumonitis is suspected. Chest CT and/or chest HRCT scans will be reviewed separately 
for safety for the presence of ILD/pneumonitis prior to administration of the next scheduled 
dose of T-DXd. 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, non-
contrast HRCT should be performed first.

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8.2.5.3
ILD/Pneumonitis Investigation
If new or worsening pulmonary symptoms (eg, dyspnea, cough or fever) or radiological 
abnormality suggestive of ILD/pneumonitis is observed, study intervention should be 
interrupted and a full investigation is required based on the investigator’s judgment as 
described in the T-DXd TMGs (Appendix O). Evaluations should include:
!
HRCT (without contrast).
!
Pulmonologist consultation (infectious disease consultation as clinically indicated).
!
Blood culture and CBC. Other blood tests could be considered as needed.
!
Bronchoscopy and 
 as clinically indicated and feasible.
!
Pulmonary function tests (Section 8.2.5.2) and SpO2.
!
Arterial blood gases if clinically indicated.
!
One blood sample collection for PK as soon as ILD/pneumonitis is suspected, if feasible.
!
Additional blood samples for 
 as soon as ILD/pneumonitis 
is suspected, if feasible (see Section◦8.6.1), as well as 
 if 
available.
!
Additional ECG, and/or MUGA and/or ECHO required for ILD investigation.
!
Collect family history and exposure history for ILD (Appendix P), in addition to prior and 
current use of substance already collected at screening/Cycle 1 Day 1.
!
Other tests could be considered, as needed.
The results of the full diagnostic workup (including HRCT [without contrast], blood and 
sputum culture, hematological parameters, etc) will be captured in the eCRF. It is strongly 
recommended to perform a full diagnostic workup to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary 
hemorrhage. In the presence of confirmatory non-contrast 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. Troponin measurements will be done to rule 
out cardiac etiology.
The following assessments should be performed, if feasible, to enhance the investigation and 
diagnosis of potential cases of ILD/pneumonitis. The results of the assessment will be 
collected.
!
Other items
∀
When ILD/pneumonitis is suspected during study treatment, the following markers 
should be measured where possible:
o
β-D-glucan
CCI
CCI
CCI

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o
Tumor markers: particular tumor markers that are related to disease progression
#
Additional clinical chemistry: C-reactive protein, lactate dehydrogenase
An ILD Advisory Committee will provide support for the assessment 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. 
The additional data collection 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 for AEs reported 
based on a set of predefined list of PTs.
8.2.5.4
ECOG Performance Status
ECOG performance status will be assessed times specified in the SoA (Section 1.3) based on 
the following:
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 will be performed as specified in the SoA (Section 1.3) and will 
include visual acuity testing (according to local clinical practice), slit lamp examination, and 
fundoscopy.
8.3
Adverse Events and Serious Adverse Events
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.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).

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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
During the pre-screening period, only SAEs directly related to tissue screening procedures (ie, 
if a patient undergoes a tumor biopsy) will be reported. All other SAEs will be recorded from 
the time of signing of the main ICF.
AEs and SAEs (other than ILD/pneumonitis) will be collected from the time of signature of 
the main ICF, throughout the treatment period and including the safety follow-up (which is 
40 + up to 7 days after the discontinuation of all study interventions). For ILD/pneumonitis, 
safety follow-up will be continued until resolution of ILD/pneumonitis. 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.
A TEAE is defined as an AE that occurs, having been absent before the first dose of study 
intervention, or has worsened in severity or seriousness after the initiating the study 
intervention until 47 days after last dose of the study intervention. SAEs with an onset or 
worsening 48 days or more after the last dose of study intervention, if considered related to the 
study intervention, are also TEAEs.
The following types of events should be reported by the investigator in eCRF AE page(s) in 
the clinical study database within 24 hours of becoming aware:
!
SAEs.
!
All potential ILD cases should be reported within 24 hours; including both serious and 
non-serious potential ILD cases (potential ILD/pneumonitis is described in the ILD Site 
Pocket Guide).
!
Hepatic events (both serious and non-serious) that meet the PHL criteria defined as an 
elevated (ALT or AST) ≥ 3 × ULN and an elevated TBL ≥2 × ULN that may occur either 
at different time points or simultaneously during the study. A targeted questionnaire is 
built within the eCRF to collect relevant additional information for these potential cases.
!
Overdose, defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important. An “excessive and medically 
important” overdose includes any overdose in which either an SAE, a non-serious AE, or 
no AE occurs and is considered by the investigator as clinically relevant, i.e. poses an 
actual or potential risk to the subject.
∀
Overdose is always serious. By definition an overdose is medically important, which 
meets the seriousness criterion of Important Medical Event. An overdose can occur 

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with or without an AE. AEs can either be serious or non-serious. Details of the 
overdose including T-DXd dosage, clinical course, associated AEs, and outcome must 
be captured in the Narrative form of the CRF within EDC.
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.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE an assessment or other 
assessment/visit as appropriate in the study are 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:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Initial CTCAE grade, plus any changes in CTCAE grade
!
Whether the AE is serious or not (Appendix B)
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to study intervention
!
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

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!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
The grading scales found in the NCI CTCAE 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).
8.3.3 Causality Collection
The investigator should assess causal relationship between T-DXd 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, 
and ECHO/MUGA scans will be summarized in the CSR.
Deterioration as compared with baseline in protocol-mandated laboratory values, vital signs, 
and ECGs should therefore only be reported as AEs if they fulfill 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 be 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, 

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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 vs low hemoglobin value). Any 
diagnosis of the undesirable clinical outcome of LV dysfunction, a valid or qualifying 
reduction of LVEF (as measured by MUGA or ECHO) should be confirmed and included in 
the AE report. In the absence of clinical signs or symptoms, clinically relevant deteriorations 
in non-mandated parameters should be reported as AEs.
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. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
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 disease progression and not an AE. Events that 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
Events related to the disease under study commonly occur in studies of chronic diseases with a 
variable pattern, eg, respiratory conditions such as asthma, COPD, or rhinitis;
neuropsychiatric conditions such as depression, seizure disorders, or multiple sclerosis; and
cardiac disorders such as angina or heart failure. Symptoms of disease under study are those 
which might be expected to occur as a direct result of breast cancer. Events that are 
unequivocally due to breast cancer should not be reported as AEs 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 

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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:
!
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. An autopsy 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 T-DXd safety profile and require close monitoring and rapid 
communication by the 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. Adverse events will be assessed by the investigator for severity, relationship to 
the study intervention, possible etiologies, and whether the event meets criteria for an SAE 
and therefore requires immediate notification to AstraZeneca. If an AE evolves into a 
condition that meets the regulatory definition of “serious,” it will be reported on the SAE 
Report Form.
Based on the available preclinical and clinical data, review of the cumulative literature, 

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reported toxicities for the same class of agents and biological plausibility, the following events 
are considered to be AESIs. Additional relevant information regarding the AESIs 
ILD/pneumonitis and LVEF decrease, for the T-DXd clinical program regardless of 
seriousness is to be collected through the targeted questionnaires within the clinical study 
database.
ILD/Pneumonitis
ILD is considered an important identified risk, based on a comprehensive cumulative review 
of potential ILD/pneumonitis cases reviewed by the independent ILD Advisory Committee, 
the available safety data from the clinical development program, available data from recent 
epidemiology/literature, biological plausibility, and safety information from drugs of similar 
class. Refer to the current T-DXd IB for a summary of preliminary clinical study data.
For broad surveillance of ILD/pneumonitis, a predefined list of PTs is utilized for enhanced 
data collection.
Refer to Appendix N for guidelines on management of study drug-induced ILD/pneumonitis.
LVEF Decrease
Left ventricular ejection fraction decrease in association with T-DXd is considered to be an
important potential risk, based on the available preclinical data, literature, and available safety 
information for drugs of similar class. Refer to the current T-DXd IB for a summary of 
preliminary clinical trial data.
For broad surveillance of LVEF decrease, relevant PTs under the Standardized MedDRA 
Queries of Cardiac Failure is included for enhanced data collection; additional data for these 
PTs are collected via the targeted safety questionnaire of heart failure.
8.3.12
Safety Data to be Collected Following the Final Data Cutoff of the 
Study
For participants continuing to receive T-DXd after the final DCO, AEs and SAEs will be 
collected, but only SAEs will be reported. In addition, it is recommended that investigators 
monitor the participant’s safety laboratory results periodically during treatment with T-DXd in 
order to manage AEs, consistent with the dose modification guidelines for management of 
study intervention-related toxicities (see Section 6.6). 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 T-DXd (or within the 40 + up to 7 days 
following the last dose of T-DXd) after the final DCO must be reported as detailed in 
Section 8.3.13.

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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.
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 an
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of an SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for T-DXd.
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.
8.3.14.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, T-DXd should be 
discontinued immediately.
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 

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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 abnormality) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs 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
Male participants should refrain from fathering a child or donating sperm during the study and 
for 4 months after the last dose of study treatment. In addition, local prescribing information 
relating to contraception and the time limit for such precautions should be followed for 
marketed products used in this study.
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 abnormality) occurring from the date of the first dose of study intervention
until 4 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 
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
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.

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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.
The definition of a medication error can be found in Appendix B.
8.3.16
Medical Device Deficiencies
This section is not applicable for oncology studies.
8.4
Overdose
Use of T-DXd of 20% more than the intended w/v dose is considered to be an overdose.
There is currently no specific treatment in the event of overdose of T-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.
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 will be stored for a maximum of 15 years from the end of the study (as defined in the 
protocol) in line with consent and local requirements, after which they will be 
destroyed/repatriated.

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!
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 the protocol). Additional use includes 
but is not limited to confirmation and/or requalification of the assay as well as additional 
assay development work. 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
Pharmacokinetic parameters are not evaluated in this study.
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 (Section 1.3). For all tumor specimens, FFPE tissue blocks 
are preferred. If it is not possible to provide a tissue block, a minimum of 20 freshly-cut 
unstained serial tumor slides are to be provided.
The following mandatory samples will be collected from all participants, including screen 
failures where possible:
Archival Tumor Tissue / Fresh Biopsy
!
A tumor sample is required from each participant from either primary or recurrent cancer.
Where possible, the most recently acquired archival sample is required. From submitted 
archival tumor blocks, cores may be removed to construct tissue microarrays for 
 
. If the sample is from a biopsy of a metastatic site, a second biopsy 
from a different metastatic site is requested (if available).
!
If an archival tumor tissue sample is not available, then a newly acquired sample from a 
biopsiable tumor must be collected prior to dosing with study treatment. Tumor lesions 
used for the biopsy should not be the same lesions used as RECIST 1.1 TLs, unless there 
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are no other lesions suitable for biopsy and, in this instance, only core needle (not 
excisional/incisional) biopsy is allowed.
!
 
 
!
 
 
 
 
 
 
 
∀
 
 
∀
 
 
 
!
 
 
 
!
 
 
 
 
 
 
 
!
 
 
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!
 
 
!
 
 
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 
 Samples
Collection of optional samples for 
 assessment is also part of this study as specified 
in the SoA (Section 1.3) and is subject to agreement to optional consent.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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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
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
8.8
 
 
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!
 
!
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9
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by AstraZeneca or its representatives.
A comprehensive SAP will be prepared before enrollment of the first participant.
9.1
Statistical Hypotheses
No formal hypothesis testing is planned for this study.
9.2
Sample Size Determination
Approximately 500 eligible participants will be treated in the study. Of these, approximately 
250 eligible participants without BM at baseline (Cohort 1) and approximately 250 eligible 
participants with BM at baseline (Cohort 2) will be treated.
 
 
 
 
 
 
 
 
Table 8
 
 
 
 
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Table 9
 
 
 
9.3
Populations for Analyses
The following populations are defined:
Table 10
Populations for Analysis
Population/Analysis 
Set
Description
Enrolled
All participants who sign the ICF.
FAS
All participants who are enrolled in the study and received at least 1 dose of treatment.
SAF
Participants who have received at least 1 dose of treatment.
 analysis 
set
The 
 analysis set includes participants 
 
ICF = informed consent document; FAS = full analysis set; PRO = patient-reported outcomes; SAF = safety 
analysis set.
Additional analysis sets will be included in the SAP as required.
9.4
Statistical Analyses
The SAP will be finalized prior to enrollment of the first participant, and it will include a more 
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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 secondary endpoints.
9.4.1
General Considerations
Summaries of data relating to participants diagnosed with COVID-19, and impact of 
COVID-19 on study conduct (in particular missed visits, delayed or discontinued study 
intervention, and other protocol deviations) may be generated. More detail will be provided in 
the SAP.
Timing of the Primary Analysis
The primary analysis for each cohort will be performed independently. If the enrollment 
completion dates for both cohorts are at least 3 months apart, to avoid delay of primary 
analysis of the earlier completed cohort, separate database locks will be performed.
9.4.2
Efficacy
9.4.2.1
Primary Endpoints
9.4.2.1.1
Calculation or Derivation of Tumor Response Variables
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.
Participants will be assessed by ICR for RECIST 1.1 response of CR, PR, SD, PD, or NE
depending on the status of their disease compared with baseline and previous assessments
(Appendix G). Baseline will be assessed within the 28 days prior to the first dose of study 
intervention. The tumor response endpoints (PFS, ORR, CNS PFS, time to progression, time 
to CNS progression, DoR, and CNS DoR) will then be derived from the scan dates and overall 
visit responses.
-based Assessments
 
 
 
 
 
 
 
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ICR
An ICR of radiological scans will be performed on all participants.
All images will be collected centrally. The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1, CNS RECIST 1.1, and 
and will be adjudicated, if 
required. For each participant, the ICR 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, 
time to progression, and DoR) will then be derived from the scan dates and overall visit 
responses.
Further details of the ICR will be documented in an Independent Review Charter.
9.4.2.1.2
Objective Response Rate
Objective response rate is defined as the proportion of participants who have a confirmed CR 
or confirmed PR, as determined by ICR per RECIST 1.1.
The analysis will include all dosed participants in Cohort 1 as a primary endpoint, and all 
dosed participants in Cohort 2 as a secondary endpoint.
Data obtained from first dose 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 stop 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 estimate of ORR. The estimate and its 95% CI using normal 
approximation will be provided. Additionally, ORR estimate and its 95% CI at selected 
intervals (eg, 6, 9, 12 months) from the first date of dosing will be summarized.
9.4.2.1.3
Progression-Free Survival
The PFS is the primary endpoint for Cohort 2.
The PFS will be defined as the time from the date of the first dose of study intervention until 
the date of objective PD per RECIST 1.1 as assessed by ICR or death (by any cause in the 
absence of progression), (ie, date of event or censoring – date of the first dose of study 
intervention + 1). The analysis will include all dosed participants, regardless of whether the 
participant withdraws from 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 
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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 Day 1, unless they die within 2 visits of baseline (6 weeks plus 1 week allowing for a late 
assessment within the visit window).
Analysis Methods
The primary PFS will be based on the ICR assessment of PD by RECIST 1.1 for all dosed 
participants in Cohort 2.
The PFS will be analyzed by Kaplan-Meier method. Median PFS and its 95% CI using 
Brookmeyer and Crowley method will be provided.
Kaplan-Meier plots of PFS will be presented. 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. The proportion of participants alive and progression-free at selected intervals (eg, 6, 
9, 12 months) from the first date of dosing will be summarized.
9.4.2.1.4
Subgroup Analyses
Subgroup analyses will be conducted by cohort, and descriptive statistics of primary endpoints 
will be provided for T-DXd in the following subgroups of the FAS (but not limited to):
!
!
!
!
!
Other baseline variables may also be assessed if there is clinical justification. The purpose of 
the subgroup analyses is to assess the consistency of treatment effect across expected 
prognostic and/or predictive factors.
The subgroup analyses 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.
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9.4.2.2
Secondary Endpoints
Overall survival, DoT on subsequent therapy, DoR, time to progression, CNS PFS, PFS2, and 
will be analyzed using the same methodology specified for PFS. Detailed censoring 
rules will be specified in SAP.
9.4.2.2.1
Overall Survival
Overall survival is defined as the time from the date of the first dose of study intervention 
until death due to any cause. The analyses will include all dosed participants, regardless of 
whether the participant withdraws from therapy or receives another anticancer therapy. 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.
Overall survival will be analyzed for participants in both cohorts and for the Cohort 2 
subgroups of stable vs active (untreated or progressing) BM at baseline.
9.4.2.2.2
Duration of Treatment on Subsequent Therapy
Duration of treatment on subsequent therapy will be defined as the time from the date of first 
dose of a subsequent therapy until date of the last dose of that therapy.
The analysis will include all dosed participants who start a subsequent line of therapy.
9.4.2.2.3
Duration of Response
Duration of response will be defined as the time from the date of first documented confirmed 
response until date of documented progression per RECIST 1.1 as assessed by ICR or death 
due to any cause.
The analysis will include all dosed participants 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.
9.4.2.2.4
Time to Progression
Time to progression per RECIST 1.1 is defined as the time from the date of the first dose of 
study intervention to the date of documented disease progression and will be summarized 
descriptively in Cohort 1 and Cohort 2.
9.4.2.2.5
PFS2
The PFS2 is defined as time from the first dose of study intervention to second progression 
(the earliest of the progression event subsequent to first subsequent therapy) or death. Second 
progression will be defined according to local standard clinical practice. Following 
discontinuation of study treatment due to disease progression, as determined by the
investigator according to RECIST 1.1 assessment, patients who started on subsequent cancer 
therapy post progression will continue to be followed at the 40 day (+ up to 7 days) follow-up 
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visit, and every 3 months (± 14 days) thereafter for documentation of progression on 
subsequent anticancer therapy.
The PFS2 will be analyzed for participants in both cohorts using the same methodology 
specified for PFS.
9.4.2.2.6
Incidence of New Symptomatic CNS Metastases
The incidence rate is defined as:
	 
  
   	 	 	


 	 
  ℎ
 
    
 
9.4.2.2.7
Time to Next Progression (CNS or Extracranial) or Death
The time to next progression is defined as the time from the date of the first documented 
isolated CNS progression to the date of the next documented disease progression (CNS or 
extracranial) per RECIST 1.1 or death and will be summarized descriptively in patients who 
develop isolated CNS progression, receive local therapy, and continue on protocol therapy.
9.4.2.2.8
Site of Next Progression
Site of next progression will be summarized descriptively in patients who develop isolated 
CNS progression, receive local therapy, continue on protocol therapy, and have a subsequent 
documented disease progression (CNS or extracranial) per RECIST 1.1.
9.4.2.2.9
CNS PFS
The endpoint of CNS PFS is defined as time from the first dose of study intervention to CNS
progression per CNS RECIST 1.1 or death resulting from any cause, whichever occurs first.
The endpoint of CNS PFS will be analyzed for participants in Cohort 2 and for the Cohort 2 
subgroups of stable vs active (untreated or progressing) BM at baseline using the same 
methodology specified for PFS.
9.4.2.2.10
Time to New CNS Lesions
The time to new CNS lesions is defined as the time from the date of the first dose of study 
intervention to the date of documented new CNS lesions, and will be summarized 
descriptively in Cohort 2.
9.4.2.2.11
CNS ORR by CNS RECIST
The CNS ORR is defined as the proportion of participants with measurable BM at baseline 
who have a confirmed CR or confirmed PR of brain lesions, as determined by ICR per CNS 
RECIST 1.1.
The analysis will include all dosed participants in Cohort 2 and for the Cohort 2 subgroups of 
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Data obtained from first dose until brain progression, or the last evaluable assessment in the 
absence of brain progression, will be included in the assessment of ORR, regardless of 
whether the participant withdraws from therapy. Participants who stop
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 estimate of CNS ORR.
9.4.2.2.12
CNS Duration of Response
The CNS DoR will be defined as the time from the date of first documented confirmed CNS 
response until date of documented CNS progression per CNS RECIST 1.1 as assessed by ICR 
or death due to any cause.
The analysis will include all dosed participants in Cohort 2 who have a confirmed response, 
regardless of whether the participants withdraws from therapy, receives another anticancer 
therapy, or clinically progresses prior to RECIST 1.1 progression. This analysis will also be 
conducted for the Cohort 2 subgroups of stable vs active (untreated or progressing) BM at 
baseline.
9.4.2.2.13
Clinical Outcome Assessments
Change in symptoms, functioning, and HRQoL as measured by the EORTC QLQ-C30,
NANO scale, and cognitive tests (for all participants), MDASI brain tumor-specific items (for
participants with BM), and SGRQ-I, (for participants with ILD/pneumonitis) while on 
treatment will be analyzed. Full details of the COA analyses will be provided in the SAP.
9.4.2.3
Exploratory Endpoints
9.4.2.3.1
 
 
 
9.4.2.3.2
 
 
 
 
 
 
 
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9.4.2.3.3
 
 
9.4.2.3.4
 
9.4.2.3.5
 
9.4.2.3.6
 
 
9.4.2.3.7
 
 
 
9.4.2.3.8
 
!
 
!
!
!
!
 
 
 
 
 
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Analysis Methods
 
 
 
 
 
9.4.3
Safety
Safety summaries will be provided using the safety analysis set. 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.
Some safety parameters will also be analyzed in the subgroup of participants who entered the 
study within less than 2 weeks of stereotactic radiation. Subgroup analyses will be described 
in the SAP.
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.
Adverse Events
Full details of AE analyses will be provided in the SAP.
Adverse events, including SAEs, AEs leading to discontinuation, AEs leading to dose 
reductions, and AESIs, will be listed individually by patient and coded using MedDRA 
Preferred Terms from the most recent version of MedDRA that will have been released for 
execution at AstraZeneca.
Adverse events will be presented by system organ class and/or PT, covering number and 
percentage of patients reporting at least one event and number of events where appropriate.
Adverse events occurring prior to start of study treatment, TEAEs, and post-treatment AEs 
will be presented separately.
An overview of AEs will be presented for the number and percentage of patients with any AE, 
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AEs with outcome of death, SAEs, and AEs leading to discontinuation of study treatment, as 
well as AEs leading to study treatment dose interruptions, AEs leading to study treatment dose 
reduction and AEs leading to withdrawal from study as well as the number of individual 
occurrences in those categories.
Separate AE tables will be provided taking into consideration the relationship to study 
treatment as assessed by the Investigator, CTCAE grade, seriousness, death, and events 
leading to discontinuation of study treatment as well as other action taken related to study 
treatment, AESIs, other significant AEs, and timing of events.
An additional table will present the number and percentage of patients with the most common 
AEs. Most common AEs will be defined in the SAP.
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of patients in any treatment group.
Key patient information will be presented for patients with AEs with outcome of death, 
serious AEs, and AEs leading to discontinuation of study treatment.
An AE listing for the safety analysis set will cover details for each individual AE.
The following events are considered treatment-emergent:
!
AEs with an onset date on or after first dose of study treatment
!
Worsening of pre-existing events on or after first dose of study treatment until 47 days 
after last dose of the study treatment
Serious AEs with an onset or worsening 48 days or more after the last dose of study treatment, 
if considered related to the study treatment, are also TEAEs.
Vital Signs
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.
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appropriate.
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.
9.4.4
Other Analyses
9.4.4.1
 status will be assessed for participants in each treatment group according to 
prespecified criteria that may be detailed in the SAP.
 
 
 analyses may be 
described in a separate analysis plan and may be reported outside the CSR in a separate report.
The results of this 
 assessment will be reported either in the CSR itself or as an 
addendum, or separately in a scientific report or publication.
9.4.4.2
Data will be reported outside the CSR (please see Appendix D).
9.5
Interim Analyses 
An interim analysis of the primary endpoint of PFS in Cohort 2 is planned for when 
approximately 125 (50%) eligible participants are enrolled in Cohort 2.
The SAP will describe the planned interim analysis in greater detail.
9.6
Data Monitoring Committees
For details on data monitoring committees, refer to Appendix A 5.
9.6.1
IDMC
An IDMC comprising independent experts will be convened and will meet approximately 
6 months after the study has started or after the first 60 participants have been treated, 
whichever occurs first, to review safety data and make recommendations to continue, amend, 
or stop the study based on safety findings. The committee will meet approximately every 
6 months thereafter.
Full details of the IDMC procedures and processes can be found in the IDMC Charter.
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety.
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9.6.2
Steering Committee
A steering committee has been established to advise the sponsor on aspects of study 
development and implementation. A subgroup of the steering committee will be set up to 
provide a parallel assessment of ILD/pneumonitis risk. This subgroup will make available to 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
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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 Organisations 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 
CRO but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward 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 an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [IB or state other documents] and will notify the IRB/IEC, 
if appropriate according to local requirements.
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 

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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
!
A pre-screen ICF must be signed for patients to permit for tumor tissue sample collection 
for HER2 status testing prior to the 28-day screening window.
!
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 
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.
 
 
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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 
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.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 7
Data Quality Assurance
!
All participant data relating to the study will be recorded on the eCRF 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.

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!
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.
!
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 handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
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, CROs).
!
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 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.
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).

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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 participant signing the pre-screen ICF is considered the first act of recruitment 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 
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 CROs 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 

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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 fulfills 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 abnormality 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 fulfill 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 an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal edema). 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 NCI CTCAE v5 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).
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 an 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 an 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.
!
Rechallenge 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
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention 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, for example, wrong route 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 fridge when it should be at room temperature
!
Wrong participant received the medication (excluding IRT errors)

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!
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
!
Errors related to background and rescue medication, or SoC medication in open-label 
studies, even if an AstraZeneca product
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.

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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 while 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 6.2 Guidance 
Document
LABELING 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/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf)
!
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content

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Appendix D
CCI
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CCI

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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.
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 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
PHL
Aspartate aminotransferase 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.
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 
phosphatase indicating cholestasis, viral hepatitis, another drug.

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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.
!
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.

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!
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 was 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 
whether the AE meets the criteria for an SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.

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!
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:
!
Provides 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 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests that are 
recommended but not mandatory when using a central laboratory. When local laboratories are 
used, this list may be modified according to clinical judgment. Any test result must be 
recorded.

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Hy’s Law lab kit for central laboratories
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HCV DNAa
IgM and IgG anti-HCV
HCV RNAa
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate-deficient transferrinb
Autoimmune hepatitis
Antinuclear antibody
Anti-liver/kidney microsomal antibody
Anti-smooth muscle antibody
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrinb
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive.
b
Carbohydrate-deficient transferrin and transferrin are not available in China. Study teams should amend this list 
accordingly.
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.
E 7
References
FDA Guidance 2009
Food and Drug Administration. Guidance for industry: Drug-induced liver injury: 
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
ASCO/CAP Guidelines on HER2 Testing in Breast Cancer
This protocol will determine HER2 status using guidelines from ASCO (per ASCO/CAP 2018 
guidelines [Wolff et al, 2018]). Per the guidelines, patients are HER2-negative if they have 
IHC 0/1+ or have a FISH ratio of <1.8 or have <4 copies per tumor cell (Table 11).
Table 11
Summary of Guideline Recommendations
Procedure
Recommendation
Optimal algorithm for HER2 
testing
Positive for HER2 is either IHC HER2 3+ (defined as uniform intense 
membrane staining of > 10% of invasive tumor cells) or FISH amplified 
(ratio of HER2 to CEP17 of > 2.2 or average HER2 gene copy number 
> 6 signals/nucleus for those test systems without an internal control 
probe)
Equivocal for HER2 is defined as either IHC 2+ or FISH ratio of 1.8 to 
2.2 or average HER2 gene copy number 4 to 6 signals/nucleus for test 
systems without an internal control probe
Negative for HER2 is defined as either IHC 0-1+ or FISH ratio of < 1.8 or 
average HER2 gene copy number of < 4 signals/nucleus for test systems 
without an internal control probe
These definitions depend on laboratory documentation of the following:
1
Proof of initial testing validation in which positive and negative 
HER2 categories are 95% concordant with alternative validated 
method or same validated method for HER2
2
Ongoing internal QA procedures
3
Participation in external proficiency testing
4
Current accreditation by valid accrediting agency
Optimal FISH testing 
requirements
Fixation for fewer than 6 hours or longer than 48 hours is not 
recommended
Test is rejected and repeated if
!
Controls are not as expected
!
Observer cannot find and count at least 2 areas of invasive tumor
!
> 25% of signals are unscorable due to weak signals
!
> 10% of signals occur over cytoplasm
!
Nuclear resolution is poor
!
Autofluorescence is strong
Interpretation done by counting at least 20 cells; a pathologist must 
confirm that counting involved invasive tumor
Sample is subjected to increased counting and/or repeated if equivocal; 
report must include guideline-detailed elements 
Optimal IHC testing 
requirements
Fixation for fewer than 6 hours or longer than 48 hours is not 
recommended
Test is rejected and repeated or tested by FISH if

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Table 11
Summary of Guideline Recommendations
Procedure
Recommendation
!
Controls are not as expected
!
Artifacts involve most of sample
!
Sample has strong membrane staining of normal breast ducts 
(internal controls)
!
Interpretation follows guideline recommendation
!
Positive HER2 result requires homogeneous, dark circumferential 
(chicken wire) pattern in > 30% of invasive tumor
!
Interpreters have method to maintain consistency and 
competency
Sample is subjected to confirmatory FISH testing if equivocal based on 
initial results
Report must include guideline-detailed elements 
Optimal tissue handling 
requirements
Time from tissue acquisition to fixation should be as short as possible; 
samples for HER2 testing are fixed in neutral buffered formalin for 6 to 48 
hours; samples should be sliced at 5 to 10 mm intervals after appropriate 
gross inspection and margins designation and placed in sufficient volume 
of neutral buffered formalin
Sections should ideally not be used for HER2 testing if cut > 6 weeks 
earlier; this may vary with primary fixation or storage conditions
Time to fixation and duration of fixation if available should be recorded 
for each sample
Optimal internal validation 
procedure
Validation of test must be done before test is offered
Initial test validation requires 25 to 100 samples tested by alternative 
validated method in the same laboratory or by validated method in another 
laboratory
Proof of initial testing validation in which positive and negative HER2 
categories are 95% concordant with alternative validated method or same 
validated method for HER2
Ongoing validation should be done biannually
Optimal internal QA procedures
Initial test validation
Ongoing quality control and equipment maintenance
Initial and ongoing laboratory personnel training and competency 
assessment
Use of standardized operating procedures including routine use of control 
materials
Revalidation of procedure if changed
Ongoing competency assessment and education of pathologists
Optimal external proficiency 
assessment
Participation in external proficiency testing program with at least 2 testing 
events (mailings)/year
Satisfactory performance requires at least 90% correct responses on 
graded challenges for either test
!
Unsatisfactory performance will require laboratory to respond 
according to accreditation agency program requirements

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Table 11
Summary of Guideline Recommendations
Procedure
Recommendation
Optimal laboratory accreditation
On-site inspection every other year with annual requirement for self-
inspection
!
Reviews laboratory validation, procedures, QA results and 
processes, results, and reports
!
Unsatisfactory performance results in suspension of laboratory 
testing for HER2 for that method
CEP17 = chromosome 17 centromere; FISH = fluorescent in situ hybridization; HER2 = human epidermal 
growth factor receptor 2; IHC = immunohistochemistry; QA = quality assurance
Excerpt from Wolff et al, 2007.
The following tables provide additional information from the ASCO/CAP Guidelines for what 
needs to be reported for IHC and FISH (Table 12 and Table 13).
Table 12
Reporting Elements for IHC (Local HER2 Test)
Patient identification information
Physician identification
Date of service
Specimen identification (case and block number)
Specimen site and type
Specimen fixative type
Time to fixation (if available)
Duration of fixation (if available)
Antibody clone/vendor
Method used (test/vendor and if FDA-approved)
Image analysis method (if used)
Controls (high protein expression, low-level protein expression, negative protein expression, internal)
Adequacy of sample for evaluation
Results
Percentage of invasive tumor cells exhibiting complete membrane staining
Uniformity of staining: present/absent
Homogeneous, dark circumferential pattern: present/absent
Interpretation
Positive (for HER2 protein expression); equivocal (FISH will be done and reported); negative (for HER2 
protein expression); not interpretable
Comment
If an FDA-approved method is used, it should be stated; if the FDA-approved method has been modified, 
a statement in the report should be included indicating what modifications were made and that the 
changes have been validated; if the test is not FDA-approved or an FDA-approved test has been modified, 
a clear statement must be made that the laboratory reporting results takes responsibility for test 
performance
IHC = immunohistochemistry; FDA = US Food and Drug Administration; FISH = fluorescent in situ 
hybridization; HER2 = human epidermal growth factor receptor 2.

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Table 13
Reporting Elements for FISH (Local HER2 Test)
Patient identification information
Physician identification
Date of service
Specimen identification (case and block number)
Specimen site and type
Specimen fixative type
Time to fixation (if available)
Duration of fixation (if available)
Probe(s) identification
Method used (specifics of test/vendor and if FDA-approved)
Image analysis method
Controls (amplified, equivocal, and nonamplified, internal)
Adequacy of sample for evaluation (adequate number of invasive tumor cells present)
Results
Number of invasive tumor cells counted
Number of observers
Average number of HER2 signals/nucleus or tile
Average number of CEP17 chromosome probes/nucleus or tile
Ratio of average HER2 signals/CEP17 probe signals
Note: Tile is unit used for image system counting
Interpretation
Positive (amplified); equivocal; negative (not amplified); not interpretable; if IHC is being done because 
of problems with assay or results, this should also be indicated
Comment
If an FDA-approved method is used, it should be noted; if the FDA-approved method has been modified, 
a statement in the report should be included indicating what modifications were made and that the 
changes have been validated; if the test is not FDA-approved or an FDA-approved test has been modified, 
a clear statement must be made that the laboratory reporting results takes responsibility for test 
performance
CEP17 = chromosome 17 centromere; FISH = fluorescent in situ hybridization; FDA = US Food and Drug 
Administration; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry.
Excerpt from: Wolff et al, 2007

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Appendix G
Guidelines for Evaluation of Objective Tumor Response 
Using RECIST 1.1 Criteria
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.
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 14.
Table 14
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
Isotopic bone scan (Scintigraphy)
18F-fluoro-deoxyglucose PET/CT
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), 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 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artifacts (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 

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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. 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:
1
Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred).
2
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.
3
Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function.

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4
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.
Brain scan
For the brain, images from MRI (preferred, unless contraindicated) with and without IV 
contrast, or contrast-enhanced CT, will be collected for all participants at baseline, and for 
participants with BMs at regular (follow-up) intervals during study intervention.
Regularly scheduled follow-up brain scans are mandatory for all patients who were enrolled 
with baseline stable or active BMs. A confirmatory scan for PD is required, no earlier than 4 
weeks and no later than the next regularly scheduled imaging assessment. Patients who 
receive local therapy for isolated CNS progression should maintain their assessment schedule 
(including scans). Patients without BMs require a brain MRI / CT scan at EOT. Additional 
brain scans for subsequent tumor assessments are not required, unless clinically indicated.
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 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 

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presence of new bone lesions.
Isotopic bone scan (scintigraphy)
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. New lesions 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 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 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 uptake2 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 
                                               
2
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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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 
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
All participants in this study will receive a baseline MRI (preferred) or CT scan and will be 
followed up with repeat scans every 6 weeks until Week 48 and every 9 weeks thereafter 
starting at Week 57. For participants suspected or diagnosed with BMs: All participants in this 
study will receive an IV contrast-enhanced MRI (preferred) or IV contrast-enhanced CT of the 
brain at screening/baseline. Regularly scheduled follow-up brain scans are mandatory for all 
participants with baseline stable BMs, while participants without BMs do not need additional 
brain scans for subsequent tumor assessments unless clinically indicated.
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 axis3 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 
                                               
3
The short axis is defined as the longest in-plane axis perpendicular to the long axis.

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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
!
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) 4
!
Previously irradiated lesions 5
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 
                                               
4
Lymph nodes with <10 mm short axis diameter are considered non-pathological and should not be recorded or followed 
as NTLs.
5
Localised 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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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 
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 MRI/CT 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.

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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).
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 15
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.

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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.
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 16
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.

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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.
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 17.
Table 17
RECIST 1.1 Overall Visit Response
Target lesions
Non-target lesions
New lesions
Overall visit response
CR
CR
No
CR
CR
NA
No
CR
NA
CR
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
NA
Non-CR/non-PD
No
SD (non-CR/non-PD)
NE
Non-PD or NE
No
NE
NA
NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Non-CR/Non-PD for overall response if only NTL (no TLs) are present at baseline.
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if ascites 
remains present radiologically.
CR = complete response; NA = not applicable (only relevant if there were no TLs at baseline or NTLs at baseline), 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:

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!
For participants with TLs (at baseline): CR, PR, SD, PD, or NE
!
For participants with NTLs only (at baseline): CR, non-CR/non-PD, PD, or NE
Central imaging
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 ICR. 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. An ICR 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 ICR will be documented in 
an Independent Review Charter.
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 tumors: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.

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Appendix H
 
Introduction
 
 
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Summary of the Response Criteria for CNS Metastases
Response criteria for 
 are summarized in Table 18.
Table 18
Response Criteria for CNS Metastases per 
CR
PR
SD
PD
TL
NTL
NLb
 
CR = complete response; NL = new lesion; NTL = non-target lesion; PD = progression of disease; PR = 
partial response; SD = stable disease; TL = target lesion.
a
Progression occurs when this criterion is met.
b
 
 
 
 
c
 
Central imaging
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 ICR. 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. An ICR 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 ICR will be documented in 
an Independent Review Charter.
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Appendix I
Contraception Requirements
Contraception requirements for this study are as follows.
I 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.
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 19). They should have been stable on their chosen 
method of birth control for a minimum of 3 months before entering the study 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. 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 T-DXd administration.  Preservation of ova may be considered prior to starting the study 
treatment.
I 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 (4 months after the last dose of study intervention) to prevent pregnancy in a partner.

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Not engaging in sexual activity for the duration of the study and drug washout period is an 
acceptable method of contraception provided that it is the 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 this period. Preservation of sperm should be considered prior to starting the study 
treatment.  
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 19).
I 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 19. 
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).
Hormonal methods of contraception are not advised in a breast cancer population and should 
only be used by the female partners of male participants.

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Table 19
Highly Effective Methods of Contraception (<1% Failure Rate)
Non-Hormonal Methods
Hormonal Methods
(Female Partners of Male Participants Only)
•
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®) 
•
Levonorgestrel-releasing intrauterine system 
(eg, Mirena®) 
•
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

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Appendix J
Patient-reported Outcomes
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Appendix K
Guidance Regarding Restricted, Prohibited, and Permitted 
Concomitant Medications
The use of any natural/herbal products or other “folk remedies” should be discouraged, but 
use of these products, as well as use of all vitamins, nutritional supplements, and all other 
concomitant medications must be recorded in the eCRF.
Restricted, prohibited, and permitted concomitant medications/therapies are described in 
Table 20, Table 21, and Table 22. Refer also to the dose modification guidelines for 
management of study intervention-related toxicities in Section 6.6. Participants must be 
instructed not to take any medications, including over-the-counter products, without first 
consulting with the investigator.
Table 20
Restricted Medications/Therapies
Medication/class of drug/therapy
Usage (including limits for duration permitted and 
special situations in which it is allowed)
Tobacco products, e-cigarettes and vaping
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.
Hematopoietic growth factors
May be used for prophylaxis or treatment based on the 
clinical judgment of the investigator.
Dietary supplements, medications not prescribed 
by the investigator, and alternative/complementary 
treatments
Concomitant use is discouraged, but not prohibited.
Prophylactic or supportive treatment of study
drug-induced AEs
As per investigator’s discretion and institutional 
guidelines.
AE = adverse event; eCRF = electronic case report form.
With the exception of medications that are under investigation in the study (eg, SoC, 
comparators, or combination therapies), the medications in Table 21 are considered 
exclusionary during the study. The sponsor must be notified if a participant receives any of 
these during the study.

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Table 21
Prohibited Medications/Therapies
Prohibited medication/class of drug/therapy
Usage
Chloroquine or hydroxychloroquine
Concomitant treatment with chloroquine or 
hydroxychloroquine is not allowed during the study 
treatment. If treatment with chloroquine or 
hydroxychloroquine treatment is absolutely required 
for COVID-19, study intervention must be interrupted. 
If chloroquine or hydroxychloroquine is administered, 
then a washout period of at least 14 days is required 
before restarting study intervention (see Appendix L
for further details).
Any concurrent chemotherapy, anticancer study 
intervention or biologic, radiotherapy (except 
palliative radiotherapy to areas other than chest, 
after consultation with the study physician) or 
hormonal therapy for cancer treatment 
Must not be given concomitantly while the participant
is on study intervention.
Concurrent use of hormones for noncancer-related 
conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.
Live vaccine during the study and up to 30 days 
after the last dose of study treatment
Patients who have received live, attenuated vaccine 
within 30 days prior to the first dose of T-DXd will be 
excluded.

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Table 21
Prohibited Medications/Therapies
Prohibited medication/class of drug/therapy
Usage
Immunosuppressive medications, including 
corticosteroids
T-DXd cannot be administered when the participant is 
taking immunosuppressive medications, including 
corticosteroids with the exception of:
•
short-term courses (< 2 weeks)
•
low to moderate dose
•
long-term, alternate-day treatment with short-
acting preparations
•
maintenance physiological doses (replacement 
therapy)
•
administered topically (skin or eyes), by aerosol, 
or by intra-articular, bursal, or tendon injection
Treatment with corticosteroids to prevent or treat 
hypersensitivity reactions to radiographic contrast 
agents is allowed. A temporary period of steroid 
treatment will be allowed for different indications after 
discussion with the study physician (eg, chronic 
obstructive pulmonary disease, radiation, nausea, etc).
Participants with bronchopulmonary disorders may use 
bronchodilators if only administered intermittently.
Use of immunosuppressive medications for the 
prevention and management of study treatment-related 
AEs or in patients with contrast allergies is acceptable.
Immunosuppressive medications also include drugs 
like methotrexate, azathioprine, and tumor necrosis 
factor-alpha blockers.
Treatment with corticosteroids to manage neurological 
symptoms in patients with BMs is permitted. The 
lowest effective dose should be used.
AE = adverse event; COVID-19 = coronavirus 2019-nCoV; T-DXd = trastuzumab deruxtecan.
Table 22
Supportive Medications/Therapies
Supportive medication/class of drug/therapy
Usage
Hormones for noncancer-related conditions 
(eg, insulin for diabetes and hormone replacement 
therapy) 
Concurrent use is acceptable.
Prophylactic anti-emetic agents
See Table 23
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate AE event
management, except for those medications 
identified as “prohibited,” as listed above 
To be administered as prescribed by the investigator 
except for those medications identified as “prohibited,” 
as listed in Table 21

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Table 22
Supportive Medications/Therapies
Supportive medication/class of drug/therapy
Usage
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy, 
etc]) except for those medications identified as 
“prohibited,” as listed above
Should be used, when necessary, for all participants 
except for those medications identified as “prohibited,” 
as listed in Table 21
Corticosteroids and/or bisphosphonates for the 
treatment of bone and CNS metastases and for the 
treatment of specific adverse drug reactions (refer 
to Toxicity Management Guidelines in 
Appendix O.
Permitted
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
Required for management of other medical 
conditions
As required except for those identified as “prohibited,” 
as listed in Table 21
AE = adverse event; CNS = central nervous system; NK1 = neurokinin 1; T-DXd = trastuzumab deruxtecan; 
5-HT3 = 5-hydroxytryptamine 3.
Table 23
NCCN Guidelines for the prevention of acute and delayed emesis by 
moderate emetic risk parenteral anticancer agents
DAY 1: Select treatment option D, E, or F.
All treatment options are category 1 and should be 
started before anticancer therapya
DAYS 2, 3:
Treatment option D, use the following combination:
!
5-HT3 RA (choose one):
∀
Dolasetron 100mg PO once
∀
Granisetron 10mg SQ onceb (preferred), or 
2 mg PO once, or 0.01 mg/kg (max 1 mg) 
IV once, or 3.1 mg/24h transdermal patch 
applied 24-48 h prior to first dose of 
anticancer therapy.
∀
Ondansetron 16-24 mg PO once or 8-16mg 
IV once
∀
Palonosetron 0.25 mg IV once (preferred)
!
Dexamethasone 12 mg PO/IV oncec,d
Treatment option D:
!
Dexamethasone 8 mgc,d PO/IV daily on days 2, 
3 OR
!
5-HT3 RA monotherapye:
∀
Granisetron 1-2 mg (total dose) PO daily 
or 0.01 mg/kg (max 1 mg) IV daily on 
days 2 and 3
∀
Ondansetron 8 mg PO twice daily or 
16 mg PO daily or 8-16 mg IV daily on 
days 2, 3
∀
Dolasetron 100 mg PO daily on days 2, 3
Treatment option E, use the following combination:f
!
Olanzapine 5-10 mg PO onceg
!
Palonosetron 0.25 mg IV once
Treatment option E:
!
Olanzapine 5-10 mg PO daily on days 2, 3g

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Table 23
NCCN Guidelines for the prevention of acute and delayed emesis by 
moderate emetic risk parenteral anticancer agents
DAY 1: Select treatment option D, E, or F.
All treatment options are category 1 and should be 
started before anticancer therapya
DAYS 2, 3:
!
Dexamethasone 12 mg PO/IV oncec,d
Treatment option F, use the following combination:f
!
NK1 RA (choose one):
∀
Aprepitant 125 mg PO once
∀
Aprepitant injectable emulsion 130 mg IV 
onceh
∀
Fosaprepitant 150 mg IV oncei
∀
Netupitant300 mg / palonosetron 0.5 mg 
(available as fixed combination product 
only) PO oncei
∀
Fosnetupitant 235 mg / palonosetron 
0.25 mg (available as fixed combination 
product only) IV oncei
∀
Rolapitant 180 mg PO oncej
!
5-HT3 RA (choose one):k,l
∀
Dolasetron 100mg PO once
∀
Granisetron 10mg SQ onceb, or 2 mg PO 
once, or 0.01 mg/kg (max 1mg) IV once, 
or 3.1 mg/24h transdermal patch applied 
24-48 h prior to first dose of anticancer 
therapy.
∀
Ondansetron 16-24 mg PO once or 
8-16 mg IV once
∀
Palonosetron 0.25 mg IV once
!
Dexamethasone 12 mg PO/IV oncec,d
Treatment option F:
!
Aprepitant 80 mg PO daily on days 2, 3 (if 
aprepitant PO used on day 1)
!
± Dexamethasone 8 mgc,d PO/IV daily on 
days 2, 3
a
See NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®) for Antiemesis, Principles of 
Managing Multiday Emetogenic Chemotherapy (AE-A)
b
Granisetron extended-release injection is a unique formulation of granisetron using a polymer-based drug 
delivery system. This formulation is specifically intended for subcutaneous administration and is NOT 
interchangeable with the intravenous formulation. Granisetron extended-release injection has an extended 
half-life and should not be administered at less than 1-week intervals.
c
Emerging data and clinical practice suggest dexamethasone doses may be individualized. Higher doses may 
be considered, especially when an NK1 RA is not given concomitantly. Lower doses, given for shorter 
durations, or even elimination of dexamethasone on subsequent days (for delayed nausea and emesis 
prevention) may be acceptable for non-cisplatin regimens based on patient characteristics. If dexamethasone 
eliminated on subsequent days for delayed nausea and emesis prevention, consider other alternative 
antiemetics (eg. Olanzapine). See NCCN Guidelines®, Antiemesis, Discussion.
d
Use of corticosteroids premedications should be avoided with cellular therapies. See NCCN Guidelines®, 
Antiemesis, Pharmacologic Considerations for Antiemetic Prescribing (AE-B).

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e
No further 5-HT3 therapy required if palonosetron or granisetron extended-release injection administered, 
or if granisetron transdermal patch applied, on day 1
f
A 3-drug prophylactic regimen (E or F) is recommended for select patients with additional patient-related 
risk factors (See AE-1) or previous treatment failure with a corticosteroid + 5-HT3 RA alone.
g
Data suggests that a 5 mg dose of olanzapine is efficacious. Consider this dose especially for elderly or 
oversedated patients. Hashimoto H, et al. Lancet Oncol 2020;21:242-49. See NCCN Guidelines®, 
Antiemesis, Pharmacologic Considerations for Antiemetic Prescribing (AE-B).
h
Aprepitant injectable emulsion is a unique formulation of aprepitant and is NOT interchangeable with the 
intravenous formulation of fosaprepitant.
i
Available as a fixed combination product only.
j
Rolapitant has an extended half-life and should not be administered at less than 2-week intervals.
k
If netupitant/palonosetron or fosanetupitant/palonosetron fixed combination product used, no further 5-HT3 
RA is required.
l
When used in combination with an NK1 RA, there is no preferred 5-HT3 RA. See NCCN Guidelines®, 
Principles of Managing Multiday Emetogenic Chemotherapy (AE-A).

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Appendix L
Instructions Related to COVID-19
L 1
Eligibility, Concomitant Medication, and T-DXd Dose 
Modification Relevant to COVID 19
Exclusion Criteria
The following exclusion criterion has been added (see Section5.2):
!
Prior exposure, without adequate treatment washout period before enrollment, to 
chloroquine/hydroxychloroquine: < 14 days
Prior and Concomitant Medications
In addition to Section 6.5, the following text is relevant for participants with COVID-19:
Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the 
study treatment. If treatment with chloroquine or hydroxychloroquine treatment is absolutely 
required for COVID-19, study intervention must be interrupted. If chloroquine or 
hydroxychloroquine is administered, then a washout period of at least 14 days is required 
before restarting study intervention.
Dose Modification Criteria
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Dose 
modifications will be based on the worst CTCAE grade. All interruptions or modifications 
must be recorded on the AE and drug administration eCRFs. Please use CTCAE v5.0 general 
grading criteria to evaluate COVID-19. All dose modifications (discontinuation, interruptions,
or reductions) must be recorded on the AE and drug administration eCRFs.
Dose Modification Criteria for Suspected or Confirmed COVID-19
In addition to Section 6.6, the following text is relevant for participants with COVID-19:
Dose modification criteria for suspected or confirmed COVID-19
If COVID-19 infection is suspected, delay T-DXd and rule out COVID-19 per local guidance.
!
If COVID-19 is ruled out, follow dose modification and management guidelines as 
outlined in the study protocol.
!
If COVID-19 is confirmed or diagnosis is suspected after evaluation, follow dose 
modification as outlined below and manage COVID-19 per local guidance until recovery 
of COVID-19. Recovery is defined as no signs/symptoms, at least 1 negative reverse 

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transcriptase-PCR test result6, and nearly or completely resolved chest CT findings). Then 
follow below dose modifications:
Table 24
COVID-19 Dose Modification Criteria
COVID-19 Worst Toxicity NCI CTCAE
Version 5.0 Grade (unless otherwise 
specified)
Schedule Modification for T-DXd
Grade 1
Resume T-DXd at the same dose.
Grade 2
Resume T-DXd at the same dose if chest CT findings are 
completely resolved.
Reduce by 1 dose level if chest CT findings are nearly 
resolved.
Grade 3
Reduce by 1 dose level if chest CT findings are completely 
resolved.
Discontinue study intervention. if chest CT findings are not
completely resolved.
Grade 4
Discontinue study intervention.
a
Closely monitor signs/symptoms after resuming T-DXd, initially with a phone call every 3 days for the first 
week, and then with a weekly phone call thereafter, for a total of 6 weeks.
COVID-19 = coronavirus 2019-nCoV; CT = computed tomography; CTCAE = Common Terminology Criteria 
for Adverse Events; NCI = National Cancer Institute; T-DXd = trastuzumab deruxtecan.
!
In addition to the recommendations outlined in the table above, Investigators may 
consider dose modifications of the study drug according to the participant’s condition and 
after discussion with the study Medical Monitor or designee.
!
If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline.
L 2
Benefit Risk Considerations for COVID-19
The emergence of COVID-19 presents a potential safety risk for participants. Several risk 
mitigation factors have been implemented in this study. 
Moreover, with the outbreak of COVID-19, there is the potential for increased use of 
chloroquine and hydroxychloroquine to treat severely symptomatic participants, or even for 
prophylactic use. Chloroquine and hydroxychloroquine have shown in vitro to substantially 
affect the pH of the lysosome, a key intracellular compartment involved in the trafficking and 
payload release of T-DXd. As it is unknown whether chloroquine/hydroxychloroquine may 
                                               
6 If PCR testing is not available, the participant must not have any sign/symptoms for at least 2 weeks, in addition 
to meeting the requirement for chest CT imaging

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affect the safety and efficacy of T-DXd, to be eligible for this clinical trial, use of chloroquine 
and hydroxychloroquine treatment must be completed at least 14 days prior to the first dose of 
T-DXd (see CSP Section 5.2). During study treatment, chloroquine and hydroxychloroquine 
are considered prohibited concomitant medications. However, in case treatment with 
chloroquine or hydroxychloroquine treatment is absolutely required for COVID-19, study 
intervention must be interrupted. After chloroquine or hydroxychloroquine is administered for 
COVID-19, then a washout period of at least 14 days is required before restarting study 
intervention.
Lastly, due to the potential overlapping impact of T-DXd and COVID-19 on the lung, the 
sponsor has also provided in this appendix, a dose modification and management plan for 
participants with confirmed or suspected COVID-19 who are being treated with T-DXd.
With these measures in place, it is considered the anticipated potential benefits for the 
participants enrolled in this study outweigh the potential risks.

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Appendix M Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: 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
agreement from the sponsor.
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 Sections 8.1 to 8.8. 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.
Rescreening of Participants to Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. 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 commencing of dosing with study intervention. If this delay is outside the 
screening window specified in Table 1, the participant will need to be rescreened to reconfirm 
eligibility before commencing study procedures. This will provide another opportunity to 
rescreen a participant in addition to that detailed in Section 5.4. The procedures detailed in
Section 1.3 must be undertaken to confirm eligibility using the same identification number as 
for the participant.
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service may visit the participant’s home or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the CSP.

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Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix and the associated study instruction manual for mitigation due to civil crisis, 
natural disaster or public health crisis, 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 AEs, concomitant medication, to be reported and documented.
At-home or Remote Location Study Intervention Administration Instructions
If a site visit is not possible, at-home or remote location administration of study intervention
may be performed by a qualified HCP, provided this is acceptable within local
regulation/guidance. The option of at home or remote location study intervention
administration ensures participants safety in cases of a pandemic where participants may be at 
increased risk by traveling to the site/clinic. This will also minimize interruption of study 
intervention administration during other study disruptions, eg, site closures due to natural 
disaster.
At-home or Remote Location Study Intervention Administration by a Qualified HCP or 
TPV Service
A qualified HCP from the study site or TPV service may administer the study intervention at 
the participant’s home or other remote location according to the CSP and the study instruction 
manual for mitigation due to civil crisis, natural disaster, or public health crisis, and if allowed 
by local SOPs, as applicable. All necessary supplies and instructions for administration and 
documentation of study intervention administration will be provided. Additional information 
related to the visit can be obtained via a telemedicine or home visit.
At-home or Remote Location Study Intervention Administration by the Participant or
His/Her Caregiver
Prior to at-home or remote location study intervention administration the investigator must 
assess the participant or his/her caregiver to determine whether they are appropriate for at
home or remote location administration of study intervention. Once the participant or his/her
caregiver is deemed appropriate for at-home or remote location administration, he/she must
receive appropriate training. All necessary supplies and instructions for administration and
documentation of study intervention administration will be provided. More information 
related to the visit can be obtained via a telemedicine or home/remote visit.
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified
HCP from the study site or TPV service in the source documents, or by the participant 
themselves.

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Appendix N
Guidance for Management of Participants with Drug-
Induced ILD/Pneumonitis
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Appendix O
Toxicity Management Guidelines
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 25
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Table 25
Toxicity Management Guidelines for T-DXd
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Table 25
Toxicity Management Guidelines for T-DXd
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Table 25
Toxicity Management Guidelines for T-DXd
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Table 25
Toxicity Management Guidelines for T-DXd
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Table 25
Toxicity Management Guidelines for T-DXd
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Table 25
Toxicity Management Guidelines for T-DXd
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Table 25
Toxicity Management Guidelines for T-DXd
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Appendix P
Family History and Exposure History for Interstitial Lung 
Disease 
 
 
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Appendix Q
Abbreviations
Abbreviation or Special 
Term
Explanation
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BM
brain metastasis
CAP
College of American Pathologists
CBC
complete blood count
CEP17
chromosome 17 centromere
CHF
congestive heart failure
CI
confidence interval
CNS
central nervous system
COA
clinical outcome assessment
COPD
chronic obstructive pulmonary disorder
COVID-19
coronavirus 2019-nCoV
CR
complete response
CRF
case report form
CrCL
calculated creatinine clearance
CRO
contract research organization
CSF
cerebrospinal fluid
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAR
drug-antibody ratio
DCO
data cut-off
DILI
drug-induced liver injury
DLCO
diffusion capacity of the lungs for carbon monoxide
DNA
deoxyribonucleic acid 
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Abbreviation or Special 
Term
Explanation
DoR
duration of response
DoT
duration of treatment
DXd
MAAA-1181a
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EORTC
European Organisation for Research and Treatment of Cancer
ePRO
electronic patient-reported outcome
EOT
end-of-treatment
ER
estrogen receptor
ESMO
European Society for Medical Oncology
FAS
Full Analysis Set
FDA
Food and Drug Administration
FFPE
formalin-fixed and paraffin-embedded
FISH
fluorescent in situ hybridization
GCP
Good Clinical Practice
GGFG
Gly-Gly-Phe-Gly
HBc
hepatitis B core antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCP
health care professional 
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HL
Hy’s Law
HR
hormone receptor
HRCT
high-resolution computed tomography
HRQoL
health-related quality of life
5-HT3
5-hydroxytryptamine 3
IATA
International Airline Transportation Association
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Abbreviation or Special 
Term
Explanation
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICR
Independent Central Review
iCRO
imaging Contract Research Organization
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IHC
immunohistochemistry
International coordinating 
investigator
If a study is conducted in several countries the international coordinating 
investigator is the investigator coordinating the investigators and/or activities 
internationally
ILD
interstitial lung disease
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
LMD
leptomeningeal disease
LV
left ventricle
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MBC
metastatic breast cancer
MDASI
MD Anderson Symptom Inventory
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
MI
myocardial infarction
mPFS
median progression-free survival
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NANO
Neurologic Assessment in Neuro-oncology
NCI
National Cancer Institute
NE
not evaluable
NK1
Neurokinin 1
NL
new lesion
NTL
non-target lesion
NYHA
New York Heart Association
ORR
objective response rate

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Abbreviation or Special 
Term
Explanation
OS
overall survival
PCR
polymerase chain reaction
PD
progression of disease
PET
positron emission tomography
PFS
progression-free survival
PFS2
time to second progression or death
PgR
progesterone receptor
PHL
Potential Hy’s Law
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcome
PT
preferred term
q3w
every 3 weeks
QLQ-C30
30 item core quality of life questionnaire
QoL
quality of life
QTc
corrected QT interval
QTcF
QT interval corrected by Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
stable disease
SGRQ-I
St. George’s Respiratory Questionnaire – idiopathic pulmonary fibrosis version
SoA
Schedule of Activities
SoC
Standard of care
SOP
standard operating procedure
SpO2
peripheral capillary oxygen saturation
TBL
total bilirubin
T-DM1
trastuzumab emtansine
T-DXd
trastuzumab deruxtecan
TEAE
treatment-emergent adverse event
TKI
tyrosine kinase inhibitor
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Abbreviation or Special 
Term
Explanation
TL
target lesion
TMG
toxicity management guideline
TOPO-1
topoisomerase I
TPV
telephone visit
ULN
upper limit of normal
US
United States
w/v
weight per volume

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Appendix R
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 1 08-April-2021
This amendment is considered 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 European Union.
Overall Rationale for the Amendment:
This amendment was prepared to provide further explanation regarding the possibility to 
continue treatment after isolated CNS progression and 
 
, to update safety monitoring requirements in line 
with requirements of the T-DXd program, to provide clarifications and complete information, 
and to correct minor inconsistencies.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
1.1 Synopsis
Revisions were made to study 
secondary objectives, description 
of overall design, participant 
population, study intervention 
and statistical methods.
The synopsis was revised to 
align with Sections 3, 4.1, 5, 6.1, 
7.1, and 9.2.
Substantial
1.3 Schedule of 
activity
Never previously HER2 positive 
patients were removed from 
examples of study candidates. 
This example was unlikely to 
happen and could be confusing.
Non-substantial
Instruction in case of abnormal 
ECG was added as footnote e.
This clarification is in line with 
Section 6.6.1.
Non-substantial
Incorrect instruction (previously 
footnote e) to conduct SpO2
assessments at end of infusion on 
Day 1 of each cycle was 
removed.
This correction is in line with 
Section 8.2.5.2.
Substantial
Instruction clarifying the time 
window for clinical laboratory 
tests at screening was added as 
footnote g.
This clarification is in line with 
inclusion criterion 10 and 
Section 8.2.4.
Non-substantial
The description of mandatory 
tumor samples was revised, as 
only 1 tumor sample is 
mandatory (from archival tissue 
or fresh biopsy).
This revision was made in line 
with revisions in Section 8.6.1.
Substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
 
 
 
Non-substantial
It was clarified that tumor 
imaging is performed until 
RECIST 1.1-defined radiological 
PD.
This clarification was added in 
line with Section 8.1.1 and 
Appendix G.
Non-substantial
The timing of brain scans was 
aligned to other tumor scans and 
footnote k (previously footnote j) 
was revised accordingly.
This correction was made to 
allow consistent assessment of 
tumor response in participants 
with and without BMs.
Substantial
Isotopic bone scans were listed 
under a separate row from tumor 
imaging.
This revision was made to 
improve clarity and in line with 
Section 8.1.1 and Appendix G
Non-substantial
The starting point of the 
12-weekly cognitive tests was 
added.
This revision was made to 
improve clarity.
Substantial
NANO scale assessments on 
Day 8 and Day 15 of Cycle 1 
were removed.
This was a correction. Day 8 and 
Day 15 assessment were 
previously included in error.
Substantial
MDASI ILD symptom-specific 
items were renamed MDASI lung 
cancer (ILD symptom-specific 
items)
This revision was in line with 
revisions in Section 8.1.5.2.
Non-substantial
2.2 Background
Treatments evaluated in the 
HER2CLIMB study were added 
in the summary of the study. 
This was added for clarity.
Non-substantial
Conditional marketing 
authorization in the European 
Union was added.
This was added for completeness 
as the information is pertinent for 
European sites.
Non-substantial
2.3.1 Risk 
assessment
The description of potential and 
identified risks was updated.
These updates were made in 
alignment with the latest 
available safety information for 
the T-DXd program.
Substantial
2.3.3 Overall 
Benefit/Risk 
Conclusion
The description of potential and 
identified risks was updated.
These updates were made in 
alignment with the latest 
available safety information for 
the T-DXd program and in line 
with revisions in section 2.3.1.
Substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Information that vaccines against 
COVID-19 were not tested when 
given with T-DXd was added.
This information was added to 
clarify that effect of T-DXd on 
the effectiveness and safety of 
COVID-19 vaccines is unknown.
Substantial
3 Objectives and 
endpoints
It was specified that RECIST and 
CNS RECIST primary/secondary 
endpoints are assessed per ICR.
This revision was a clarification 
in line with Section 9.4.2.
Non-substantial
The PFS, ORR, and DoR 
endpoints (CNS RECIST and 
) related to brain/CNS 
lesions were renamed.
This revision was made to 
improve consistency in wording.
Substantial
Local therapy for patients with 
BMs is no longer mentioned 
under the second secondary 
objective.
This information is not pertinent 
for the study objective.
Non-substantial
Safety endpoints were revised to 
include standard safety 
parameters in addition to 
study-specific AE analysis.
The revisions were made to 
provide a more general 
description of safety analysis in 
line with Sponsor standards.
Substantial
The objective to investigate 
immunogenicity of T-DXd was 
revised and 
 
Collected samples will be 
 
 
Substantial
 
 
This revision was made to 
improve consistency.
Substantial
MDASI ILD symptom-specific 
items were renamed MDASI lung 
cancer (ILD symptom-specific 
items)
This revision was in line with 
revisions in Section 8.1.5.2.
Non-substantial
4.1 Overall 
design
The description of the study 
population was revised and 
simplified.
Text was deleted to avoid 
redundancy with Section 5 and 
revisions were in line with 
revisions to inclusion criterion 8.
Non-substantial
4.4 End of study 
definition
Statement regarding patient 
withdrawal if the study is stopped 
was deleted. 
This information is not pertinent 
for the end of study definition.
Non-substantial
Reference to Section 9.2 was 
added for the definition of final 
DCO.
This was added for clarity.
Non-substantial
5 Study 
population
The overall description of the 
study population was revised.
Revisions were in line with 
revisions to inclusion criterion 8.
Non-substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
5.1 Inclusion 
criteria
The description of screening 
brain scans in inclusion 
criterion 3 was reworded.
This revision was made for 
clarity and consistency with 
brain imaging methods in 
Section 8.1.1.
Substantial
Inclusion criterion 5 was 
reworded to clarify that the 
criterion is related to the washout 
period required between 
radiotherapy and start of study 
treatment.
This revision was made to 
improve clarity.
Substantial.
Inclusion criterion 7 to provide 
mandatory tumor sample was 
modified.  
This revision was in line with 
revisions in Section 8.6.1.
Substantial
Inclusion criterion 8 was 
reworded and split into 8(a) for 
evidence of disease progression 
after anti-HER2 treatments and 
8(b) for maximum number of 
lines of therapy in the metastatic 
setting. 
This revision was made to 
improve clarity and does not 
change the requirements.
Non-substantial
Inclusion criterion 9 was 
reworded and split into 9(a) for 
measurable disease and 9(b) for 
non-measurable disease.
This revision was made to 
improve clarity and does not 
change the requirements.
Non-substantial
Under inclusion criterion 10, 
calculation of CrCL is no longer 
optional.
This revision was made for 
alignment with other studies in 
the T-DXd program.
Substantial
Under inclusion criterion 15 for 
female contraception 
requirement, duration of 
abstinence was changed to 
7 months, in line with duration of 
contraception and further 
guidance was added as to when 
abstinence is an acceptable 
method of contraception.
This was a correction of an error 
with the duration of abstinence 
and further clarifications are in 
line with Appendix I..
Non-substantial
Under inclusion criterion 15 for 
female contraception 
requirement, restrictions and 
recommendations regarding 
donation, use and preservation of 
ova was added.
These revisions are in line with 
Appendix I and safety 
recommendations for studies in 
the T-DXd program.
Substantial

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Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
Under inclusion criterion 16 for 
male contraception requirement, 
further guidance was added as to 
when abstinence is an acceptable 
method of contraception.
The added guidance is in line 
with Appendix I.
Non-substantial
Under inclusion criterion 16 for 
male contraception requirement, 
preservation of sperm prior to 
starting study treatment was 
added.
This revision is in line with 
safety recommendations for 
studies in the T-DXd program 
and added in response to MHRA.
Substantial
5.2 Exclusion 
criteria
Exclusion criterion 4 (related to 
the presence of pleural effusion, 
ascites, or pericardial effusion) 
was deleted.
This criterion was not necessary 
because it is already addressed 
under broader lung criteria listed 
under exclusion criterion 18(a), 
previously numbered as 19 (a).
Substantial
Exclusion criterion 6 (previously 
criterion 7) was revised to 
exclude participants with 
persistent toxicities (CTCAE 
Grade >1) as Grade 2 toxicities 
can be significant.
This revision is in line with 
safety recommendations for 
studies in the T-DXd program 
and included in response to 
MHRA.
Substantial
The description of screening 
brain scans in exclusion 
criterion 7 (previously 
criterion 8) was reworded.
This revision was made for 
consistency with brain imaging 
methods in Section 8.1.1.
Substantial
Inclusion criterion 9 (previously 
criterion 10) regarding hepatitis B 
or C infection was revised.
This revision is in line with 
safety recommendations for 
studies in the T-DXd program, 
for clarification of which patients 
would be considered eligible.
Substantial
6.1 Study 
intervention 
administered
Duration of treatment was 
updated in alignment with 
discontinuation criteria.
This revision was made for 
consistency.
Non-substantial
6.3 Measures to 
minimize bias: 
randomization 
and blinding
Description of prescreening and 
collection of the mandatory 
tumor sample was revised.
This revision was in line with 
revisions to Section 8.6.1.
Substantial
6.6 Dose 
modification
Review of potential 
ILD/pneumonitis by the medical 
monitor and safety physician was 
described further.
This revision was added for 
clarity and for consistency with 
Section 8.2.
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
7.1 
Discontinuation 
of study 
intervention
Description that all study 
intervention should be returned 
by the participant was deleted.
This revision is a correction. The 
deleted statement is not 
applicable to the study, as all 
treatments are administered at 
the site.
Non-substantial
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial
8.1 Efficacy 
assessments
Instruction to rule out COVID-19 
and other infective 
lymphadenopathies when 
assessing whether a progression 
event occurred was added.
COVID-19 and other infective 
lymphadenopathies have a 
potential to bias the assessment 
of disease progression.
Substantial
Clarification was added regarding 
the inclusion of CNS TLs for the 
assessment of tumor response 
endpoints per RECIST and CNS 
RECIST in patients with baseline 
BMs. 
This revision was added to 
improve clarity.
Substantial
For MDASI, the 3 ILD 
symptom-specific items were not 
modified, but it was clarified that 
they are taken from the lung 
cancer module instead of the 
MDASI symptom library.
This description is more specific.
Non-substantial
For other COAs, an at-home 
pulse oximetry device is to be 
provided to participants 
diagnosed with ILD/pneumonitis 
and not all participants. 
Clarification was added that pulse 
oximetry while resting should be 
evaluated after at least 10 minutes 
of rest.
At-home pulse oximetry is only 
performed after diagnosis of 
ILD/pneumonitis.
The clarification was added to 
ensure SpO2 is measured 
consistently under the same 
resting conditions.
Substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
For the administration of ePRO 
questionnaires, clarification was 
added that these should only be 
completed by participants if a 
linguistically validated version is 
available in the language of their 
country of residence.
Possibility that participants will 
complete questionnaires using 
their own device was deleted.
Completing the questionnaire 
will not be possible if a 
linguistically validated version is 
not available.
All participants will be provided 
a handheld device to complete 
questionnaires.
Substantial
8.2 Safety 
assessments
For pulmonary assessment at the 
site, it was clarified that pulse 
oximetry should be evaluated 
after at least 10 minutes of rest.
This clarification was added to 
ensure SpO2 is measured 
consistently under the same 
resting conditions.
Substantial
For pulmonary assessments, 
DLCO and HRCT at screening 
were changed to mandatory 
rather than strongly encouraged if 
feasible. 
This is in line with necessary 
assessments for studies in the 
T-DXd program.
Substantial
Collection of additional samples, 
safety evaluations, family history 
and exposure history for ILD was 
added in case of potential 
ILD/pneumonitis.
The additional data is necessary 
for the medical evaluation of 
potential ILD /pneumonitis.
Substantial
Review of potential 
ILD/pneumonitis cases by an ILD 
Advisory Committee was added.
This review supports the 
assessment of potential 
ILD/pneumonitis cases.
Substantial
8.3 Adverse 
events and 
serious adverse 
events
Clarification was added that 
diagnosis of the undesirable 
clinical outcome of ‘LV 
dysfunction’, a valid or 
qualifying reduction of LVEF (as 
measured by MUGA or ECHO) 
should be confirmed and included 
in the AE report.
This is in line with the reporting 
of LV dysfunction for studies in 
the T-DXd program.
Substantial
A description of predefined PTs 
for surveillance of 
ILD/pneumonitis was added.
This is in line with the 
surveillance of ILD/pneumonitis 
for studies in the T-DXd
program.
Substantial
A description of predefined PTs 
for surveillance of LVEF 
decrease was added.
This revision is in line with the 
surveillance of LVEF decrease 
for studies in the T-DXd
program.
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
8.6 Human 
biological sample 
biomarkers
The mandatory tumor sample was 
changed to include an archival 
tumor sample or a fresh biopsy (if 
archival tumor tissue is not 
available).
 
 
Only 1 mandatory sample is 
required for retrospective central 
confirmation of HER2 status. 
 
 
 
Substantial
9.2 Sample size 
determination
The description of sample size 
was reworded from 500 eligible 
participants enrolled to 
500 eligible participants treated 
in the study.
The note defining “enrolled” 
participants was deleted because 
the text describes the number of 
eligible participants rather than 
all “enrolled” participants.
These revisions were made to 
improve clarity and do not 
change the number of study 
participants.
Non-substantial
The determination of sample size 
was revised, without changing the 
sample size.
The revision is a correction in 
line with information provided in 
Table 9.
Non-substantial
The DCO for final analysis for 
Cohort 1 and Cohort 2 was 
defined.
Definition was not provided 
previously.
Substantial
9.4 Statistical 
analyses
The description of PFS, ORR, 
and DoR endpoints (CNS 
RECIST and 
) related 
to brain/CNS lesions was revised.
These revisions were made in 
alignment with revisions to 
Section 3.
Substantial
The assessment of PFS2 was 
removed from ICR.
This was previously included in 
error, as PFS2 is assessed 
locally.
Non-substantial
Description of COA secondary 
endpoints was revised.
The correction was made for 
consistency with the SoA and 
Section 3.
Non-substantial
A subgroup analysis of 
 
 
 
 
was added.
This subgroup analysis was 
added to analyze 
 
 
 
Substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
The description of the AE 
statistical analysis was reworded, 
but does not modify the planned 
analyses.
The revisions were made to 
provide a more general 
description of AE analysis in line 
with Sponsor standards.
Non-substantial
9.6 Data 
monitoring 
committees
Review of efficacy data and 
interim analysis were removed 
from this section.
The IDMC will review safety 
data periodically and this is 
different from the interim 
efficacy analysis.
Substantial
Appendix A
Consent for 
 was 
added in Appendix A3.
This revision was in line with 
revisions in Section 7.1.
Substantial
Appendix G 
Guidelines for 
evaluation of 
objective tumor 
response using 
RECIST 1.1 
criteria
Recommendations for brain scans 
were added.
Brain scans are needed for the 
evaluation of tumor response in 
patients with BMs.
Substantial
Appendix I 
Contraception 
requirements
Appendix I1 was revised to add 
text for preservation of ova prior 
to starting study treatment.
This revision is in line with 
safety recommendations for 
studies in the T-DXd program.
Substantial
Appendix I2 was revised to add 
text for sexual abstinence. 
This revision is in line with 
Appendix I3 and revisions made 
to inclusion criterion 16.
Substantial
Appendix I2 was revised to add 
text for preservation of sperm 
prior to starting study treatment.
This revision is in line with 
safety recommendations for 
studies in the T-DXd program 
and added in response to MHRA.
Substantial
Appendix I3 and Table 19 were 
revised to clarify that hormonal 
methods of contraception are not 
advised in a breast cancer 
population and should only be 
used by the female partners of 
male participants. 
Hormonal methods of 
contraception are not 
recommended for breast cancer 
patient due to the 
hormone-sensitive nature of the 
tumor.
Substantial
Appendix L 
Instructions
related to 
COVID-19
PK sampling was deleted from 
the title of Appendix L1.
This was a correction, as 
Appendix L1 does not describe 
PK sampling.
Non-substantial
The description of the COVID-19 
eligibility criteria was aligned to 
description in Section 5.
This revision was made to 
improve consistency.
Non-substantial
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/ 
Non-substantial
COVID-19 dose modification 
criteria were added.
T-DXd treatment 
recommendations in case of 
COVID-19 were provided due to 
the potential overlapping impact 
of T-DXd and COVID-19 on the 
lungs.
Substantial
Appendix O 
Toxicity 
management 
guidelines
Additional recommendations for 
Grade 4 hematological toxicity 
were provided.
These revisions are in line with 
recommendations for studies in 
the T-DXd program.
Substantial
Additional clarification for 
Grade 1 pulmonary toxicity was 
provided.
These revisions are in line with 
recommendations for studies in 
the T-DXd program.
Substantial
Appendix P 
Family history 
and exposure 
history for 
interstitial lung 
disease
This appendix was created to 
describe the collection of 
additional family history and 
exposure history for ILD in case 
of potential ILD/pneumonitis.
This revision was included in 
alignment with revisions made in 
Section 8.2.
Substantial
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not been 
summarized
Non-substantial

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11
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