A Phase 3, Randomized, Multi-center, Open-label Study of Trastuzumab Deruxtecan (T-DXd) Versus Investigator's Choice Chemotherapy in HER2-Low, Hormone Receptor Positive Breast Cancer Patients Whose Disease Has Progressed on Endocrine Therapy in the Metastatic Setting (DESTINY-Breast06)
Phase: PHASE3
Conditions: Advanced or Metastatic Breast Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol 
Investigational drug
Trastuzumab Deruxtecan 
(T-DXd; AZD4552; 
DS-8201a) 
Study Code
D9670C00001
Version
5.0
Date
23 May 2023
A Phase 3, Randomized, Multi-center, Open-label Study of Trastuzumab 
Deruxtecan (T-DXd) Versus Investigator’s Choice Chemotherapy in 
HER2-low, Hormone Receptor Positive Breast Cancer Patients whose 
Disease has Progressed on Endocrine Therapy in the Metastatic Setting 
(DESTINY-Breast06)
Sponsor Name: 
AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Numbers:
US IND number: 146,111
EudraCT number: 2019-004493-26
EU CT number: 2023-505554-18-00
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol 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: D9670C00001
Amendment Number: 4
Study Treatments: Trastuzumab Deruxtecan (T-DXd; AZD4552; DS-8201a; 
fam-trastuzumab deruxtecan-nxki), capecitabine, paclitaxel and nab-paclitaxel
The non-proprietary name for the drug under investigation is trastuzumab deruxtecan except 
in the United States where it is fam-trastuzumab deruxtecan-nxki.
Study Phase:
Phase 3
Short Title: 
Study of T-DXd vs Investigator’s Choice Chemotherapy in HER2-low, Hormone Receptor 
Positive Breast Cancer Patients whose Disease has Progressed on Endocrine Therapy in the 
Metastatic Setting
Acronym: DESTINY-Breast06
Study Physician Name and Contact Information will be provided separately
International coordinating Investigators: 
Aditya Bardia, MD, MPH
Massachusetts General Hospital Cancer Center
55 Fruit Street, Boston, MA 02114-2696
Giuseppe Curigliano MD, PhD
Istituto Europeo di Oncologia
Via Ripamonti 435, 20141 Milano, Italy

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VERSION HISTORY
DOCUMENT HISTORY
Document
Date
Amendment 4 (Version 5.0)
23 May 2023
Amendment 3 (Version 4.0)
27 April 2022
Amendment 2 (Version 3.0)
23 July 2021
Amendment 1 (Version 2.0)
22 May 2020
Original Protocol (Version 1.0)
20 March 2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 4 (23 May 2023)
The primary reasons for this amendment are to reduce informative censoring in PFS by BICR, 
including collection of additional tumor assessment scans following investigator-determined 
disease progression, based on RECIST 1.1, and to align with the EU CTR requirements. All 
available scans beyond disease progression (per investigator) will be collected. 
Substantial and non-substantial changes to the CSP and rationale for each change are noted in
the tables below. 
Substantial Changes
Section Number and Name
Description of Change
Brief Rationale
1.1 Synopsis
1.3.2 Treatment Period
1.3.3 Follow-up Period
4.1 Overall Design
7.1.2  Procedures for 
Discontinuation of Study 
Treatment
8.1.1 RECIST 1.1 Assessments
Appendix G  Guidelines for 
Evaluation of Objective Tumor 
Response using RECIST 1.1 
Criteria (Response Evaluation 
Criteria in Solid Tumors)
Added clarification that it is mandatory to 
perform an additional imaging assessment 
following investigator-determined RECIST 
progression.  
Added requirement for submission of any 
available subsequent tumor assessment 
scans for central review until the primary 
PFS analysis DCO or until the Sponsor 
notifies the site to discontinue (whichever 
is earlier).   
Added that subsequent imaging 
assessments should include brain scans for 
patients enrolled with stable brain 
metastases or if clinically indicated.
To reduce informative 
censoring in PFS by BICR, 
when investigator has 
assessed progression but 
BICR does not agree.
2.3.1  Potential Risks of 
T-DXd
2.3.4 Overall Benefit/Risk 
Conclusion
Added text regarding higher incidence of 
ILD in patients with baseline moderate 
renal impairment and increased ILD 
education requirements for these patients.
To provide guidance to 
Investigators regarding ILD 
education expectations.

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Non-substantial Changes
Section Number and Name
Description of Change
Brief Rationale
Title page
Added EU CT number
To conform to the  EU CTR 
transition
1.1  Synopsis
9.1.1  Multiple Testing 
Procedure
Revised text to clarify that the same 
significance levels will be used for the 
interim OS analyses in the HER2-low and 
ITT population.
To clarify how the 
significance levels for the 
interim OS analyses will be 
determined in the two 
populations
1.1  Synopsis
9.3  Populations for Analysis
Revised description for HER2-low and 
HER2-low SAF analysis sets to specify that 
IHC status will be obtained from IRT.
To clarify the data source for 
HER2 IHC status
1.3 Schedule of Assessments 
1.3.3 Follow-up Period
8.6.2 Immunogenicity 
Assessments
Removed requirement for the collection of 
blood samples for ADA evaluation at EOT 
and follow up
To align with sponsor 
standards for the T-DXd
program
1.3.2  Treatment Period
Removed requirement for collection of 
blood sample for plasma exploratory 
clinical benefit or safety analyses 
(mandatory) 
To align with sponsor 
standards for the T-DXd
program
1.3.2  Treatment Period
For clarification, added requirement to SoA 
for additional blood samples for plasma and 
serum exploratory clinical or safety analysis 
if ILD/ pneumonitis is suspected 
For clarification and 
consistency
1.3.2 Treatment Period
Revised footnote p to refer to Section 8.2.10 
for further instructions on PK sampling 
related to ILD
For clarification and 
consistency
1.3.2  Treatment Period 
8.2.9  Ophthalmologic 
Assessments
Removed requirement for ophthalmologic 
assessment at EOT
To align with sponsor 
standards for the T-DXd
program
1.3.2  Treatment Period
8.2.7  Echocardiograms/ Multi 
Gated Acquisition Scans
Removed requirement for troponin 
measurement at EOT
To align with sponsor 
standards for the T-DXd
program
4.4  End of Study Definition
Revised definition to encompass both FDA 
and EU regulatory requirements. 
Update required to comply 
with regulatory requirement 
(e.g., EU CTR) 
1.3.2  Treatment Period
6.5 Concomitant Therapy 
8.6.1  Pharmacokinetics
Removed instructions relating to the use of, 
and PK sampling for chloroquine/ 
hydroxychloroquine from text and updated 
corresponding SoA table footnote. These 
medications are simply prohibited. 
To align with sponsor 
standards for the T-DXd
program
5.2  Exclusion Criteria
6.5  Concomitant Therapy
6.5.2  Restrictions on 
Replaced “prednisone” with 
“prednisone/prednisolone” throughout
Update required to comply 
with regulatory requirement 
(e.g., EU CTR)

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Non-substantial Changes
Section Number and Name
Description of Change
Brief Rationale
Concomitant Medications/ 
Therapies
Appendix H  Toxicity 
Management Guidelines for 
T-DXd
1.3.2 Treatment Period
8.2.10  Other Safety 
Assessments
Appendix H  Toxicity 
Management Guidelines for 
T-DXd
Added clarifications to wording on 
identification, evaluation and management 
of ILD.
To align with sponsor 
standards for the T-DXd
program
8.4  Medication Error, Drug 
Abuse, and Drug Misuse
Appendix B4  Medication 
Error, Drug Abuse, and Drug 
Misuse
Added 4 subsections to (renamed) section:
8.4.1  Timelines
8.4.2  Medication Error
8.4.3  Drug Abuse
8.4.4  Drug Misuse
Added sections on drug abuse and drug 
misuse to Appendix B4
Update required to comply 
with regulatory requirement 
(e.g., EU CTR) 
8.5  Overdose
Added further detail on timing for reporting 
of overdose
Update required to comply 
with regulatory requirement 
(e.g., EU CTR)
8.6  Human Biological 
Samples
Updated retention times for PK and ADA 
samples
To comply with ICH GCP, 
China Human Genetic 
Resources (HGR) regulation 
and AZ HBS global standards 
and policies for sample 
storage and retention
9.4  Statistical Analyses
Additional analyses to be performed at the 
time of the PFS and OS analyses for the 
HER2 IHC >0<1+ population will be 
specified in the SAP.
To clarify timing of 
additional analyses in HER2 
IHC >0<1+ population.
Appendix A1  Regulatory and 
Ethical Considerations
Added subsection for “Regulatory 
Reporting Requirements for Serious 
Breaches.”
Added clarifications on investigator 
responsibility for oversight of study conduct 
at the site.
Added clarifications on regulatory reporting 
requirements for SAEs.
Update required to comply 
with regulatory requirement 
(e.g., EU CTR) 
Appendix A6  Dissemination 
of Clinical Study Data
Updated information regarding timelines for 
submission of trial results summaries to EU 
CTIS
Update required to comply 
with regulatory requirement 
(e.g., EU CTR) 

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Non-substantial Changes
Section Number and Name
Description of Change
Brief Rationale
Appendix A7  Data Quality 
Assurance
Revised text to include quality tolerance 
limits, specify medical oversight, and 
increase the minimum time that 
Investigators are required to maintain 
records and documents.
Update required to comply 
with regulatory requirement 
(e.g., EU CTR) 
Appendix H  ILD/Pneumonitis 
Management Guidance 
Flowchart for T-DXd
Deleted appendix and renumbered 
subsequent appendices
To remove repetition of 
information 
Appendix H  Toxicity 
Management Guidelines for 
T-DXd
Renumbered appendix due to deletion of 
previous Appendix H.
Added footnote ‘a’ to table for dose 
modification clarification
Updated QTc to QTcF in ECG QTcF 
prolonged section
Alignment with sponsor 
standards for the T-DXd
program
Appendix I1  Concomitant 
Medication and T-DXd Dose 
Modification Relevant to 
COVID-19
Renumbered appendix due to deletion of 
previous Appendix H.
Added details on COVID-19 testing, 
updated definition of COVID-19 recovery 
and made some other minor clarifications
To align with sponsor 
standards for the T-DXd
program
Appendix K Country-specific 
Protocol Information
Added appendix
Update required to comply 
with EU CTR (EU CTR 
submissions only allow one 
version of the protocol used 
by all EU/EEA countries).
Amendment 3 (27 April 2022)
The primary reasons for this amendment are as follows:
!
Removing the enrollment pause for HER2 IHC > 0 <1+ patients while awaiting the 
futility analysis.
!
Updating inclusion criterion #2c to remove the requirement for matched results between 
historical/local HER2 results and central test results.
!
Updating the multiple testing procedure (MTP) for the study.
The Phase 2 DAISY study (see Section 4.2.2 for further details) has provided further data 
showing T-DXd activity in patients with IHC0+ expression (inclusive of the HER2 IHC 
> 0 <1+ population included in this study). In view of this information, the enrollment pause 
that was initially conservatively included in this protocol for the HER2 IHC > 0< 1+ 
population after the first 70 patients were randomized until the IDMC makes a 

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recommendation on whether or not to stop recruitment in this population (approximately 32 
weeks after the 70th HER2 IHC > 0 <1+ patient had been randomized), is being removed. The 
new available DAISY data support the removal of this pause, while the futility analysis 
(performed on the first 70 randomized HER2 IHC > 0 <1+ patients) is itself maintained.
Inclusion criteria 2c has been modified to remove the requirement that the central HER2 test 
result must match the local HER2 test result (i.e., local status as HER2 Low or HER2 >0<1+ 
must match central status) in order for a patient to be eligible for study participation. This 
modification will ensure that the central HER2 test is the primary determinant for study 
eligibility and will streamline enrollment procedures and reduce screen failures.
Lastly, this amendment will include a revision to the MTP of the study to allow immediate 
allocation of alpha to PFS ITT after the primary endpoint is significant. Specifically, if PFS 
HER2-low is significant, the 5% alpha will be split between PFS ITT (1.5% alpha) and OS 
HER2-low (3.5% alpha). To achieve 80% power for OS HER2-low at 3.5% alpha, the final 
OS analysis will now be performed when approximately 521 OS events have been observed in 
the HER2-low population.
Substantial and non-substantial changes to the CSP and rationale for each change are noted in 
the tables below. 
Substantial changes
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis; 9.1.1 Multiple 
Testing Procedure and 9.2 
Sample Size Determination
Change in the MTP such that if PFS 
HER2-low is significant, the 5% 
alpha will be split between PFS ITT  
(1.5% alpha) and OS HER2-low 
(3.5% alpha)
Change in the target number of 
events at the final OS analysis from 
489 to 521 OS events in the HER2-
low population; Expected 
information fraction at the first and 
second interim OS analyses were 
changed to 41% and 75% 
respectively.
To allow immediate allocation of 
alpha to PFS ITT if the primary 
endpoint is significant.
Number of OS events in the HER2-
low population that will trigger the 
final OS analysis was increased to 
achieve 80% power at 3.5% alpha
1.1 Synopsis; 9.1.1 Multiple 
Testing Procedure; 9.5.1 
Interim Futility Analysis
Removal of the enrolment pause in 
the HER2 IHC > 0< 1+ patient 
population during the futility 
analysis.
Clinical evidence from the DAISY 
study providing confidence for the 
efficacy of T-DXd in the HER2 
IHC > 0< 1+ population.
5.1 Inclusion Criteria
Removal of the requirement for 
matched results between 
historical/local HER2 results and 
To ensure that the central HER2 test 
is the primary determinant for study 
eligibility to streamline enrolment 

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Substantial changes
Section # and Name
Description of Change
Brief Rationale
central test results (IC#2[c] of CSP 
version 3.0)
procedures and reduce screen 
failures
5.1 Inclusion Criteria
Reduction in the minimum age for 
eligible patients in Japan from 20 
years to 18 years (IC#1)
Revision of Japanese civil code
5.2 Exclusion Criteria
Addition of statement that pre-
screening for this study while a 
patient is on treatment in another 
clinical study is acceptable (EC#18)
Clarification
5.3 Lifestyle Considerations
Removal of bilateral tubal ligation 
as a recognized method of surgical 
sterilisation
Correction
5.4 Screen Failures
Update allowing rescreening of 
patients who previously had the 
local HER2 test result not confirmed 
by central HER2 testing, provided 
they have not been previously 
rescreened and did not have a HER2 
positive central test result
Changes to IC#2
6.5 Concomitant Therapy
Addition of the recommendation to 
administer a combination regimen 
of two or three anti-emetic agents 
prior to each dose of T-DXd
Alignment with sponsor standards 
for the T-DXd program
6.6.1.1 T-DXd; 8.3.14.1 
Specific Toxicity Management 
and Dose Modification 
Information for T-DXd
Increase in the permitted delay in 
T-DXd dosing from 49 days to 126 
days since the previous dose
Alignment with sponsor standards 
for the T-DXd program
8.2.10.1 Pneumonitis (ILD) 
Investigation; 8.3.11 Adverse 
Events of Special Interest; 
8.3.14.1 Specific Toxicity 
Management and Dose 
Modification Information for 
T-DXd
Addition of the requirement for 
patients with suspected 
ILD/pneumonitis to undergo a 
SARS-CoV-2 (COVID-19) test
IDMC request
9.5.1 Interim Futility Analysis
Addition of treatment 
recommendations for patients with 
HER2 IHC >0 <1+ in the event that 
recruitment in that subgroup is 
stopped
Clarification
Appendix I
Increase in the time after which 
T-DXd should be discontinued in 
the case of Grade 1 ILD/ 
pneumonitis occurring beyond cycle 
Alignment with sponsor standards 
for the T-DXd program

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Substantial changes
Section # and Name
Description of Change
Brief Rationale
Day 22 from 49 days to 126 days 
since the previous dose
Non-substantial changes
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis; 2.1 Study 
Rationale; 2.3.2 Potential 
Benefits of T-DXd; 2.3.4 
Overall Benefit/Risk 
Conclusion; 4.2.2 Rationale for 
T-DXd in HR+, HER2 IHC >0 
<1+, Advanced or Metastatic 
Breast Cancer
Addition of confirmed ORR and 
PFS results indicating efficacy of 
T-DXd in HER2 expression below 
IHC 1+ in patients with advanced 
breast cancer
Read-out of results for the DAISY 
study
1.1 Synopsis; 3 Objectives and 
Endpoints; 8.6 Human 
Biological Sample Biomarkers
Addition of statement allowing 
blood and tissue samples collected 
for exploratory biomarker analysis 
and associated data to be used for 
diagnostic development
Clarification
1.1 Synopsis; 1.3.2 Treatment 
Period; 1.3.3 Follow-up Period; 
4.1 Overall Design; 7.1.2 
Procedures for Discontinuation 
of Study Treatment; 8.1.1 
RECIST 1.1 Assessments; 
Appendix G Guideline for 
Evaluation of Objective Tumor 
Response using RECIST 1.1 
Criteria (Response Evaluation 
Criteria in Solid Tumors)
Re-labeling of the additional tumor 
assessment following investigator 
determined RECIST 1.1 progression 
as an additional tumor evaluation 
scan
Clarification that only an additional 
scan is required in this case, and that 
tumor assessment by the 
investigator is not expected
1.1 Synopsis; 9.1.1 Multiple 
Testing Procedure; 9.5.1 
Interim Futility Analysis
Removal of statement “have 
discontinued from study treatment” 
to clarify how interim futility data 
cut off will be triggered .
Correction to language for data cut 
off trigger for interim futility 
analysis.
1.2 Study Schema
Removal of the requirement for the 
tissue for central IHC assessment to 
be archival
Correction
1.3.1 Enrollment/Screening 
Period; 1.3.2 Treatment Period; 
8.2.4 Electrocardiograms; 
8.3.11 Adverse Events of 
Special Interest
Reduction in the time window for 
recording triplicate ECGs from 15 
minutes to 5 minutes
Alignment with sponsor standards 
for the T-DXd program

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Non-substantial changes
Section # and Name
Description of Change
Brief Rationale
1.3.2 Treatment Period; 8.2.7 
Echocardiograms/ Multiple 
Gated Acquisition Scans; 
8.3.14.1 Specific Toxicity 
Management and Dose 
Modification Information for 
T-DXd
Removal of the requirement for a 
repeat troponin assessment in the 
event of a Grade 3 troponin result
Alignment with sponsor standards 
for the T-DXd program
1.3.2 Treatment Period
Replacement of the ± 3 day window 
for ctDNA samples with a 
recommendation to collect the 
samples as close as possible to the 
RECIST assessment
Alignment with sponsor standards 
for the T-DXd program
2.2.2 Background Information 
on T-DXd
Update to the number of patients 
exposed across the T-DXd program 
and the approval status of T-DXd
Alignment with updates to the 
T-DXd investigator’s brochure
2.3.1 Potential Risks of T-DXd
Removal of asthenia as an identified 
risk for T-DXd
Alignment with sponsor standards 
for the T-DXd program
2.3.2 Potential Benefits of 
T-DXd; 4.2.1 Rationale for 
T-DXd in HR+, HER2-low, 
Advanced or Metastatic Breast 
Cancer
Addition of successful outcome for 
PFS and OS for T-DXd compared to 
physician’s choice of chemotherapy 
in later line HER2 low, advanced or 
metastatic breast cancer patients for 
whom ET is no longer an option and 
who have received 1 to 2 lines of 
chemotherapy in the metastatic 
setting
Read-out of results for the 
DESTINY-Breast04 study
2.3.2 Potential Benefits of 
T-DXd.
Text revised for comparison of 
DAISY study to historical 
chemotherapy data 
Text revised for better 
contextualisation of DAISY study 
data
4.1 Overall design; 8.6.1 
Collection of Mandatory 
Samples for Biomarker 
Analysis
Re-labeling of the IHC 2+, IHC 1+ 
and IHC >0 <1+ algorithms as cut-
offs
Clarification
4.1 Overall design
Clarification of stratification factors 
at time of randomization  
Clarification; to ensure proper 
balance and correct stratification 
across treatment arms, all 
stratification factors must be known 
for each patient at the time of 
randomization
6.2.1 T-DXd (DS-8201a)
Addition of a statement allowing 
T-DXd dose modification if a 
patient’s body weight has changed 
below the threshold of ± 10%
Flexibility for sites which have a 
more conservative policy regarding 
dose modification for weight 
changes

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Non-substantial changes
Section # and Name
Description of Change
Brief Rationale
6.2.2 Paclitaxel, Capecitabine 
and Nab-paclitaxel
Addition of statement that 
investigator’s choice 
chemotherapies will be administered 
according to drug label for centrally 
sourced medications
Alignment with the practice 
followed in the study
8.3.14.1 Specific Toxicity 
Management and Dose 
Modification Information for 
T-DXd
Removal of statement defining 
SAEs with onset or worsening after 
the safety follow-up visit as TEAEs 
if considered related to study 
treatment
Alignment with sponsor standards 
for the T-DXd program
8.3.14.1 Specific Toxicity 
Management and Dose 
Modification Information for 
T-DXd
Removal of the requirement for 
consultation with Study Physician or 
designee for dose reductions or 
discontinuation of T-DXd for 
patients with a delay in T-DXd
dosing
Correction of an oversight error
9.2 Sample Size Determination
Re-labeling of the estimated number 
of patients to be screened/enrolled 
as the number of patients to be 
screened
Correction in line with Section 1.1
Appendix A4
Addition of a statement that results 
from the optional biopsy at disease 
progression will be provided back to 
the patient
Correction
Appendix I
Removal of the requirement for 
prior agreement of the Study 
Physician for dose reductions
Correction
Amendment 2 (23 July 2021)
The primary modification in this amendment is to update the patient population of the study to
include patients who have progressed within 6 months of first line ET + CDK4/6i in the 
metastatic setting. The rationale for including this population is discussed below.
In the past few years, ET + CDK4/6 inhibitor regimens have become established as the
standard of care for HR+, HER2-negative metastatic breast cancer (Cardoso et al 2020). 
However, following progression on ET + CDK4/6 inhibitor regimens, the median time to 
treatment failure or duration of treatment on subsequent regimens is short, as evidenced from 
the PALOMA-3, MONARCH-2 and TRend trials, for both subsequent chemotherapy (4.4 to 
5.6 months) and endocrine therapy (3.7 to 5.3 months) (Rossi et al 2019, Sledge et al 2020, 
Turner et al 2018).

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Therefore, patients whose HR+, HER2-negative breast cancer is classified as primary 
endocrine resistant (i.e., progression within 6 months of starting first-line treatment with ET + 
CDK4/6 inhibitors) for whom chemotherapy is considered the next most appropriate treatment 
represent a population of high unmet medical need in which T-DXd may potentially provide 
benefit. The criteria for this additional study population is consistent with the definition of 
primary endocrine resistance in the European Society of Medical Oncology guidelines 
(Cardoso et al 2020).
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
1.1 Synopsis; 1.2 Schema; 
2.1 Study Rationale; 2.2.1 
Background Information 
on the Disease to be 
Treated; 4.1 Overall 
Design; 5 Study 
Population; 5.1 Inclusion 
Criteria
The study population was 
updated to include patients 
who progress on first line 
endocrine therapy + CDK4/6i 
within 6 months of starting 
therapy 
To expand study population 
who have progressed on 
endocrine therapy + CDK4/6i 
and deemed appropriate to 
receive chemotherapy as next 
treatment
Substantial
5.1 Inclusion Criteria
IC #12 updated to add 
non-antibody based 
immunotherapy washout 
period
Added immunotherapy 
washout period, which was 
previously omitted by 
oversight
Substantial
5.1 Inclusion Criteria; 5.3 
Lifestyle Considerations 
Updated text (IC#14 and 16) 
regarding females of 
childbearing potential 
To align with sponsor 
standards for the T-DXd
program, MHRA and PEI 
feedback and CTFG guidelines 
Substantial
5.1 Inclusion Criteria; 
8.3.13.1 Paternal 
Exposure; Appendix A3
IC #15 updated with text 
regarding male contraception, 
and added text regarding 
preservation of sperm 
To align with sponsor 
standards for the T-DXd
program, MHRA and PEI 
feedback and CTFG guidelines
Substantial
5.2 Exclusion Criteria
Updated EC #4 to exclude 
patients with history of (non-
infectious) ILD/pneumonitis 
that required steroids
Updated to allow patients with 
prior ILD/pneumonitis that did 
not require management with 
steroids to no longer be 
excluded; this is now aligned 
with sponsor standards for the 
T-DXd program 
Substantial
Title page
Addition of co-international 
coordinating investigator
To include Giuseppe 
Curigliano as co-ICI
Non-
substantial
1.1 Synopsis; 1.3.2 
Treatment Period; 1.3.3 
Follow-up Period; 4.1 
Addition of scan following 
investigator determined 
To confirm radiological 
progressive disease
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Overall Design; 8.1.1 
RECIST 1.1 Assessments; 
Appendix G
RECIST 1.1 progression, if 
feasible
1.1 Synopsis; 9.6.2 ILD 
Adjudication Committee
Addition of imaging data
Clarified that imaging data is 
also included for evaluation by 
the ILD Adjudication 
Committee
Non-
substantial
1.3 Schedule of 
Assessments
Updated text to state patients 
will begin screening/baseline 
procedures after signing the 
main ICF
Clarification
Non-
substantial
Footnotes in Table 3 updated 
for corrections and 
clarifications
Correction and clarification
Non-
substantial
1.3.1 
Enrollment/Screening 
Period; 1.3.2 Treatment 
Period; 1.3.3 Follow-up 
Period; 8.2.5 Clinical 
Safety Laboratory 
Assessments
Addition of ‘where available’ 
for bicarbonate test
No longer a mandatory test, 
only performed where required
Non-
substantial
1.3.2 Treatment Period
PK timepoints included in 
table and removed from 
footnotes
For clarity
Non-
substantial
Updated footnote h
To include guidance for SpO2 
evaluation
Non-
substantial
Addition of text to footnote g 
to clarify ECG does not need 
to be repeated at Day 1 if 
performed within 3 days prior 
in screening period
Clarification
Non-
substantial
Laboratory related text in 
footnote i moved to create 
separate footnote k
Correction
Non-
substantial
1.3.2 Treatment Period; 
1.3.3 Follow-up Period
Updated text to specify 
targeted physical examination
To allow targeted physical 
examinations after the 
screening period
Non-
substantial
1.3.2 Treatment Period; 
8.2.7 
Echocardiograms/Multiple 
Gated Acquisition Scans; 
8.3.14.1 Specific Toxicity 
Removed text from footnote n 
stating repeat testing is not 
required if troponin levels at 
baseline are above the upper 
To align with sponsor 
standards for the T-DXd
program
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Management and Dose 
Modification Information 
for T-DXd
limit of normal and below the 
level of myocardial infarction
1.3.2 Treatment Period; 
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis
Update of blood sampling 
timing
To include blood sampling 
collection up to disease 
progression
Non-
substantial
1.3.2 Treatment Period; 
8.6.2 Collection of 
Optional Biomarker 
Samples
Clinical care tumor biopsy 
replaced with tumor sample at 
disease progression
To clarify language of only 
collecting tumor samples at 
time of disease progression if 
consented for and not at other 
timepoints
Non-
substantial
Updated text to clarify tumor 
biopsy collection timing
Clarification
Non-
substantial
2.3.1 Potential Risks of 
T-DXd
Updated text with most recent 
potential risks of T-DXd
To align with sponsor 
standards for the T-DXd
program
Non-
substantial
4.1.2 Duration of Patient 
Participation
Addition of text to state 
pre-screening period is 
included if signing optional 
pre-screen ICF
Clarification of pre-screening 
period
Non-
substantial
4.2.2 Rationale for T-DXd
in HR+, HER2 IHC >0 
<1+, Advanced or 
Metastatic Breast Cancer
Text updated with regards to 
membrane staining
Clarification
Non-
substantial
5 Study Population
Addition of definition of 
enrolled and randomized 
patients
Updated enrollment to 
randomization throughout 
section
To clarify terms used in 
inclusion/exclusion criteria
Non-
substantial
5.1 Inclusion Criteria
Literature reference in IC #2 
updated
To use most recent literature 
reference for HR test results
Non-
substantial
IC #6 updated to state disease 
recurrence within 24 months of 
starting ET will be considered 
a line of therapy and include 
PARP inhibitor therapy is not 
considered a line of ET
To clarify that patients must be 
on adjuvant endocrine therapy 
when they recur in this time 
period and include PARP 
inhibitor therapy in the 
guidance for previous ET 
requirements 
Non-
substantial
IC #11 updated to specify that 
all laboratory parameters listed 
To ensure all patients meet all 
elements of the inclusion 
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
in #11 must be met by the 
most recent results available
criteria at the time of 
enrollment
5.1 Inclusion Criteria
IC #13 updated to include 
definition of women of 
childbearing potential 
To clarify definition of women 
of childbearing potential in 
alignment with project 
standards for the T-DXd
program
Non-
substantial
5.2 Exclusion Criteria
EC #1 updated to include 
reference to contraindications 
section of local prescribing 
information
To update in line with MHRA 
and PEI feedback and local 
protocol versions
Non-
substantial
EC #6 updated to specify 
patients with complete 
pneumonectomy at screening 
will be excluded from the 
study
To clarify that only patients 
with complete 
pneumonectomy should be 
excluded. This is to align with 
sponsor standards for T-DXd
program. 
Non-
substantial
EC# 10, 11, 12, and 13 
updated 
To align with sponsor 
standards for the T-DXd
program
EC#10 updated to clarify that 
mRNA and replication 
deficient adenoviral vaccines 
are not considered live 
vaccines
EC#11 updated to provide 
definition of chronic, stable 
toxicities with included 
examples 
EC#12 updated to clarify that 
criteria also excludes patients 
intending to become pregnant 
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
in addition to pregnant or 
breastfeeding patients 
EC#13 wording updated from 
excluding patients with a 
history of severe 
hypersensitivity to patients 
with known hypersensitivity
Removal of (old) EC #12 
regarding concurrent 
chemotherapy, biologic, or 
hormonal therapy for cancer 
treatment
To remove repetition as 
previous anticancer therapy 
washout included in inclusion 
criterion #12 and concurrent 
treatments are prohibited 
medications 
Non-
substantial
EC #18 and 19 added
EC#18 added to exclude 
patients who participated in 
another clinical study with a 
study treatment administered 
in the last 30 days prior to first 
dose of study treatment or 
concurrent enrollment in 
another clinical study
EC#19 added to exclude 
patients with history of 
substance abuse or 
psychological conditions that 
may interfere with patient’s 
participation 
Non-
substantial
5.4 Screen Failures
Text added for screen fails due 
local HER2 test results not 
confirmed by central HER2 
testing and clarifying the 
possibility that patients can 
rescreen with pre-screening
To provide instructions for 
rescreen of patients who have 
screen failed due to IC #2(c) 
and clarify the possibility of 
pre-screening for rescreened 
patients
Non-
substantial
6.1.1 Study Treatments; 
6.4 Study Treatment 
Compliance
Updated packaging and 
labelling requirements for 
capecitabine
Correction
Non-
substantial
6.2.1 T-DXd (DS-8201a)
Updated instruction for dose 
recalculation if patients weight 
change by ≥± 10% during the 
study
To align with sponsor 
standards for the T-DXd
program
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
6.3.1 Patient Enrollment at 
Randomization
Addition of text to clarify 
patients who sign 
pre-screening ICF will be 
considered enrolled.
Clarification
Non-
substantial
6.5 Concomitant Therapy
Text deleted from Table 10 
that restrictions on the use of 
immunosuppressive 
medications may vary based 
on specific studies
To align with sponsor 
standards for the T-DXd
program
Non-
substantial 
8.1.3 PFS2
Removed text regarding
patients who started on 
subsequent cancer therapy post 
progression
Correction
Non-
substantial
8.1.4.9 Administration of 
Patient-Reported Outcome 
Measures
Addition of text to include 
considering an appropriate 
back-up option for completion 
of PRO measures
To include a back-up option 
for flexibility if required
Non-
substantial
8.2.6 Pulmonary 
Assessments
Text added to state SpO2 
should be evaluated at end of 
infusion where applicable 
For consistency with schedule 
of assessments
Non-
substantial
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information; 
8.3.6 Hy’s Law; 8.3.11 
Adverse Events of Special 
Interest
Removal of text regarding 
targeted questionnaires
To align with sponsor 
standards for the T-DXd
program. Questions already 
integrated as part of data 
collection through eCRFs. 
Non-
substantial
8.3.12 Reporting of 
Serious Adverse Events
Text added to include 
completion of a paper SAE 
form if EDC not available
To align with sponsor 
standards for the T-DXd
program
Non-
substantial
8.4 Overdose
Use of email address for 
reporting overdose replaced 
with RAVE, or if technical 
issues by fax
Correction
Non-
substantial
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis
Text added to exploratory 
biomarker information 
regarding IHC analysis and 
referring to the China lab 
manual for China-specific 
sample requirements
Clarification of collection of 
samples and sample 
requirements specific to China
Non-
substantial 
8.7 Optional Genomics 
Initiative Sample
Removal of text regarding 
collection of replacement 
genetic blood samples
This process is not being 
performed
Non-
substantial 

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
9.3 Populations for 
Analyses
ADA population/analysis set 
amended to include reference 
to all patients who receive at 
least 1 dose of T-DXd per the 
protocol
Clarification
Non-
substantial
9.4.2.2 Secondary 
Endpoints
Disease control rate definition 
updated
Correction
Non-
substantial
9.4.3 Safety
Additional detail and text 
amended on how AE, vital 
signs, and laboratory data will 
be summarized/provided in 
CSR
To align with project-level 
updates
Non-
substantial
Appendix A6
Addition of posting to 
European Union clinical trial 
register
To include description of 
clinical study on the European 
Union clinical trial register
Non-
substantial
Appendix F
ASCO/CAP guidelines on 
HER2 testing in breast cancer 
updated
Correction to most recent 
guidelines
Non-
substantial
Appendix G
Updated guidelines for 
evaluation of objective tumor 
response using RECIST 1.1 
criteria
To update in line with the 
guideline for evaluation of 
objective tumor response using 
RECIST 1.1 criteria
Non-
substantial
Appendix I
Table 27 (Toxicity 
Management Guidelines for 
T-DXd) updated to include 
further guidance for 
hematologic toxicity, cardiac 
toxicity, and pulmonary 
toxicity
To align with sponsor 
standards for the T-DXd
program
Non-
substantial
Appendix J1; 1.3.2 
Treatment Period; 6.5 
Concomitant Therapy; 
8.5.1 Pharmacokinetics 
Removed all reference to 
hydroxychloroquine and 
chloroquine from appendix. 
Language to these medications 
kept in or moved to (PK 
assessments) body of protocol.  
Updated due to changing 
patterns of management of 
COVID. However, these 
medications may be used for 
purposes other than COVID-
19 so information still stored 
in body of protocol. 
Non-
substantial
Appendix J2
Clarified CTCAE v5.0 is to be 
used for evaluating and 
reporting COVID-19-related 
AEs
Clarification
Non-
substantial 
Appendix K
Updated EORTC QLQ-BR45 
To use most recent version
Non-
substantial

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Amendment 1 (22 May 2020)
Overall Rationale for the Amendment:
The overall rationale for the amendment is to provide additional guidance for investigators on 
the management of T-DXd in respect to COVID-19 and associated treatments. In addition, 
provision was made to collect plasma and serum samples to help assess potential impact of 
COVID-19 on data obtained in this trial. Furthermore, the schedule of assessments, 
inclusion/exclusion criteria and toxicity management guidelines were updated. The rationale 
for each of these changes is provided in the table below.
Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
Throughout
Updated post-treatment 
follow-up schedule at 40 days 
window from ±7 days to 
+7 days
Amended window for follow-up 
visit to allow for adequate safety 
follow-up, given the half-life of 
T-DXd
Substantial
1.3 Schedule of 
Assessments 2.3.4 
Overall Benefit/Risk 
Conclusion
5.1 Inclusion criteria
6.6.1 Individual Patient 
Dose Modifications
8.3.14 Management of 
Study Treatment-related 
Toxicities
8.6.1 Collection of 
Mandatory Samples for 
Biomarker Analysis  
8.6.3 Other Study Related 
Biomarker Research
Guidance added on the 
management of T-DXd in 
respect to COVID-19 and 
associated treatments along with 
provision for additional blood 
samples for exploratory analyses 
of clinical benefit or safety
COVID-19 presents a potential 
safety risk, including respiratory 
manifestations. Management 
guidelines and benefit/risk 
considerations for COVID-19 
have been included in 
Appendix J, and additional 
reporting and sampling 
procedures have been added to 
help assess potential impact of 
COVID-19 on data obtained in 
this trial
Substantial
1.3 Schedule of 
Assessments
5.1 Inclusion Criteria
6.5 Concomitant Therapy
Appendix J
Specification of washout period 
prior to randomization for 
chloroquine/hydroxychloroquine 
and provided instructions related 
to restrictions and additional 
sample collection should T-DXd
patients receive concomitant 
treatment with chloroquine or 
hydroxychloroquine.
A washout period and 
instructions related to 
restrictions and additional 
sample collections specified due 
to a possible interaction between 
T-DXd and chloroquine/ 
hydroxychloroquine
Substantial 
5.2 Exclusion Criteria
Added exclusion criterion for 
patients randomized in a 
previous T-DXd trial 
Added to discourage early 
patient withdrawal from earlier 
line T-DXd studies where 
patients are assigned to control 
Substantial 

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
5.2 Exclusion Criteria
Removal of exclusion criterion 
#5 (history of clinically 
significant corneal disease), 11 
(infection relating to active 
tuberculosis [covered by 
separate criterion excluding 
ongoing or active infection], 21 
(drainage and CART not 
allowed within 2 weeks of 
randomization)  
Removal of exclusion criterion 
#5 based on cumulative review 
of clinical data
Exclusion criterion #11 removed 
as already covered under 
exclusion criterion #2 
(Uncontrolled intercurrent 
illness, including but not limited 
to, ongoing or active 
infection…)
Exclusion criterion #21 removed 
as not relevant for breast cancer 
indication
Substantial
5.2 Exclusion Criteria
Amendment of exclusion 
criteria #6 for prior ILD to 
remove phrase on requiring 
steroid treatment. Patient’s prior 
ILD no longer requires 
treatment with corticosteroid for 
patient to be excluded.
Updated exclusion criteria to 
exclude all patients with prior 
ILD to further mitigate the 
incidence of pulmonary 
toxicities
Substantial
5.2 Exclusion Criteria
Updated exclusion criterion #3 
to remove the phrase “unstable 
angina pectoris, clinically 
important cardiac arrhythmias, 
or a recent (< 6 months) CV 
event including, unstable angina 
pectoris, and stroke” and 
included the provision for a 
cardiologist consultation for 
patients with troponin levels 
above ULN at screening and 
without any myocardial related 
symptoms.
Updated to remove redundant 
text and include the need for 
cardiologist consultation in 
patients with elevated troponin 
levels, as defined by the 
manufacturer, to rule out any 
asymptomatic signs of 
myocardial infarction
Substantial
1.3 Schedule of 
Assessments
8.2.7 Echocardiograms/ 
Multi gated Acquisition 
Scans 
8.3.11 Adverse Events of 
Special Interest
Updated ECG and troponin 
collection frequency
Updated ECG measurements in 
line with the observations from 
a clinical study that showed no 
clinically meaningful impact of 
T-DXd on QTc.
Data to date have shown that 
troponin-T testing is not an 
Substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
8.3.14.1 Specific Toxicity 
Management and Dose 
Modification Information 
for T-DXd
indicator of LVEF decrease and 
therefore troponin will be 
measured at screening and EOT 
and as clinically indicated.
1.3 Schedule of 
Assessments 
8.5.2 Immunogenicity 
Assessments
Addition of ADA sample 
collection after 40-day (+7 day) 
follow-up for select patients 
Provision of additional 
collection of ADA samples to 
monitor ADA positive patients 
at follow-up
Substantial 
Appendix H Guidance for 
Management of Patients 
with Drug-Induced 
ILD/Pneumonitis and 
Appendix I Toxicity 
Management Guidelines 
for T-DXd
Update to ILD/pneumonitis 
management guidelines
Further recommendations 
provided on management of 
ILD/pneumonitis, in particular, 
more detailed recommendations 
around duration of systemic 
steroid treatment.
Substantial
Appendix I Toxicity 
Management Guidelines 
for T-DXd
Updates to AST/ALT increased, 
cardiac toxicity, and QTc 
prolongation management 
guidelines and removal of 
troponin management guidelines
Management of AST/ALT 
increased amended to provide 
greater clarity in patients with 
elevated AST/ALT at baseline.
ECG QTc prolonged toxicity 
management guidelines 
amended to advise ruling out 
serum electrolyte related ECG 
changes.
Data to date has shown that 
troponin testing is not an 
indicator of LVEF decrease. 
Troponin will only be measured 
at screening, at EOT and as 
clinically indicated.
Substantial
1.3 Schedule of 
Assessments
Allowance of a non-contrast 
enhanced CT instead of non-
contrast HRCT if not feasible
Allowance for another modality 
if not feasible to attain HRCT 
Non-
substantial
1.3 Schedule of 
Assessments
5.1 Inclusion Criteria
8.2.5 Clinical Laboratory 
Assessments
Amended inclusion criterion h 
from “International normalized 
ratio (INR)/Prothrombin time 
(PT) and activated partial 
thromboplastin time” to 
“INR/PT and either partial 
thromboplastin or activated 
To clarify that results from 
either partial thromboplastin or 
aPTT tests are acceptable
Non-
substantial 

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Section # and Name
Description of Change
Brief Rationale
Substantial/ 
Non-
substantial
partial thromboplastin time 
(aPTT)” 
5.2 Exclusion Criteria
Updated wording for exclusion 
criterion #8 (lung-specific 
intercurrent illness) and 
10 (spinal cord compression or 
CNS metastases) 
Clarification of exclusion 
criteria to make them more 
specific to patients under 
treatment
Non-
substantial 
5.2 Exclusion Criteria
Exclusion criterion #4 “History 
of active primary 
immunodeficiency” removed
Exclusion criterion #12 updated 
to include patients with “active 
primary immunodeficiency”
To only exclude patients with 
active primary 
immunodeficiency and not 
history of such disease
Non-
substantial
6.5 Concomitant Therapy
Guidance regarding anti-emetics 
included
Based on current safety data, use 
of anti-emetics is recommended 
prior to and following T-DXd
infusions
Non-
substantial
1.3 Schedule of 
assessments
6.5.2 Restrictions on 
Concomitant 
Medications/Therapies
Use of tobacco products, 
e-cigarettes and vaping is 
strongly discouraged but not 
prohibited. History and current 
usage to be recorded. Minimum 
requirements for pulmonary 
function tests defined.
To gather further information on 
current tobacco usage and 
pulmonary function that may be 
relevant following review of 
vaping/e-cigarette literature.
Non-
substantial
Throughout
Minor changes to protocol 
wording, tables and figures
To align with project standard or 
to provide clarification
Non-
substantial
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not been 
summarized
Non-
substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY ........................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES .................................................. 3
TABLE OF CONTENTS .................................................................................................... 23
1
PROTOCOL SUMMARY ................................................................................ 29
1.1
Synopsis ........................................................................................................... 29
1.2
Study Schema ................................................................................................... 39
1.3
Schedule of Assessments .................................................................................. 40
1.3.1
Enrollment/Screening Period ............................................................................ 40
1.3.2
Treatment Period .............................................................................................. 45
1.3.3
Follow-up Period .............................................................................................. 55
2
INTRODUCTION............................................................................................ 58
2.1
Study Rationale ................................................................................................ 58
2.2
Background ...................................................................................................... 59
2.2.1
Background Information on the Disease to be Treated....................................... 59
2.2.2
Background Information on T-DXd................................................................... 63
2.3
Benefit/Risk Assessment................................................................................... 64
2.3.1
Potential Risks of T-DXd .................................................................................. 64
2.3.2
Potential Benefits of T-DXd.............................................................................. 67
2.3.3
Standard of Care (Investigator’s Choice Chemotherapy)................................... 68
2.3.4
Overall Benefit/Risk Conclusion....................................................................... 68
3
OBJECTIVES AND ENDPOINTS................................................................... 70
4
STUDY DESIGN ............................................................................................. 73
4.1
Overall Design.................................................................................................. 73
4.1.1
Duration of the Study........................................................................................ 75
4.1.2
Duration of Patient Participation....................................................................... 75
4.2
Scientific Rationale for Study Design ............................................................... 75
4.2.1
Rationale for T-DXd in HR+, HER2-low, Advanced or Metastatic Breast Cancer
......................................................................................................................... 75
4.2.2
Rationale for T-DXd in HR+, HER2 IHC >0 <1+, Advanced or Metastatic 
Breast Cancer ................................................................................................... 76
4.2.3
Rationale for Efficacy Endpoints....................................................................... 77
4.2.4
Rationale for Other Study Endpoints................................................................. 78
4.3
Justification for Dose........................................................................................ 79
4.3.1
T-DXd Dose Rationale...................................................................................... 79
4.3.2
Chemotherapy Dose Rationale.......................................................................... 79
4.4
End of Study Definition.................................................................................... 81
5
STUDY POPULATION.................................................................................... 81
5.1
Inclusion Criteria .............................................................................................. 82

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5.2
Exclusion Criteria ............................................................................................. 86
5.3
Lifestyle Considerations ................................................................................... 88
5.4
Screen Failures ................................................................................................. 90
6
STUDY INTERVENTIONS (TREATMENTS)................................................. 91
6.1
Study Interventions (Treatments) Administered................................................. 91
6.1.1
Study Treatments.............................................................................................. 91
6.1.2
T-DXd .............................................................................................................. 94
6.2
Preparation/Handling/Storage/Accountability of Study Treatments ................... 94
6.2.1
T-DXd (DS-8201a) ........................................................................................... 94
6.2.2
Paclitaxel, Capecitabine and Nab-paclitaxel...................................................... 95
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 96
6.3.1
Patient Enrollment and Randomization ............................................................. 96
6.3.2
Procedures for Handling Incorrectly Randomized Patients................................ 97
6.3.3
Methods for Assigning Treatment Groups (Randomization).............................. 97
6.3.4
Methods for Ensuring Blinding......................................................................... 98
6.4
Study Treatment Compliance ............................................................................ 98
6.5
Concomitant Therapy........................................................................................ 98
6.5.1
Other Concomitant Medications...................................................................... 101
6.5.2
Restrictions on Concomitant Medications/Therapies....................................... 102
6.6
Dose Modification .......................................................................................... 102
6.6.1
Individual Patient Dose Modifications ............................................................ 102
6.6.1.1
T-DXd ............................................................................................................ 102
6.6.1.2
Investigator’s Choice Chemotherapy............................................................... 103
6.7
Intervention after the End of the Study............................................................ 103
7
DISCONTINUATION 
OF 
STUDY 
TREATMENT 
AND 
PATIENT 
DISCONTINUATION/WITHDRAWAL......................................................... 104
7.1.1
Permanent Discontinuation of Study Treatment............................................... 104
7.1.2
Procedures for Discontinuation of Study Treatment ........................................ 105
7.2
Patient Withdrawal from the Study.................................................................. 106
7.3
Lost to Follow up............................................................................................ 106
8
STUDY ASSESSMENTS AND PROCEDURES............................................ 107
8.1
Efficacy Assessments...................................................................................... 108
8.1.1
RECIST 1.1 Assessments................................................................................ 108
8.1.1.1
Central Reading of Scans................................................................................ 109
8.1.2
Overall Survival (OS) ..................................................................................... 109
8.1.3
PFS2............................................................................................................... 110
8.1.4
Patient-Reported Outcome (PRO) Measures ................................................... 110
8.1.4.1
EORTC QLQ-C30 ...........................................................................................111
8.1.4.2
EORTC QLQ-BR45.........................................................................................111
8.1.4.3
EQ-5D-5L .......................................................................................................111
8.1.4.4
PGIS............................................................................................................... 112
8.1.4.5
PGIC .............................................................................................................. 112
8.1.4.6
PGI-TT........................................................................................................... 112

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8.1.4.7
PGI-BR........................................................................................................... 112
8.1.4.8
PRO-CTCAE.................................................................................................. 112
8.1.4.9
Administration of Patient-Reported Outcome Measures.................................. 113
8.2
Safety Assessments......................................................................................... 115
8.2.1
Informed Consent ........................................................................................... 115
8.2.2
Physical Examinations.................................................................................... 115
8.2.3
Vital Signs ...................................................................................................... 115
8.2.4
Electrocardiograms......................................................................................... 116
8.2.5
Clinical Safety Laboratory Assessments.......................................................... 117
8.2.6
Pulmonary Assessments.................................................................................. 119
8.2.7
Echocardiograms/Multiple Gated Acquisition Scans ....................................... 120
8.2.8
ECOG Performance Status.............................................................................. 120
8.2.9
Ophthalmologic Assessments.......................................................................... 121
8.2.10
Other Safety Assessments ............................................................................... 121
8.2.10.1
Pneumonitis (ILD) Investigation..................................................................... 121
8.3
Adverse Events and Serious Adverse Events................................................... 122
8.3.1
Time Period and Frequency for Collecting AE and SAE Information.............. 122
8.3.2
Follow-up of AEs and SAEs ........................................................................... 123
8.3.3
Causality Collection........................................................................................ 124
8.3.4
Adverse Events Based on Signs and Symptoms .............................................. 125
8.3.5
Adverse Events Based on Examinations and Tests .......................................... 125
8.3.6
Hy’s Law........................................................................................................ 126
8.3.7
Disease Progression........................................................................................ 126
8.3.8
Disease Under Study....................................................................................... 126
8.3.9
New Cancers................................................................................................... 126
8.3.10
Deaths ............................................................................................................ 126
8.3.11
Adverse Events of Special Interest.................................................................. 127
8.3.12
Reporting of Serious Adverse Events.............................................................. 128
8.3.13
Pregnancy....................................................................................................... 129
8.3.13.1
Paternal Exposure........................................................................................... 130
8.3.14
Management of Study Treatment-related Toxicities......................................... 130
8.3.14.1
Specific Toxicity Management and Dose Modification Information for T-DXd131
8.3.14.2
Toxicity Management and Dose Modification Information for Investigator’s 
Choice of Chemotherapy ................................................................................ 133
8.4
Medication Error, Drug Abuse, and Drug Misuse............................................ 133
8.4.1
Timelines........................................................................................................ 133
8.4.2
Medication Error............................................................................................. 133
8.4.3
Drug Abuse..................................................................................................... 134
8.4.4
Drug Misuse ................................................................................................... 134
8.5
Overdose ........................................................................................................ 134
8.6
Human Biological Samples............................................................................. 135
8.6.1
Pharmacokinetics............................................................................................ 135
8.6.2
Immunogenicity Assessments ......................................................................... 136
8.7
Human Biological Sample Biomarkers ........................................................... 136
8.7.1
Collection of Mandatory Samples for Biomarker Analysis .............................. 136

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8.7.2
Collection of Optional Biomarker Samples ..................................................... 139
8.7.3
Other Study Related Biomarker Research ....................................................... 140
8.8
Optional Genomics Initiative Sample.............................................................. 141
8.9
Medical Resource Utilization.......................................................................... 141
9
STATISTICAL CONSIDERATIONS.............................................................. 141
9.1
Statistical Hypotheses..................................................................................... 141
9.1.1
Multiple Testing Procedure ............................................................................. 142
9.2
Sample Size Determination............................................................................. 143
9.3
Populations for Analyses................................................................................. 144
9.4
Statistical Analyses ......................................................................................... 145
9.4.1
General Considerations................................................................................... 145
9.4.2
Efficacy .......................................................................................................... 146
9.4.2.1
Primary Endpoint (PFS by BICR in the HER2-low Population) ...................... 146
9.4.2.2
Secondary Endpoints ...................................................................................... 147
9.4.3
Safety ............................................................................................................. 150
9.4.4
Other Analyses................................................................................................ 152
9.4.4.1
Patient-reported Outcomes.............................................................................. 152
9.4.4.2
Healthcare Resource Utilization...................................................................... 152
9.4.4.3
Pharmacokinetic Data..................................................................................... 152
9.4.4.4
Immunogenicity Data...................................................................................... 152
9.5
Interim Analyses............................................................................................. 153
9.5.1
Interim Futility Analysis ................................................................................. 153
9.5.2
Interim Efficacy Analysis................................................................................ 153
9.6
Data Monitoring Committees.......................................................................... 153
9.6.1
IDMC Committee........................................................................................... 153
9.6.2
ILD Adjudication Committee.......................................................................... 154
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 154
11
REFERENCES............................................................................................... 233
LIST OF FIGURES
Figure 1
Multiple Testing Procedure...................................................................... 37
Figure 2
Study Design ........................................................................................... 39
Figure 3
Hormone Receptor-positive Breast Cancer Segmented by HER2 
Receptor Status........................................................................................ 62
LIST OF TABLES
Table 1
Objectives and Endpoints......................................................................... 30

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Table 2
Study Treatments and Duration................................................................ 33
Table 3
Schedule of Assessments for Screening/Baseline ..................................... 41
Table 4
Schedule of Assessments During the Treatment Period and at End of 
Treatment ................................................................................................ 46
Table 5
Schedule of Assessments for Post-treatment Follow-up and Long-term 
Follow-up................................................................................................ 55
Table 6
ASCO/CAP HER2 2018 Testing Guidelines and Nomenclature Used in 
this Study................................................................................................. 61
Table 7
Objectives and Endpoints......................................................................... 70
Table 8
Highly Effective Methods of Contraception( < 1% failure rate) ............... 89
Table 9
Study Treatments..................................................................................... 92
Table 10
Prohibited Concomitant Medications ....................................................... 99
Table 11
Supportive Medications ......................................................................... 101
Table 12
Clinical Chemistry................................................................................. 118
Table 13
Hematology........................................................................................... 118
Table 14
Urinalysis .............................................................................................. 118
Table 15
Spirometry Components ........................................................................ 119
Table 16
Dose Reduction Levels for T-DXd......................................................... 132
Table 17
Populations for Analyses ....................................................................... 144
Table 18
Summary of Outcome Variables and Analysis Populations .................... 145
Table 19
Hy’s Law Lab Kit for Central Laboratories............................................ 179
Table 20
Summary of ASCO/CAP Guideline Recommendations 2018................. 182
Table 21
Reporting Elements for IHC .................................................................. 185
Table 22
Reporting Elements for FISH (Local HER2 Test) .................................. 185
Table 23
Summary of Imaging Modalities for Tumor Assessment........................ 187
Table 24
RECIST 1.1 Evaluation of Target Lesions ............................................. 195
Table 25
RECIST 1.1 Evaluation of Non-target Lesions....................................... 196
Table 26
RECIST 1.1 Overall Visit Response ...................................................... 197
Table 27
Toxicity Management Guidelines for T-DXd......................................... 199

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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 154
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 162
Appendix C
Handling of Human Biological Samples ................................................ 168
Appendix D
Optional Genomics Initiative Sample..................................................... 170
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 174
Appendix F
ASCO/CAP Guidelines on HER2 Testing in Breast Cancer ................... 181
Appendix G
Guidelines for Evaluation of Objective Tumor Response using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumors).... 187
Appendix H
Toxicity Management Guidelines for T-DXd......................................... 199
Appendix I
Instructions Related to COVID-19......................................................... 207
Appendix J
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire C30 and BR45 ......................................................... 209
Appendix K
Country-specific Protocol Information................................................... 224
Appendix L
Abbreviations ........................................................................................ 228

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title
A Phase 3 Randomized, Multi-center, Open-label Study of Trastuzumab Deruxtecan (T-DXd; 
DS-8201a) vs Investigator’s Choice Chemotherapy in Human Epidermal Growth Factor 
Receptor 2 (HER2)-low, Hormone Receptor (HR) Positive Breast Cancer Patients whose 
Disease has Progressed on Endocrine Therapy (ET) in the Metastatic Setting 
(DESTINY-Breast06).
Study Rationale 
Within breast cancers traditionally classified as HER2-negative, there exists a spectrum of 
HER2 expression. In addition to tumors with no detectable HER2 staining (i.e., 
immunohistochemistry [IHC] null), the category encompasses IHC 2+/in situ hybridization 
(ISH) negative and IHC 1+ cancers (defined in this study collectively as HER2-low), as well 
as cancers that have lower, but detectable HER2 staining, i.e., faint or barely perceptible and 
incomplete membrane staining that is seen in 10% or fewer tumor cells. These latter cancers 
are included in the IHC 0 category according to the American Society of Clinical 
Oncology/College of American Pathologists (ASCO/CAP) guidelines, and in this study are 
referred to as HER2 IHC >0 <1+.
Currently, patients with HR+, HER2-low or HER2 IHC >0 <1+ advanced or metastatic breast 
cancer follow the same treatment paradigm as HR+, HER2-negative breast cancer patients. In 
general, ET is considered the preferred option for HR+, HER2-negative breast cancer. The 
optimal treatment sequence is considered to be the use of ET + CDK4/6 inhibitors first line, 
followed by subsequent ET with targeted therapies (e.g., mTOR or PI3-K inhibitors [for PI3-K 
mutant tumors]) (Cardoso et al 2020). In patients whose disease has progressed after multiple 
lines of ET with or without targeted therapies, or in patients whose disease has primary 
endocrine resistance (progressive disease within the first 6 months of first-line ET for 
advanced breast cancer), chemotherapy may be appropriate as currently available anti-HER2 
therapy has not demonstrated clinical benefit in these patients. In addition, for patients who 
have primary endocrine resistance (i.e., progressive disease within the first 6 months of first-
line ET for advanced breast cancer), chemotherapy may also be appropriate as continued 
treatment with endocrine therapies following progression on ET + CDK4/6 inhibitors has been 
shown to provide less benefit (Rossi et al 2019, Sledge et al 2020, Turner et al 2018).
In clinical trials, in a heterogeneous breast cancer population, treatment with standard of care 
with single agent chemotherapy leads to response rates of 10% to 30%, a median 
progression-free survival (PFS) of 4-6 months and a median overall survival (OS) of 

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15-25 months. Chemotherapy is also associated with significant adverse events (AEs), 
including hematologic toxicities, nausea, vomiting, alopecia, and skin reactions. Therefore, 
there is a need for treatments with a better benefit/risk profile in this patient population who 
receive chemotherapy after endocrine treatment. 
In the Phase 1 DS8201-A-J101 clinical trial (NCT02564900), trastuzumab deruxtecan 
(T-DXd; previously known as DS-8201a) demonstrated promising antitumor activity with an 
objective response rate (ORR) of 37% in HER2-low patients, with a majority of patients 
experiencing tumor shrinkage with durable response (Modi et al 2020). In addition, there were 
11 patients in this study whose HER2 expression was locally reported (results from a local 
HER2 assay) as IHC 1+, 2+ or 3+ but who were categorized by a central laboratory as HER2 
IHC 0 as per ASCO/CAP guidelines 2018. Of these 11 patients, 5 (45.5%) had a tumor 
response. In the Phase 2 DAISY clinical trial (NCT04132960), patients with advanced breast 
cancer who had received at least one prior line of chemotherapy were treated with T-DXd. In 
37 patients with HER2 IHC 0+, confirmed ORR was 29.7% and median PFS was 4.2 months 
(Diéras et al 2022). Data from both studies suggest that the antitumor activity of T-DXd may 
extend to the population of patients with HER2 IHC < 1+, warranting further evaluation.
Therefore, in this Phase 3 study, T-DXd will be compared against investigator’s choice single 
agent chemotherapy to determine if T-DXd can improve outcomes in HER2-low 
(IHC 2+/ISH- and IHC 1+), HR+ breast cancer patients whose disease has progressed on at 
least 2 lines of prior ET or within 6 months of first line ET + CDK4/6i in the metastatic 
setting (N=700). In addition to the primary population of HER2-low patients being studied, 
the study will also randomize approximately 150 patients with HER2 IHC >0 <1+ expression.
Objectives and Endpoints
Table 1
Objectives and Endpoints
Objectives
Endpoints
Primary
!
To assess the efficacy of T-DXd compared with 
investigator’s choice chemotherapy in terms of 
PFS by BICR in the HR+, HER2-low 
(IHC 2+/ISH- and IHC 1+) population
!
PFS by BICR according to RECIST 1.1 in the 
HR+, HER2-low population 
Secondary
The key secondary objectives are:
!
To assess the efficacy of T-DXd compared with 
investigator’s choice chemotherapy in terms of 
OS in the HR+, HER2-low population
!
To assess the efficacy of T-DXd compared with 
investigator’s choice chemotherapy in terms of 
PFS by BICR and OS in the ITT population 
(HER2 IHC >0 <1+ and HER2-low)
The key secondary endpoints are:
!
OS in the HR+, HER2-low population
!
PFS by BICR according to RECIST 1.1 in the 
ITT population (HER2 IHC >0 <1+ and 
HER2-low)
!
OS in the ITT population 

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Table 1
Objectives and Endpoints
Objectives
Endpoints
The other secondary objectives are:
!
To further assess the efficacy of T-DXd
compared with investigator’s choice 
chemotherapy in terms of PFS by Investigator 
assessment, ORR and DoR by BICR and 
Investigator assessment in the HR+, HER2-low 
population
!
To further assess the efficacy of T-DXd
compared with investigator’s choice 
chemotherapy in terms of ORR and DoR by 
BICR and Investigator assessment in the ITT 
population
The other secondary endpoints are:
!
ORR and DoR by BICR and Investigator 
assessment according to RECIST 1.1 in the 
HR+, HER2-low population
!
PFS by Investigator assessment according to 
RECIST 1.1 in the HR+, HER2-low population
!
ORR and DoR by BICR and Investigator 
assessment according to RECIST 1.1 in the ITT 
population (HER2 IHC >0 <1+ and HER2-low)
!
To compare the effect of T-DXd with 
investigator’s choice chemotherapy in terms of 
PFS2 according to Investigator assessment, time 
to first subsequent treatment or death (TFST) 
and time to second subsequent treatment or 
death (TSST) in the HR+, HER2-low population 
and the ITT population
!
PFS2, TFST, TSST in the HR+, HER2-low 
population and the ITT Population
!
To assess the safety and tolerability profile of 
T-DXd compared with investigator’s choice 
chemotherapy
!
AEs, changes from baseline in laboratory 
findings, ECHO/MUGA scans, ECGs and vital 
signs
!
To assess the PK of T-DXd
!
T-DXd, total anti-HER2 antibody and 
MAAA-1181a concentrations in serum
!
To assess symptoms, functioning and HRQoL in 
patients treated with T-DXd compared with 
investigator’s choice single agent chemotherapy
The PROs include:
!
Change from baseline in EORTC QLQ-C30 and 
EORTC QLQ-BR45 scale scores
!
Time to deterioration in EORTC QLQ-C30 
scores
!
To investigate the immunogenicity of T-DXd
!
Number and percentage of patients who develop 
ADA for T-DXd
Exploratory a
!
To collect blood and tissue samples 
pre-treatment, on-treatment and post-treatment 
for defining biological responses to T-DXd and 
to investigate predictive markers of response, 
acquired resistance and other markers that may 
correlate with likelihood of clinical benefit or 
tolerability; samples and generated data may be 
used to support diagnostic development
Biomarkers that include but are not limited to 
biomarkers of T-DXd sensitivity/resistance and 
immunological biomarkers are:
!
Protein expression (IHC and proteomic analysis 
including, but not limited to ERBB2, related 
family members and TOPO-1 expression)
!
Mutational profiling in tissue, blood and ctDNA
!
Plasma and blood analysis for ctDNA 
(exploration of genetic alterations in ctDNA and 
dynamic changes, including ctDNA clearance)
!
mRNA expression (exploration of gene 
expression, molecular subtype and gene 

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Table 1
Objectives and Endpoints
Objectives
Endpoints
expression changes following treatment) in 
tissue and blood
!
To explore the impact of treatment and disease 
state on health utility using the EQ-5D-5L
!
To assess patient-reported treatment tolerability 
!
To assess the patient’s overall impression of the 
severity of their cancer symptoms, change in 
condition since starting the study and 
benefit/risk assessment
!
To explore the impact of treatment and disease 
on health care resource use
!
EQ-5D-5L health state utility index
!
Patient-reported treatment tolerability 
(PRO-CTCAE and PGI-TT)
!
Proportion of patients with overall PGIS, PGIC 
and PGI-BR
!
Health care resource use will be captured, 
including inpatient admissions, intensive care 
unit admissions, and length of stay in hospital.
!
To explore & optimize technologies for 
detection of HER2 protein expression
!
Exploration of IHC and non-IHC methods to 
determine tumoral HER2 expression
ADA = anti-drug antibody; AE = adverse events; BICR = Blinded independent central review; 
ctDNA = circulating tumor DNA; DoR = duration of response; ECG = electrocardiogram; 
ECHO/MUGA = echocardiogram/multigated acquisition; EORTC QLQ = European Organization for the 
Research and Treatment of Cancer Quality of Life Questionnaire; EQ-5D-5L = European Quality of Life 5-
Domain 5-Level Scale; ERBB = erythroblastic oncogene B; HER2 = human epidermal growth factor 2; HR = 
hormone-receptor; HRQoL = health-related quality of life; IHC = immunohistochemistry; ISH = in situ 
hybridization; ITT = intent-to-treat population; mRNA = messenger RNA; ORR = objective response rate; 
OS = overall survival; PFS = progression-free survival; PFS2 = time from randomization to second 
progression or death; PGI-BR = Patient Global Impression – Benefit/Risk; PGIC = Patient Global Impression–
Change; PGIS = Patient Global Impression–Severity; PGI-TT = Patient Global Impression–Treatment 
Tolerability; PK = pharmacokinetics; PRO = patient-reported outcome; PRO-CTCAE = patient-reported 
outcomes version of the Common Terminology Criteria for Adverse Events; RECIST 1.1 = Response 
Evaluation Criteria In Solid Tumors 1.1; TFST = time to first subsequent treatment or death; TOPO = 
topoisomerase; TSST = time to second subsequent treatment or death.
a
Patients randomized into the study in China will be excluded from exploratory objectives requiring the 
provision of additional tumor or blood samples, with the exception of samples for exploratory safety or 
clinical benefit analyses to identify candidate markers which may correlate with likelihood of clinical 
benefit/tolerability (Section 8.7.1).
Overall Design
The study is an open-label, multi-center, randomized study in HR+, HER2-low breast cancer 
patients whose disease has progressed on at least 2 lines of prior ET or within 6 months of 
first line ET + CDK4/6i in the metastatic setting. The primary purpose of the study is to 
determine the efficacy and safety of T-DXd compared with investigator’s choice single agent 
chemotherapy in the target population. Approximately 850 patients (700 patients with HER2 
IHC 2+/ISH- and IHC 1+ [HER2-low] expression and 150 patients with HER2 IHC >0 <1+ 
expression) will be randomized 1:1 across approximately 300 centers globally to receive 
either T-DXd or investigator’s choice single agent chemotherapy (capecitabine, paclitaxel or 
nab-paclitaxel) until RECIST 1.1 defined disease progression (PD), unless there is 
unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met. 

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The details of study treatment and their schedules are provided in Table 2. To ensure adequate 
representation of each subgroup of the HER2-low population, at least 240 patients in each 
HER2 IHC group (IHC 2+/ISH- and IHC 1+) across both treatment arms (120 patients per 
arm) will be randomized.
Table 2
Study Treatments and Duration
Compound
Dose
Route
Schedule
T-DXd
5.4 mg/kg
IV
Every 3 weeks
Capecitabine
1000 or 1250 mg/m2
Oral
Twice daily orally for 2 weeks followed by a 
1-week rest period in 3-week cycles
Paclitaxel
80 mg/m2
IV
Every week (qw) in 3-week cycles
Nab-paclitaxel a
100 mg/m2
IV
Every week (qw) for 3 weeks followed by a 
one-week rest period in 4-week cycles
IV = intravenous; qw = every week
a
Although nab-paclitaxel is given in 4-week cycles, the schedule of assessments must be followed (see 
Table 5; e.g., tumor assessment scans every 6 weeks [q6w ± 1 week]).
RECIST 1.1 tumor assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis at screening (as baseline) with follow-ups at q6w ± 1 week from the date 
of randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48, until objective 
RECIST 1.1 disease progression by investigator assessment (see SoAs in Section 1.3). 
Patients who permanently discontinue study treatment for reasons other than objective 
RECIST 1.1 disease progression, withdrawal of consent, closure of study or death (regardless 
of whether subsequent anticancer therapy was started) should continue to have RECIST 1.1 
scans performed as per schedule until RECIST 1.1 disease progression. Following 
investigator-determined RECIST 1.1 progression, it is mandatory to perform an additional 
imaging assessment (preferably within 4 to 6 weeks after investigator PD) for central review 
to support the primary endpoint of PFS by BICR. In addition, every attempt should be made to 
continue to collect and submit subsequent scans (completed per standard practice / as 
clinically indicated) for central review until the primary PFS analysis DCO, or until the 
Sponsor notifies the site to discontinue (whichever is earlier) regardless of whether the subject 
has started another anti-cancer therapy. Scans following investigator determined RECIST 1.1 
progression should include brain scans for patients who are enrolled with baseline stable brain 
metastases or if clinically indicated.
The study will compare PFS, OS and other measures of efficacy between the study treatment 
groups and further characterize the safety and tolerability profile of T-DXd.
Duration of Treatment: Unless specific treatment discontinuation criteria are met or the 
patient withdraws consent, all patients will continue receiving treatment until RECIST 1.1 
defined disease progression. For patients randomized to the investigator’s choice single agent 

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chemotherapy arm, crossover to T-DXd will not be permitted.
Follow-up of Patients post Discontinuation of Study Treatment: After discontinuation of 
study treatment, all patients will have post-treatment follow-up scheduled at 40 days (+7 days) 
after their last dose of study treatment. Patients who have discontinued treatment for reasons 
other than progressive disease per RECIST 1.1 will also be followed up with tumor 
assessments until radiological progression (or death). All patients will be followed up for 
PFS2 and survival status, unless consent was withdrawn.
Survival: All patients randomized should be followed up for survival unless consent was 
withdrawn. Long-term/survival follow-up visits will be performed every 3 months (±14 days) 
from the date of the 40-day (+7 days) follow-up visit until death, withdrawal of consent, or 
study closure, whichever occurs first.
Number of Patients:
The study will screen approximately 1417 patients to randomize approximately 850 patients 
(700 HER2 IHC 2+/ISH- and IHC 1+ [HER2-low] patients and 150 HER2 IHC >0 <1+ 
patients). To ensure adequate representation of each subgroup of the HER2-low population, at 
least 240 patients in each HER2 IHC group (IHC 2+/ISH- and IHC 1+) across both treatment 
arms (120 patients per arm) will be randomized. The HER2-low (IHC 2+/ISH- and IHC 1+) 
strata will be closed once a total of 700 patients have been randomized in these strata. At this 
time, a decision will be made by AstraZeneca on whether recruitment into the 
HER2 IHC >0 <1+ population will be stopped if the 150-patient target has not been met.
Data Monitoring Committees: 
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. An IDMC comprised of 
independent experts will be convened and will meet approximately 6 months after the study 
has started or after the first 60 patients have been randomized, whichever occurs first. The 
IDMC will review unblinded 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 and at each meeting make recommendations to continue, amend, or stop 
the study based on safety findings. In addition, the IDMC will be asked to review efficacy 
data at pre-specified timepoints (e.g., interim futility analysis for HER2 IHC >0 <1+ 
population).
An interstitial lung disease (ILD) Adjudication Committee will review all cases of potential 
ILD/pneumonitis. To ensure adequate evaluation, relevant additional data from within the 

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clinical database and other sources, including imaging data, may be provided to the 
adjudication committee to fully characterize medical history (e.g., smoking, radiation and 
pulmonary history), diagnostic evaluation, treatment and outcome of the event. Further details 
can be found in the ILD Adjudication Charter.
Statistical methods
Efficacy
The primary endpoint of the study is PFS by BICR according to RECIST 1.1 in the HER2-low 
population. PFS is defined as the time from the date of randomization until the date of disease 
progression, as defined by RECIST 1.1, or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from randomized therapy or receives another 
anticancer therapy prior to progression. The key secondary efficacy endpoints include OS in 
the HER2-low population, PFS by BICR according to RECIST 1.1 in the Intent-to-treat (ITT) 
population and OS in the ITT population. The null hypothesis for the primary and key 
secondary efficacy endpoints (PFS and OS) is that there is no difference in PFS/OS 
distribution between T-DXd and the investigator’s choice chemotherapy. Other secondary 
efficacy endpoints include PFS by Investigator assessment according to RECIST 1.1 in the 
HER2-low population and objective response rate (ORR) and duration of response (DoR) by 
BICR and Investigator assessment according to RECIST 1.1, time to second progression or 
death (PFS2), time to first subsequent treatment or death (TFST) and time to second 
subsequent treatment or death (TSST) in the HER2-low and ITT populations. 
The ITT population comprises all patients randomized (HER2 IHC >0 <1+/1+/2+ population). 
The HER2-low population comprises the subset of patients included in the ITT population 
with HER2 IHC 1+/2+ as determined per the IRT data for HER2 IHC expression. The ITT 
population and HER2-low population will be used for all efficacy endpoints and will be 
analyzed according to randomized treatment regardless of the treatment received (ITT 
principle). 
PFS in the HER2-low population and ITT population will be tested once, when PFS reaches 
approximately 65% maturity (456 events) in the HER2-low population. This is estimated to 
occur 29 months after the first patient is randomized (4 months after randomization is 
completed) assuming a non-uniform accrual of patients with a duration of 25 months. At this 
time, it is expected that at least 553 events (65% maturity) will have been observed in the ITT 
population.
OS in the HER2-low population and ITT population will be tested at two interim and one final 

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analyses as described below:
!
The first interim OS analysis will be performed at the time of the final PFS analysis. It is 
expected that 216 OS events (31% maturity or 41% information fraction) will have been 
observed in the HER2-low population and 263 OS events will have been observed in the 
ITT population. 
!
The second interim OS analysis will occur when approximately 392 OS events have been 
observed in the HER2-low population (56% maturity or 75% information fraction). This 
is anticipated to occur approximately 44 months after the first patient is randomized. It is 
expected that 477 OS events have been observed in the ITT population at this time.
!
The final OS analysis will be performed when approximately 521 OS events have been 
observed in the HER2-low population (74% maturity), which is expected to occur 
approximately 63 months after the first patient is randomized. At this time, it is estimated 
that 632 OS events will have been observed in the ITT population.
To strongly control the family wise error rate at 5% in terms of the primary and key secondary 
endpoints, a multiple testing procedure (MTP) with the following gatekeeping strategy will be 
employed:
Step 1: Test PFS in the HER2-low population at a 5% alpha level. If significance is achieved, 
go to Step 2.
Step 2: Test PFS in the ITT population at a 1.5% alpha level and OS in the HER2-low 
population at the 3.5% alpha level. If PFS in the ITT population is significant, the 1.5% alpha 
will be recycled to OS in the HER2-low population. Similarly, if OS in the HER2-low 
population is significant at either the interim or final analysis, the 3.5% alpha will be recycled 
to PFS in the ITT population (i.e., PFS in the ITT population at the PFS analysis data cut off 
(DCO) will be tested at 5% alpha). If both PFS in the ITT population and OS in the HER2-low 
population are significant, go to Step 3.
Step 3: Test OS in the ITT population at a 5% alpha level.
The 3.5% initial alpha allocated to OS in the HER2-low population will be distributed 
between the two interim and final analyses using the Lan DeMets spending function that 
approximates the O’Brien Fleming alpha-spending approach (Lan and DeMets 1983). Under 
this procedure, the adjusted significance levels at the interim and final analyses are determined 
by the information fraction available at the time of analysis (i.e., exact number events 
observed), giving greater weight to analyses performed at the end of the study than those 
performed earlier. 
If PFS in the ITT population is significant at 1.5% alpha (Step 2 above) such that this alpha is 

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reallocated to OS in the HER2-low population, the adjusted significance levels at each of the 
analysis time points for OS in the HER2-low population will be updated per the Group 
sequential Holm variable procedure (Ye et al 2013). The Lan DeMets spending function that 
approximates the O'Brien-Fleming alpha-spending approach will be used to derive the 
updated significance levels. The same significance levels will be used for the interim OS 
analyses in the HER2-low population and ITT population. The significance level at the final 
OS analysis will be derived separately for each population and will be based on the actual 
number of events at the interim and final analysis, and the alpha already spent at the interim 
analyses for the HER2-low and ITT population, respectively.
The gatekeeping procedure is also shown in Figure 1.
An interim futility analysis will be performed after the first 70 patients in the 
HER2 IHC >0 <1+ population have been randomized and have had at least 24 weeks of 
follow-up from the point of randomization or withdrawn from the study. The IDMC will make 
a recommendation on whether or not to stop recruitment in the HER2 IHC >0 <1+ population 
based on the results of the futility analysis. If it is decided to limit further recruitment only to 
the HER2-low population, tests on the ITT population will not be performed.
Figure 1
Multiple Testing Procedure

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HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; ITT = intent-to-treat; 
OS = overall survival; PFS = progression-free survival
Note: Tests on the ITT population will not be performed if the interim futility analysis in the HER2 IHC>0 <1+ 
population results in the cessation of enrollment of HER2 IHC>0 <1+ patients in this study.
For the primary endpoint, PFS distribution in the HER2-low population will be compared 
between T-DXd and investigator’s choice chemotherapy using a stratified log-rank test 
adjusting for prior CDK4/6 inhibitor use (yes vs no), HER2 IHC expression (IHC 1+ vs 
IHC 2+/ISH-), and prior taxane use in the non-metastatic setting (yes vs no). The stratification 
variables in the statistical modelling will be based on the values entered in interactive 
response technology (IRT). If there are insufficient events per stratum, the strata will be 
pooled following a pooling strategy that will be prespecified in the statistical analysis plan 
(SAP). The hazard ratio and its confidence interval (CI) will be estimated from a stratified 
Cox Proportional Hazards model with strata being the same as the stratification variables from 
IRT.
Sample Size Estimate
The study provides adequate power to show a statistically significant between-treatment 
difference in PFS in the HER2-low population. Based on a 2-sided significance level of 5%, 
a total of 456 PFS events (65% maturity) will provide at least 95% power to detect a hazard 
ratio of 0.55 (increase in median PFS from 5.5 to 10 months) in the HER2-low population, 
assuming an exponential distribution for both treatment groups.
If PFS in the HER2-low population is significant, the study also provides sufficient power to 
demonstrate a statistically significant difference in OS in the HER2-low population. Based on 
a 2-sided alpha of 3.5% and taking into account two interim OS analyses, a total of 521 OS 
events will be required to achieve 80% power to detect a hazard ratio of 0.77 (increase in 
median OS from 20.5 to 26.6 months) in the HER2-low population, assuming an exponential 
distribution for both treatment groups. Assuming 74% maturity at the time of the final OS 
analysis, approximately 700 patients will need to be randomized in the HER2-low population. 
In addition to the 700 patients in the HER2-low population, approximately 150 patients with 
HER2 IHC >0 <1+ expression will be randomized, which will total up to approximately 
850 patients randomized in the study. 
Safety
Safety summaries will be provided using the safety analysis set (SAF) and the HER2-low 
SAF. The SAF will include all patients who received at least 1 dose of study treatment while 
HER2-low SAF will include the subset of patients from SAF with HER2 IHC 1+/2+ as 
determined per the IRT data for the HER2 IHC expression. Safety data will be presented using 

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descriptive statistics unless otherwise specified. Safety data will be summarized according to 
the treatment received. Data from all cycles of treatment will be combined in the presentation 
of safety data. AEs including serious adverse events (SAEs), AEs leading to discontinuation, 
AEs leading to dose reductions, and adverse events of special interest (AESIs) will be listed 
individually by patient using Medical Dictionary for Regulatory Activities (MedDRA) 
preferred terms and National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0. The number of patients experiencing each AE will be 
summarized by treatment arm and CTCAE Grade. Other safety summaries will be outlined in 
the SAP.
1.2
Study Schema
The study design is summarized in Figure 2.
Figure 2
Study Design
BICR = blinded independent central review; CDK = cyclin-dependent kinase; ctDNA = circulating tumor DNA; 
DoR = duration of response; ET = endocrine therapy; HER2 = human epidermal growth factor receptor 2; 
HR = hormone receptor; HRQoL = health-related quality of life; IHC = immunohistochemistry; ISH = in situ 
hybridization; ITT = intent-to-treat; ORR = objective response rate; OS = overall survival; PFS = progression-
free survival; T-DXd = trastuzumab deruxtecan

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1.3
Schedule of Assessments
The procedures for the screening and treatment periods of this study are presented in Table 3
and Table 4, respectively. Whenever vital signs and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: vital signs and then blood 
draws. Whenever electrocardiograms (ECGs), vital signs, and blood draws are scheduled for 
the same nominal time, the assessments should occur in the following order: ECG, vital signs, 
and then blood draws. The timing of the first 2 assessments should be such that it allows the 
blood draw (e.g., pharmacokinetic [PK] blood sample) to occur at the timepoints indicated in 
the schedule of assessments (SoAs).
After signing the main informed consent form (ICF), patients 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, the patients who pass the eligibility criteria check will be 
randomized into the study. Every effort should be made to minimize the time between 
randomization and dosing. Dosing should occur no more than 3 days after randomization. If it 
is anticipated that dosing cannot occur within 3 days, a discussion with the AstraZeneca Study 
Physician is required. Patients who fail to meet the eligibility criteria will be termed as “screen 
failures.”
An optional pre-screen ICF may 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 history, availability of required number of slides for study, never previously 
HER2-positive). When a pre-screen ICF is signed, it is recommended that the main ICF and 
other study procedures not be started until the sample submitted for HER2 testing is accepted 
for central laboratory testing. 
1.3.1
Enrollment/Screening Period
Table 3 shows all procedures to be conducted at the screening visit.

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Table 3
Schedule of Assessments for Screening/Baseline 
Procedures
Screening/Baseline
For details, 
see Section
Days -28 to -1
Days -14 to -1 a
Informed consent
Written informed consent; consent for study 
procedures b
X
5.1 and 8.2.1
Informed consent: blood sample collection for 
optional genetic analysis
X
8.8
Tumor assessments
Tumor assessment by RECIST 1.1 (CT or MRI 
±X-ray) c; Submit baseline images for BICR
X
8.1.1
Brain MRI/CT imaging d
X
8.1.1
Whole body bone (scintigraphy) scan e
X
8.1.1
Study procedures and assessments
Verify inclusion/exclusion criteria
X
5.1 and 5.2
History of prior cancer treatment
X
5.1
Demographics, including baseline characteristics
X
5.1
High Resolution CT of the chest f
X
8.2.6
Pulmonary function test g
X
8.2.6
SpO2 
X
8.2.6
Medical history h
X
5.1
Physical examination (full)
X
8.2.2
ECOG performance status
X
8.2.8
ECHO/MUGA scan (for LVEF evaluation) i
X
8.2.7
12-lead ECG (triplicate) j
X
8.2.4
Vital signs k
X
8.2.3
Assessment of AEs/SAEs l
X
8.3
Concomitant medications
X
6.5
Ophthalmologic assessments m
X
8.2.9
Laboratory assessments
Clinical chemistry a, n
X
Table 12
Hematology a, n
X
Table 13
Troponin o
X
8.2.7
Coagulation a, p
X
Table 13
Urinalysis q
X
Table 14
Pregnancy test r
X
8.2.5
Hepatitis B Surface Antigen / Hepatitis C serology
X 
8.2.5
HIV Antibody test (as required by local regulations) 
X 
8.2.5

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Table 3
Schedule of Assessments for Screening/Baseline 
Procedures
Screening/Baseline
For details, 
see Section
Days -28 to -1
Days -14 to -1 a
Biomarker assessments
FFPE tumor tissue sample for confirmation of 
HER2 status centrally (mandatory) s, t
X
8.7.1
Blood sample for plasma biomarker assessment 
(ctDNA) (mandatory) u
X
8.7.1
Blood sample for gene expression assessment 
(mandatory) u
X
8.7.1
Blood sample for PBMC isolation (mandatory) u
X
8.7.1
Paired biopsies (optional) v
X
8.7.2
Other Assessments
Healthcare resource use (HOSPAD)
X
8.9
AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; aPTT = activated partial 
thromboplastin time; AST = aspartate transaminase; BICR = blinded independent central review; 
BUN = blood urea nitrogen; CT = computed tomography; ctDNA = circulating tumor DNA; 
DLCO = diffusing capacity of the lungs for carbon monoxide; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; FFPE = formalin-fixed and 
paraffin-embedded; FEV1 = forced expiratory volume; FVC = forced vital capacity; G-CSF = granulocyte-
colony stimulating factor; HER2 = human epidermal growth factor receptor 2; HIV = human 
immunodeficiency virus; HRCT = high-resolution computed tomography; ICF = Informed Consent Form; ILD 
= interstitial lung disease; INR = international normalized ratio; IV = intravenous; LDH = lactate 
dehydrogenase; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
MUGA = multiple gated acquisition scans; PBMC = periphery blood mononuclear cell; PFT = pulmonary 
function test; PT = prothrombin time; PTT = partial thromboplastin time; RECIST = Response Evaluation 
Criteria in Solid Tumors; SAE = serious adverse event; SpO2 = pulse oximetry; TBL = total bilirubin; 
ULN = upper limit of normal
Note: Dosing should occur no more than 3 days after randomization. If it is anticipated that dosing cannot 
occur within 3 days, a discussion with the AstraZeneca Study Physician is required.
a
For enrollment into the study, adequate organ and bone marrow function (values mentioned below for 
different parameters) should be confirmed within 14 days before randomization: (see inclusion criterion 
#11; Section 5.1)
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. All 
patients will be required to provide consent to supply a sample of their tumor for entry into this study. 
This consent is included in the main patient ICF. An optional pre-screen ICF may be signed for 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 a candidate for this study based on available information (e.g., 
medical history, availability of required number of slides for study). The collection of additional biopsies 
upon progression is strongly encouraged. 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 
patient. However, all results from the screening assessments must have been obtained within 14 or 28 
days of randomization depending on procedure

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Table 3
Schedule of Assessments for Screening/Baseline 
Procedures
Screening/Baseline
For details, 
see Section
Days -28 to -1
Days -14 to -1 a
c
RECIST 1.1 assessments will be performed on images from IV contrast-enhanced CT (preferred) or MRI 
of the chest, abdomen, and pelvis for all patients. For patients with bone-only disease that is 
non-measurable, X-ray is also an acceptable imaging modality in addition to the required CT or MRI of 
the chest, abdomen and pelvis. Additional anatomy should be imaged based on signs and symptoms of 
individual patients at baseline and follow-up. Digital copies of all scans should be maintained at the 
Investigative site as source documents.
d
Brain imaging by IV contrast-enhanced MRI (preferred) or IV contrast-enhanced CT will be required for 
all patients at screening/baseline. If brain metastases are discovered at baseline, note that patient must not 
meet exclusion criterion #8 to be eligible for the study and those patients who are enrolled with baseline 
stable brain metastases will receive regularly scheduled follow-up brain scans (q6w ±1 week from the 
date of randomization for 48 weeks, and then q9w ±1 week, starting at Week 48 thereafter until 
RECIST 1.1 disease progression) while on study. 
e
Any suspicious abnormalities (i.e., hotspots) identified on the bone scans at baseline and on subsequent 
bone scans MUST be confirmed by X-ray, CT scan with bone windows or MRI. The same modality must 
be used throughout the trial for confirmation for a given lesion/patient. Bone lesions identified as target 
lesions or non-target lesions at baseline will be followed up according to the same assessment schedule 
as for all other lesions. 
f
A non-contrast HRCT scan of the chest is preferred if feasible, otherwise a non-contrast CT is 
acceptable. The HRCT/CT chest scan will be performed for all patients, in addition to standard CT/MRI 
scans of chest/abdomen/pelvis for tumor assessments. If both an HRCT/CT of the chest for assessment of 
ILD/pneumonitis and a diagnostic IV contrast enhanced chest CT scan for tumor response assessment (as 
part of chest-abdomen-pelvis imaging) are to be acquired in the same imaging session, HRCT/CT should 
be performed first. HRCT scans are acquired on study as and when ILD/pneumonitis is suspected/as 
clinically indicated.
g
PFT at a minimum should include spirometry (minimum requirement of: FVC [L], FVC % predicted, 
FEV1 [L], FEV1 % predicted, FEV1/FVC %). DLCO will be performed (when feasible), but for patients 
with prior severe and/or clinically significant pulmonary disorders, DLCO is a requirement.
h
To include history, type and frequency of tobacco use, e-cigarette use, vaping (including dates)
i
An ECHO/MUGA scan to assess LVEF will be conducted at screening. The modality of the cardiac 
function assessments must be consistent within patient (i.e., if ECHO is used for the screening 
assessment, then ECHO should also be used for subsequent scans if required). The patients should also 
be examined using the same machine and operator whenever possible.
j
At screening, ECGs will be obtained in triplicate (3 individual ECG tracings should be obtained in 
succession, no more than 2 minutes apart. The full set of triplicates should be completed within 
5 minutes). ECGs will be taken in a supine/semi-recumbent position.
k
Height will be measured at screening only
l
For patients who sign the pre-screening ICF, only SAEs directly related to tissue screening procedure 
(i.e., if a patient undergoes a tumor biopsy) will be reported during the pre-screening period.
m
Ophthalmologic assessments including visual acuity testing, slit lamp examination and fundoscopy will 
be performed at screening.
n
Laboratory tests 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, ALP, ALT, AST, total bilirubin, 
BUN/urea, calcium, chloride, serum creatinine, LDH, sodium, potassium, bicarbonate (where available) 
and magnesium
o
Collect blood samples for troponin (preferably high-sensitivity troponin-T) at screening 
p
Coagulation parameters: PT or INR and PTT or aPTT are to be assessed at baseline.
q
Protein, blood, microscopy assessment (if indicated), and specific gravity

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Table 3
Schedule of Assessments for Screening/Baseline 
Procedures
Screening/Baseline
For details, 
see Section
Days -28 to -1
Days -14 to -1 a
r
For women of childbearing potential, a negative result from a serum pregnancy test must be available at 
the screening visit (see inclusion criterion #13). A pregnancy test (urine or serum test per institutional 
guideline) 72 hours before randomization is required. Within 72 hours before randomization, if a positive 
urine pregnancy test result is confirmed using a serum test in a female patient of child bearing potential, 
then the patient should not be randomized into the study. 
s
A mandatory FFPE tumor sample obtained at the time of metastatic disease or later must be provided; the 
most recently collected pre-randomization tumor sample from the time of metastatic disease or later is 
required. If no archival specimens are available, a newly acquired biopsy specimen is acceptable. If 
applicable, a coagulation sample (not needed for needle biopsies but needed for surgical biopsies) should 
be taken 24 hours prior to tumor biopsy. 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.
t
Not applicable if the patient went through pre-screening and tumor sample was collected and submitted 
to HER2 central laboratory before screening.
u
This sample will not be collected in China.
v
Paired biopsies (optional): Baseline sample: at screening or pre-dose on Cycle 1, Week 1, Day 1 (see 
Table 5 for more details on on-treatment schedules)

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1.3.2
Treatment Period
Procedures to be conducted during the treatment period through end of treatment (EOT) are 
presented in Table 5. Patients must not be randomized and must not be treated unless all 
eligibility criteria have been met.
At study visits when patients do not receive study treatment, all of the assessments scheduled 
to be done before infusion will be performed.
The timing of ECGs and vital sign assessments should be such that it allows the blood draw 
(e.g., PK blood sample) to occur at the exact nominal time. All samples are collected before 
infusion unless otherwise indicated.

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
Study procedures and assessments
Physical 
examination 
(targeted)
X d
X d
X d
X d
X
8.2.2
Vital signs 
X
X
X
X
X
X
X
X
X
X
8.2.3
Body weight e
X
X
X
X
X
8.2.3
High resolution 
CT of the chest 
f
Only if ILD/pneumonitis is suspected
8.2.6
12-lead ECG g
X
X 
(C4 and every 4 cycles 
thereafter until EOT)
X
8.2.4
SpO2
X h
X
X
X
X h
X
X h
X
X h
X
8.2.6
ECOG 
performance 
status
X d
X d
X d
X d
X
8.2.8
Concomitant 
medications
X
6.5
AEs/ SAEs
X
8.3

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
ECHO or 
MUGA (LVEF) 
X i
(Day 1 of Cycle 5 and 
every 4 cycles [± 7 days] 
thereafter until EOT)
X
8.2.7
Ophthalmologic 
assessments j
As clinically indicated
8.2.9
Laboratory assessments 
Clinical 
chemistry l
X d, k
X
X
X d
X d
X d
X 
Table 12
Hematology l
X d, k
X
X
X d
X d
X d
X 
Table 13
Coagulation m
As clinically indicated
Table 13
Troponin n
As clinically indicated
8.2.7
Pregnancy test
X o
X o
X o
X o
X 
8.2.5
Urinalysis
As clinically indicated
Table 14
Pharmacokinetic and Immunogenicity assessments (only for patients who receive T-DXd) p
Pre-dose blood 
sample for 
T-DXd PK 
analysis 
X 
(Within 
6 h BI)
X 
(Within 
6 h BI)
X (Within 6 h BI at C4, 
C6, and C8)
8.6.1
Post-dose blood 
sample for 
T-DXd PK 
analysis 
X (Within 15 
min after EOI, 
and 5 hrs [± 2 
hrs] post-
infusion)
X 
(Within 
15 min 
after 
EOI)
X 
(Within 
15 min 
after 
EOI, C4 
only)
8.6.1

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
Blood sample 
for T-DXd
ADA 
assessment in 
serum
X 
(Within 
8 h BI) 
X 
(Within 
8 h BI)
X
(Within 8 h BI at C4 and 
every 4 cycles thereafter 
until EOT)
8.6.2
Study treatment administration
T-DXd
Administered intravenously on Day 1 of each 3-week cycle
Table 9
Capecitabine
Ingested twice daily orally for 2 weeks, followed by a 1-week rest period in 3-week cycles
Table 9
Paclitaxel
Administered intravenously every week in 3-week cycles
Table 9
Nab-paclitaxel q
Administered intravenously every week for 3 weeks, followed by a 1-week rest period in 4-week cycles
Table 9
Tumor assessments
Tumor 
assessment by 
RECIST 1.1 
(CT or MRI ±
X-ray) r
RECIST 1.1 tumor assessments will be performed using CT or MRI scans of the chest, abdomen and pelvis at screening (as baseline) with 
follow-ups at q6w ± 1 week from the date of randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48, until objective RECIST 
1.1 disease progression by investigator assessment. Patients who permanently discontinue study treatment for reasons other than objective 
RECIST 1.1 disease progression, withdrawal of consent, closure of study or death (regardless of whether subsequent anticancer therapy was 
started) should continue to have RECIST 1.1 scans performed as per schedule until RECIST 1.1 disease progression. Following investigator-
determined RECIST 1.1 progression, it is mandatory to perform an additional imaging assessment (preferably within 4 to 6 weeks after 
investigator PD) for central review to support the primary endpoint of PFS by BICR. In addition, every attempt should be made to continue to 
collect and submit subsequent scans (completed per standard practice / as clinically indicated) for central review until the primary PFS analysis 
DCO, or until the Sponsor notifies the site to discontinue (whichever is earlier) regardless of whether the subject has started another anti-cancer 
therapy.
8.1.1
Brain MRI/CT 
imaging
Regularly scheduled follow-up brain scans (q6w ±1 week from the date of randomization for 48 weeks, and then q9w ±1 week, starting at Week 
48 thereafter until RECIST 1.1 disease progression per investigator assessment) are mandatory for all patients who are enrolled with baseline 
stable brain metastases, while patients without brain metastases do not need additional brain scans for subsequent tumor assessments, unless 
clinically indicated. Following investigator determined RECIST 1.1 progression, subsequent imaging assessments as described above should 
include brain scans for patients who are enrolled with baseline stable brain metastases or if clinically indicated.
8.1.1

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
Whole body 
bone scan
As clinically indicated
8.1.1
Biomarker assessments 
Tumor sample 
at disease 
progression 
(optional) s
If consented for, this tumor sample should be obtained at time of disease progression.
8.7.2
Blood sample 
for plasma 
biomarker 
assessment 
(ctDNA) 
(mandatory) t
X
X
X
X u
(C4-7 Day 1, then every 
6 weeks [q6w ±1 week; in 
alignment with RECIST 
assessments])
X (At 
progression)
8.7.1
Blood sample 
for gene 
expression 
assessment 
(mandatory) t
X
X
X (At 
progression 
only)
8.7.1
Blood sample 
for PBMC 
isolation 
(mandatory) t
X
X
X
8.7.1

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
Additional 
blood samples 
for plasma and 
serum 
exploratory 
clinical or 
safety analyses
If ILD/pneumonitis is suspected
8.2.10
Blood sample 
for serum 
exploratory 
clinical benefit 
or safety 
analyses 
(mandatory) v
X
X
(C4 and every 4 cycles 
thereafter until EOT)
X
8.7.1
Blood sample 
for Genomics 
Initiative 
(optional)
X t, w
8.8
Paired biopsies 
(optional) t, x
X 
X
8.7.2
Other assessments and procedures
Healthcare 
resource use 
(HOSPAD) y
At each scheduled visit, the site should review clinical notes for any non-study related 
hospital admissions and visits that have occurred.
8.9
Allocate ePRO 
device z
X
8.1.4

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
ePRO patient 
training aa
X
8.1.4
EORTC QLQ-
C30, EORTC 
QLQ-BR45, 
EQ-5D-5L, 
PRO-CTCAE, 
PGIS, 
PGIC, 
PGI-TT, 
PGI-BR 
EORTC QLQ-C30, EORTC QLQ-BR45, EQ-5D-5L, PGIS, PGIC:
!
Before infusion on Cycle 1 Day 1 (up to -3 days)
!
Q3W (±3 days) relative to Cycle 1 Day 1 dosing until PFS2 regardless of delays in dosing 
!
Also at EOT visit unless already completed the same day; if discontinued treatment for reasons other than disease progression, also at 
disease progression visit unless already completed the same day
!
PGIC: As above except no assessment on Cycle 1 Day 1.
PRO-CTCAE and PGI-TT: As above except assessments will stop at EOT rather than continue to PFS2
PGI-BR: Weeks 12, 15, 18, 21 (±3 days) relative to Cycle 1 Day 1 dosing unless EOT occurs first, at EOT visit unless completed the same day, 
and stops at EOT.
8.1.4
ADA = anti-drug antibody; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine transaminase; aPTT = activated partial thromboplastin time; AST = aspartate 
transaminase; BI = before infusion; BUN = blood urea nitrogen; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ctDNA = circulating tumor DNA; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOI = end of infusion; EORTC 
QLQ = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; EOT = end of treatment; EQ-5D-5L = European Quality of Life 5-
Domain 5-Level Scale; FDG-PET = fluorodeoxyglucose-positron emission tomography; HOSPAD = hospital admission; ILD = interstitial lung disease; INR = international 
normalized ratio; IV = intravenous; LDH = lactate dehydrogenase; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; MUGA = multiple gated 
acquisition scans; PBMC = periphery blood mononuclear cell; PD = disease progression; PFS2 = time from randomization to second progression or death; PGI-BR = Patient 
Global Impression – Benefit/Risk; PGIC = Patient Global Impression–Change; PGIS = Patient Global Impression–Severity; PGI-TT = Patient Global Impression–Treatment 
Tolerability; PK = pharmacokinetic; PRO = patient reported outcomes; PT = prothrombin time; PTT = partial thromboplastin time; q3w = every 3 weeks; q6w = every 6 weeks; 
q9w = every 9 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE = serious adverse event; SpO2 = pulse oximetry
Note: Dosing should occur no more than 3 days after randomization. If it is anticipated that dosing cannot occur within 3 days, a discussion with the AstraZeneca Study 
Physician is required.
a
Laboratory, SpO2, and vital sign assessments on D8 and D15 after Cycle 1, and D22 (D22 only applicable if on nab-paclitaxel) visits are performed per local standard 
practice and will need to be recorded only as clinically indicated.
b
For paclitaxel and nab-paclitaxel, a window of ± 1 day is applied for all infusions.
c
EOT is the date the Investigator decides to discontinue a patient from study treatment; the visit should occur within 7 days of the decision.
d
Within 3 days before study treatment administration.
e
Body weight is recorded at Day 1 of each cycle until EOT.

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
f
A non-contrast HRCT scan of the chest is preferred if feasible, otherwise a non-contrast CT is acceptable. The HRCT/CT chest scan will be performed for all patients, in 
addition to standard CT/MRI scans of chest/abdomen/pelvis for tumor assessments. If both an HRCT/CT of the chest for assessment of ILD/pneumonitis and a diagnostic 
IV contrast enhanced chest CT scan for tumor response assessment (as part of chest-abdomen-pelvis imaging) are to be acquired in the same imaging session, HRCT/CT 
should be performed first. HRCT scans are acquired on study as and when ILD/pneumonitis is suspected/as clinically indicated. 
g
ECGs are performed within 3 days prior to dosing. ECGs will be performed in triplicate only if an abnormality is noted. When performed in triplicate, 3 individual ECG 
tracings should be obtained in succession, no more than 2 minutes apart. The full set of triplicates should be completed within 5 minutes, while in a supine/semi-
recumbent position. If the screening ECG is performed within 3 days prior to Cycle 1 Day 1 (first infusion day), it does not have to be repeated at Day 1.
h
Within 3 days prior to Day 1 of each cycle, SpO2 should be evaluated by the Investigator or the delegate physician. SpO2 should be evaluated by the Investigator or the 
delegate physician at the timepoints specified in the schedule of assessments. 
i
ECHO or MUGA scan assessments (note: the same test must be used for the patient throughout the study) will be performed before infusion on Cycle 5 and every 4 cycles 
(e.g., Cycles 5, 9, 13). The modality of the cardiac function assessments must be consistent within patient (i.e., if ECHO is used for the screening assessment, then ECHO 
should also be used for subsequent scans if required). The patients should also be examined using the same machine and operator whenever possible.
j
Ophthalmologic assessments including visual acuity testing, slit lamp examination and fundoscopy will be performed at screening, and as clinically indicated.
k
If screening laboratory assessments are performed within 3 days prior to Cycle 1 Day 1 (first infusion day), they do not need to be repeated at Day 1.
l
Laboratory tests 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, ALP, ALT, AST, total bilirubin, BUN/urea, calcium, chloride, 
serum creatinine, LDH, potassium, sodium, bicarbonate (where available) and magnesium.
m
Coagulation parameters: PT or INR and PTT or aPTT will be assessed as clinically indicated.
n
Collect blood samples for troponin (preferably high-sensitivity troponin-T) at screening and if at any time a patient reports signs or symptoms suggesting congestive heart 
failure, myocardial infarction, or other causes of myocyte necrosis. If ECG is abnormal, follow institutional guidelines. 
o
Perform repeat pregnancy tests (urine or serum test per institutional guideline) 72 hours BI of each cycle and at end of treatment.
p
Please see Section 8.2.10 for further instruction on PK sampling related to ILD.
q
Although nab-paclitaxel is given in 4-week cycles, the schedule of assessments must be followed (e.g., tumor assessment scans every 6 weeks ± 1 week)
r
RECIST 1.1 assessments will be performed on images from IV contrast-enhanced CT (preferred) or MRI of the chest, abdomen, and pelvis, with or without X-Ray (for 
patients with bone-only, non-measurable disease where X-Ray was used as part of baseline assessment). Additional anatomy should be imaged based on signs and 
symptoms of individual patients at baseline and follow-up. If an unscheduled assessment was performed (e.g. to investigate clinical signs/symptoms of progression) and 
the patient has not progressed, every attempt should be made to perform the subsequent imaging at the next regularly scheduled visit. New RECIST 1.1 lesions may be 
identified also by FDG-PET scans, X-ray, bone (scintigraphy) scans. Response assessment scans must be reviewed for evidence of disease progression and 
ILD/pneumonitis prior to administration of the next scheduled dose of study treatment. Digital copies of all scans should be maintained at the investigative site as source 
documents.
s
Optional additional tumor biopsies collected upon disease progression can be submitted for further analysis.

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
t
This sample will not be collected in China
u
ctDNA to be drawn at next RECIST scan after Cycle 7 Day 1. Following this draw, subsequent ctDNA collection will be q6w ± 1 week until Week 48, and q9w ± 1 week 
post Week 48 and at disease progression, in alignment with RECIST assessments. Samples should be drawn as close as possible to the RECIST assessment (preferably 
within a window of +/- 3 days).
v
Blood samples for serum isolation will be analyzed for all patients. Blood samples will be collected from patients assigned to the investigator’s choice chemotherapy arm. 
Samples for patients assigned to T-DXd will be obtained from already collected T-DXd samples (e.g., back-up ADA samples), thus an additional sample will not be 
required for serum isolation. 
w
The blood sample will be obtained from the patients on Cycle 1 Day 1 (first infusion day) prior to study treatment administration (at or after randomization). If for any 
reason the sample is not drawn on Cycle 1 Day 1, it may be taken at any visit until the last study visit. Only 1 sample should be collected per patient. Although DNA is 
stable, early sample collection is preferred to avoid introducing bias through excluding patients who may withdraw due to an AE.
x
Paired biopsies (optional): Baseline sample: at screening or pre-dose on Cycle 1 Week 1 Day 1. On-treatment sample: at Cycle 2, Week 1, Day 1 (any day between Cycle 
2, Week 1, Day 2 and Cycle 2, Week 3 is allowed) recommended >4 hours post-dose.
y
If a patient discontinues study treatment for reasons other than RECIST 1.1 progression, the HOSPAD form should continue to be administered until progression has been 
confirmed.
z
The electronic PRO device should be charged and fully functional prior to the patient’s arrival at the site for Cycle 1 Day 1 (-3 days) to ensure that the PROs can be 
completed at the start of the visit.
aa
The patient should be trained on the use of the device, including the importance of completing the PRO questionnaires throughout the study in accordance with the 
completion schedule.
Note: For suspected ILD/pneumonitis, treatment with study treatment should be interrupted pending evaluation. 
Evaluations should include:
1
high resolution CT of the chest
2
pulmonologist consultation (infectious disease consultation if clinically indicated)
3
pulmonary function tests (including FVC and CO diffusing capacity) and pulse oximetry (SpO2)
4
arterial blood gases if clinically indicated
5
bronchoscopy and bronchoalveolar lavage as clinically indicated and feasible
6
COVID-19 test
7
CBC, blood culture, differential WBC, CRP
8
one blood sample collection for PK analysis as soon as ILD/pneumonitis is suspected, if feasible
9
additional blood samples for plasma and serum exploratory biomarker analysis as soon as ILD/pneumonitis is suspected, if feasible

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Table 4
Schedule of Assessments During the Treatment Period and at End of Treatment
Procedures
Cycle 1 
Cycle 2 a
Cycle 3
Cycle 4 and subsequent cycles until 
PD
Day 1 ± 1 day (paclitaxel, nab-
paclitaxel)/± 2 days (T-DXd, 
capecitabine) b
EOT c
For 
details, 
see 
Section
Day 1
Day
8
Day
15
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 days 
(T-DXd, 
capecitabine)b
Day 1 ± 1 day 
(paclitaxel, nab-
paclitaxel)/± 2 
days (T-DXd, 
capecitabine)b
BI
EOI
(±1 
day)
(±1 
day)
BI
EOI
BI
EOI
BI
EOI
Other tests could be considered, as needed.

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1.3.3
Follow-up Period 
Table 5
Schedule of Assessments for Post-treatment Follow-up and Long-term Follow-up
Procedures
Post-treatment follow-up 
[40 days (+7 days) after last dose] 
a
Long term/Survival follow-up (every 3 months 
after the post-treatment follow-up ± 14 days) b
For details, see Section
Vital signs
X
8.2.3
Body weight
X
8.2.3
Physical examination (targeted)
X
8.2.2
SpO2 c
X
8.2.6
ECOG performance status
X
8.2.8
Clinical chemistry d
X
Table 12
Hematology d
X
Table 13
Coagulation tests
As clinically indicated
Table 13
Pregnancy test
X
8.2.5
Concomitant medications
X
6.5
AEs/SAEs e
X
8.3
PFS2 assessment 
X
X f
8.1.3
Healthcare resource use (HOSPAD)
X
8.9
EORTC QLQ-C30, EORTC QLQ-
BR45, EQ-5D-5L, PGIS, PGIC
Q3W (±3 days) relative to Cycle 1 Day 1 dosing until PFS2. For PGIC, note that no 
assessment on Cycle 1 Day 1 is performed.
8.1.4
Survival status
X
8.1.2
Subsequent cancer therapy 
following discontinuation of study 
treatment 
X
X
8.1.2

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Table 5
Schedule of Assessments for Post-treatment Follow-up and Long-term Follow-up
Procedures
Post-treatment follow-up 
[40 days (+7 days) after last dose] 
a
Long term/Survival follow-up (every 3 months 
after the post-treatment follow-up ± 14 days) b
For details, see Section
Tumor assessment by RECIST 1.1 
(CT or MRI ± X-ray) g
RECIST 1.1 tumor assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis at screening (as baseline) with follow-ups at q6w ± 1 week from the 
date of randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48, until 
objective RECIST 1.1 disease progression per investigator assessment. Patients who 
permanently discontinue study treatment for reasons other than objective RECIST 1.1 
disease progression, withdrawal of consent, closure of study or death (regardless of 
whether subsequent anticancer therapy was started) should continue to have RECIST 1.1 
scans performed as per schedule until RECIST 1.1 disease progression. Following 
investigator-determined RECIST 1.1 progression, it is mandatory to perform an additional 
imaging assessment (preferably within 4 to 6 weeks after investigator PD) for central 
review to support the primary endpoint of PFS by BICR. In addition, every attempt should 
be made to continue to collect and submit subsequent scans (completed per standard 
practice / as clinically indicated) for central review until the primary PFS analysis DCO, or 
until the Sponsor notifies the site to discontinue (whichever is earlier) regardless of 
whether the subject has started another anti-cancer therapy. Scans following investigator 
determined RECIST 1.1 progression should include brain scans for patients who are 
enrolled with baseline stable brain metastases or if clinically indicated.
8.1.1
Whole body bone scan
Patients who permanently discontinue study treatment for reasons other than objective 
RECIST 1.1 disease progression, withdrawal of consent, closure of study or death 
(regardless of whether subsequent anticancer therapy was started) should have bone scans 
as clinically indicated
8.1.1
ADA = anti-drug antibody; AEs = adverse events; ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood 
urea nitrogen; CRO = Contract Research Organization; CT = computer tomography; ECOG = Eastern Cooperative Oncology Group; EORTC 
QLQ = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; EOT = end of treatment; EQ-5D-5L = European 
Quality of Life 5-Domain 5-Level Scale; FDG-PET = fluorodeoxyglucose-positron emission tomography; IV = intravenous; LDH = lactate dehydrogenase; 
MRI = magnetic resonance imaging; PFS2 = time from randomization to second progression or death; PGIC = Patient Global Impression–Change; 

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Table 5
Schedule of Assessments for Post-treatment Follow-up and Long-term Follow-up
Procedures
Post-treatment follow-up 
[40 days (+7 days) after last dose] 
a
Long term/Survival follow-up (every 3 months 
after the post-treatment follow-up ± 14 days) b
For details, see Section
PGIS = Patient Global Impression–Severity; q3w = every 3 weeks; q6w = every 6 weeks; q9w = every 9 weeks; RECIST = Response Evaluation Criteria in 
Solid Tumors; SAEs = serious adverse events; SpO2 = pulse oximetry
a
If EOT is >40 days (+7 days) after last treatment, then the EOT assessments can also function as the 40-Day (+7 days) follow-up visit.
b
Long-term/Survival follow-up visits will be performed every 3 months (±14 days) from the date of 40-Day (+7 days) follow-up visit until death, 
withdrawal of consent, or study closure, whichever occurs first.
c
SpO2 should be evaluated by the Investigator or the delegate physician. 
d
Laboratory tests 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, ALP, ALT, AST, total bilirubin, BUN/urea, 
calcium, chloride, serum creatinine, LDH, potassium, sodium, bicarbonate (where available) and magnesium.
e
If any event that starts post the defined safety follow-up period noted above is considered to be due to a late onset toxicity to study treatment, then it 
should be reported as an AE or SAE as applicable.
f
PFS2 is time from randomization to second progression (the earliest of the progression event subsequent to first subsequent anticancer 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 Investigator according to RECIST 1.1 assessment, patients who started on subsequent anticancer therapy post progression will continue 
to be followed at the 40-day (+7 days) follow-up visit, and every 3 months (±14 days) thereafter for documentation of progression on subsequent 
anticancer therapy. 
g
RECIST 1.1 assessments will be performed on images from IV contrast-enhanced CT (preferred) or MRI of the chest, abdomen, and pelvis, with or 
without X-ray (for patients with bone-only, non-measurable disease where X-ray was used as part of baseline assessment). Regularly scheduled 
follow-up brain scans (q6w±1 week from the date of randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48 thereafter until RECIST 
1.1 disease progression per investigator assessment) are mandatory for all patients who are enrolled with baseline stable brain metastases, while patients 
without brain metastases do not need additional brain scans for subsequent tumor assessments, unless clinically indicated. New lesions may be identified 
also by FDG-PET scans, X-ray, bone (scintigraphy) scans. If an unscheduled assessment was performed (e.g., to investigate clinical signs/symptoms of 
progression) and the patient has not progressed, every attempt should be made to perform the subsequent imaging at the next regularly scheduled visit. 
Digital copies of all scans should be maintained at the site as source documents. Digital images are sent to the Imaging CRO by electronic transfer.

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2
INTRODUCTION
2.1
Study Rationale
Within breast cancers traditionally classified as HER2-negative, there exists a spectrum of 
HER2 expression. In addition to tumors with no detectable HER2 staining 
(i.e., immunohistochemistry [IHC] null), the category encompasses IHC 2+/ ISH negative and 
IHC 1+ cancers (defined in this study collectively as HER2-low), as well as cancers that have 
lower, but detectable HER2 staining, i.e., faint or barely perceptible and incomplete 
membrane staining that is seen in 10% or fewer tumor cells. These latter cancers are included 
in the category IHC 0 according to the ASCO/CAP guidelines, and in this study are referred to 
as HER2 IHC >0 <1+.
Currently, patients with HR+, HER2-low or HER2 IHC >0 <1+ advanced or metastatic breast 
cancer follow the same treatment paradigm as HR+, HER2-negative breast cancer patients. In 
general, ET is considered the preferred option for HR+, HER2-negative breast cancer. The 
optimal treatment sequence is considered to be the use of ET + CDK4/6 inhibitors first line, 
followed by subsequent ET with targeted therapies (e.g., mTOR or PI3-K inhibitors [for PI3-K 
mutant tumors]) (Cardoso et al 2020). In patients whose disease has progressed after multiple 
lines of ET with or without targeted therapies, chemotherapy may be appropriate (Cardoso et 
al 2018) as currently available anti-HER2 therapy has not demonstrated clinical benefit in 
these patients. In addition, for patients who have primary endocrine resistance (i.e., 
progressive disease within the first 6 months of first-line ET for advanced breast cancer), 
chemotherapy may also be appropriate as continued treatment with endocrine therapies 
following progression on ET + CDK4/6 inhibitors has been shown to provide less benefit 
(Rossi et al 2019, Sledge et al 2020, Turner et al 2018).
In clinical trials in a heterogeneous breast cancer population, the standard of care with single 
agent chemotherapy leads to response rates of 10% to 30%, median PFS of 4-6 months and 
median OS of 15-25 months. Chemotherapy is also associated with significant AEs, including 
hematologic toxicities, nausea, vomiting, alopecia, and skin reactions; thus, there is a need for 
treatments with a better benefit/risk profile in this patient population who receive 
chemotherapy after endocrine treatment. 
In the Phase 1 DS8201-A-J101 clinical trial (NCT02564900), trastuzumab deruxtecan 
(T-DXd; previously known as DS-8201a) demonstrated promising antitumor activity with an 
ORR of 37% in HER2-low tumors, with a majority of patients experiencing tumor shrinkage 
with durable responses (Modi et al 2020). In addition, there were 11 patients in this study 
whose HER2 expression was locally reported as IHC 1+, 2+ or 3+ but were categorized by a 
central laboratory as HER2 IHC 0 as per ASCO/CAP guidelines 2018 (Table 6). Of these 11 
patients, 5 (45.5%) had a tumor response. In the Phase 2 DAISY clinical trial 
(NCT04132960), patients with advanced breast cancer who had received at least one prior line 

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of chemotherapy were treated with T-DXd. In 37 patients with HER2 IHC 0+, confirmed ORR 
was 29.7% and median PFS was 4.2 months (Diéras et al 2022). Data from both studies 
suggest that the antitumor activity of T-DXd may extend to the population of patients with 
HER2 IHC < 1+, warranting further evaluation.
Therefore, in this Phase 3 study, T-DXd will be compared against investigator’s choice single 
agent chemotherapy to determine if T-DXd can improve outcomes in HER2-low 
(IHC 2+/ISH- and IHC 1+), HR+ breast cancer patients whose disease has progressed on at 
least 2 lines of prior ET or within 6 months of first line ET + CDK4/6i in the metastatic setting 
(N=700). In addition to the primary population of HER2-low patients being studied, the study 
will also randomize approximately 150 patients with HER2 IHC >0 <1+ expression.
2.2
Background
A detailed description of the chemistry and pharmacology of T-DXd, the non-clinical and 
clinical efficacy and safety results of T-DXd are provided in the Investigator’s Brochure (IB).
2.2.1
Background Information on the Disease to be Treated
Breast cancer is the second most common cancer in the world and the most frequent cancer in 
women with an estimated 2 million new cases in 2018 globally (11.6% of all new cancers). 
Breast cancer is also the fifth most common cause of death from cancer with an estimated 
626,000 deaths. In Europe, an estimated 522,000 women were diagnosed with breast cancer in 
2018 and 137,000 died from the disease (GLOBOCAN 2018). According to 2019 estimates, 
over 268,000 women in the United States (US) were diagnosed with breast cancer and 41,000 
died from the disease (National Cancer Institute 2019). Despite advances in diagnosis and 
treatment, about 6% of women diagnosed with breast cancer in the US have metastatic disease 
at the time of first presentation and up to 30% of women with early stage non-metastatic 
breast cancer will develop distant metastatic disease (O'Shaughnessy 2005). Although 
treatable, metastatic breast cancer remains largely an incurable disease with an estimated 
5-year OS of only 25% (Cardoso et al 2018). Breast cancer treatment paradigms in the 
metastatic setting are defined by the expression of the HER2 and the estrogen receptor (ER) 
and progesterone receptor (PgR), which are collectively referred to as hormone receptors 
(HR).
In approximately 20% of breast cancer cases, there is overexpression and/or overamplification 
of HER2. According to ASCO/CAP guidelines (see Appendix F), HER2 positivity is defined 
as tumors that have an IHC 3+ score or that show HER2 gene amplification by ISH; ISH 
testing is recommended in cases of IHC 2+ scoring. Several anti-HER2 targeted therapies 
such as HERCEPTIN® (trastuzumab), PERJETA® (pertuzumab), KADCYLA®
(ado-trastuzumab emtansine [T-DM1]), and TYKERB® (lapatinib) have improved outcomes 
in breast cancer patients who have HER2 overexpression/overamplification, classified as 
HER2-positive tumors. Any tumor not meeting these criteria for HER2-positivity has 

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traditionally been referred to as “HER2-negative.” 
The ASCO/CAP testing guidelines and nomenclature used in this study are outlined in 
Table 6. Refer to Figure 3 for HR+ breast cancer segmented by HER2 receptor status.

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Table 6
ASCO/CAP HER2 2018 Testing Guidelines and Nomenclature Used in 
this Study
HER2 IHC 
testing result
IHC staining pattern
HER2 status per
ASCO/CAP 
guidelines
Nomenclature 
used in this 
protocol
Staining 
intensity
Membrane 
staining
Frequency
IHC 3+
Intense
Complete, 
circumferential
>10% of 
tumor cells
HER2-positive
(IHC2+ must be 
ISH+)
HER2-positive
(IHC 2+ must be 
ISH+) a
IHC 2+b
Weak to 
moderate
Complete
>10% of 
tumor cells
HER2-negative
(IHC 2+ must be 
ISH-; 
IHC 1+ and 
IHC 0 must be 
ISH- or untested)
HER2-low
(IHC 2+ must be 
ISH-; IHC 1+ must 
be ISH- or 
untested)
IHC 1+
Faint/ 
barely 
perceptible
Incomplete
>10% of 
tumor cells
IHC 0
Faint/ 
barely 
perceptible
Incomplete
>0 and 
≤10% of 
tumor cells 
HER2 IHC >0 <1+
(must be ISH- or 
untested)
No staining observed
HER2 null
ASCO/CAP = American Society of Clinical Oncology/College of American Pathologists; HER2 = human 
epidermal growth factor receptor 2; IHC = immunohistochemistry; ISH = in situ hybridization.
a
HER2-positive patients will not be included in this study.
b
Unusual staining patterns of HER2 by IHC can be encountered that are not covered by these definitions. 
In practice, these patterns are rare and if encountered should be considered IHC 2+ equivocal. As one 
example, some specific subtypes of breast cancers can show IHC staining that is moderate to intense but 
incomplete (basolateral or lateral) and can be found to be HER2-amplified. Another example is 
circumferential membrane IHC staining that is intense but in ≤10% of tumor cells (heterogeneous but 
limited in extent). Such cases can be considered 2+ equivocal, but additional samples may reveal 
different percentages of HER2-positive staining.

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Figure 3
Hormone Receptor-positive Breast Cancer Segmented by HER2 
Receptor Status
HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; ISH = in situ hybridization.
a
HER2 standard-of-care IHC assay, ISH per guidelines. Prevalence estimates from (Owens et al 2004), 
(Lambein et al 2013) and data on file (available upon request).
b
Lower confidence due to limited data
Currently, HR+ breast cancer patients whose tumors are HER2-low or HER2 IHC >0 <1+ 
follow the treatment paradigm for HR+, HER2-negative breast cancer patients and receive 
single agent chemotherapy after disease progression on ET and/or targeted therapy 
(e.g., CDK4/6 inhibitor) regimens as no anti-HER2 therapy has been approved for this 
population. Endocrine therapy, including aromatase inhibitors (AIs), selective ER modulators, 
and selective ER down-regulators, as well as targeted therapies such as CDK4/6 inhibitors, 
PI3-K inhibitors, and mTOR inhibitors have been shown to improve outcomes for patients 
with HR+, HER2-negative metastatic breast cancer and are considered standard of care for 
most patients in the metastatic setting (Andre et al 2019, Matutino et al 2018). Several studies 
have demonstrated a PFS benefit of AIs and fulvestrant, both of which have recently been 
used in combination with CDK4/6 inhibitors (Finn et al 2016, Goetze et al 2017, Hortobagyi 
et al 2018, Slamon et al 2018). The combination of ET and ribociclib has demonstrated an OS 
benefit among premenopausal women as first line therapy (Im et al 2019). In addition, 
combinations of abemaciclib (Sledge et al 2020) and ribociclib (Slamon et al 2019) with 
fulvestrant have demonstrated OS benefit.
The optimal treatment sequence for patients with HR+, HER2-negative metastatic breast 
cancer is considered to be the use of ET + CDK4/6 inhibitors first line, followed by 
subsequent ET with targeted therapies (e.g., mTOR or PI3-K inhibitors [for PI3-K mutant 
tumors]) (Cardoso et al 2020). In patients whose disease has progressed after multiple lines of 

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ET with or without targeted therapies, or patients whose disease has primary endocrine 
resistance (progressive disease within the first 6 months of first-line ET for advanced breast 
cancer), chemotherapy may be appropriate as currently available anti-HER2 therapy has not 
demonstrated clinical benefit in these patients.
When chemotherapy is recommended, the choice between single agent and combination 
therapy is decided based on several factors to individualize therapy. Generally, sequential 
single agent therapy is preferred over combination therapy (Cardoso et al 2009, NCCN 2019). 
Chemotherapy combinations may be used in select patients with rapidly progressing disease 
and visceral crisis. Single agent therapy options include anthracyclines, taxanes 
(e.g., paclitaxel and nab-paclitaxel), and anti-metabolites (e.g., capecitabine). Because of the 
availability of many agents and the lack of clear superiority of one agent over others, there is 
no ideal sequence of treatments that can be applied to all patients. Most studies have 
demonstrated responses of approximately 10% to 30%, a median PFS between 4 and 6 months 
and a median OS between 15 and 25 months in a heterogeneous metastatic breast cancer 
setting, with chemotherapy being associated with many adverse effects including hematologic 
toxicities, alopecia, skin reactions, nausea, diarrhea and vomiting (Baselga et al 2017, 
Gradishar et al 2005, Kaufman et al 2015, Miller et al 2007, Piccart-Gebhart et al 2008). 
Hence, a high unmet medical need exists and new treatment options are needed to further 
improve outcomes. 
2.2.2
Background Information on T-DXd
Trastuzumab deruxtecan (T-DXd; DS-8201a) is a HER2-targeting antibody-drug conjugate 
(ADC) that is being developed as a therapeutic candidate for breast cancer and other 
HER2-expressing tumors. 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. 
T-DXd consists of an anti-HER2 antibody, MAAL-9001, covalently linked to ~8 molecules of
MAAA-1162a (GGFG tetra-peptide cleavable linker and a topoisomerase I inhibitor 
[MAAA-1181a]). The antibody MAAL-9001 has the same amino acid sequence as 
HERCEPTIN® (trastuzumab), and thus T-DXd is similarly targeted to HER2-expressing 
tumors. The drug MAAA-1181a, a derivative of exatecan, is released after internalization and 
leads to apoptosis of the target tumor cells via the inhibition of topoisomerase I.
Due to incorporation of a novel linker, T-DXd achieves a higher drug-to-antibody ratio (DAR) 
of approximately 8 with homogeneous conjugation of MAAA-1181a, compared with all other 
currently 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.

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T-DXd exhibits HER2-specific antitumor activity via a mechanism of action that combines the 
monoclonal antibody (mAb) specificity with the broad cytotoxicity of the released drug. After 
binding to HER2 and internalization, T-DXd is cleaved by lysosomal enzymes preferentially 
expressed in tumor cells and releases the drug MAAA-1181a in the cytoplasm. MAAA-1181a 
is an exatecan derivative with greater potency than SN-38, the active metabolite of irinotecan 
(Ogitani et al 2016). T-DXd is expected to exhibit antitumor activity through 
MAAA-1181a-induced apoptosis and, potentially, the antibody-dependent cellular cytotoxicity 
(ADCC) activity of MAAL-9001, which leads to the inhibition of Akt phosphorylation.
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. 
As of 08 June 2021, an estimated total of 3462 patients have been treated with T-DXd (alone 
or in combination with nivolumab or pembrolizumab) or a comparator in 27 completed or 
ongoing clinical studies across multiple HER2-expressing tumor types including breast 
cancer, gastric cancer, non-small cell lung cancer (NSCLC), and colorectal cancer.
T-DXd is approved as a treatment in 40 countries including the US, European Union, and 
Japan for patients with unresectable or metastatic HER2-positive breast cancer who have 
received prior anti-cancer therapies. It is also approved in the US, Israel, Singapore, and Japan 
for the treatment of patients with locally advanced or metastatic HER2-positive gastric or 
gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based 
regimen.
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 International Council for Harmonisation 
(ICH)/Good Clinical Practice (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
Potential Risks of T-DXd
Based on data from clinical trials, toxicities considered to be associated with administration of 
T-DXd include the important identified risks of ILD/pneumonitis and neutropenia (including 
febrile neutropenia). A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed 
in patients with moderate renal impairment at baseline. Participants with moderate renal 
impairment should be monitored carefully. Other identified risks for T-DXd are 
infusion-related reactions, hematological adverse events (anemia, leukopenia, lymphopenia, 
thrombocytopenia), pulmonary/respiratory adverse events (cough, dyspnea, upper respiratory 

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tract infection, epistaxis), gastrointestinal AEs (abdominal pain, constipation, diarrhea, 
dyspepsia, nausea, stomatitis, vomiting), hepatic adverse events (hepatic function abnormality, 
alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and 
alkaline phosphatase increased), skin adverse events (alopecia, rash, pruritus), blood bilirubin 
increased, pneumonia, dry eye, dehydration, hypokalemia, decreased appetite, dizziness, 
fatigue, peripheral edema, pyrexia, and headache. 
Based on the available pre-clinical data, review of the cumulative literature, and reported 
toxicities for the same class of agents, the important potential risks for T-DXd are left 
ventricular ejection fraction (LVEF) decrease (re-labelled as ‘Left ventricular dysfunction’ as 
the undesirable outcome of LVEF reductions, in accordance with the Revision 2 of the 
European Medicines Agency guidelines on Good Pharmacovigilance Practice. The 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) and embryo-fetal toxicity. Keratitis is considered a 
potential risk for T-DXd.
ILD/pneumonitis and LVEF decrease are considered adverse events of special interest (AESI).
T-DXd has not been studied in patients with severe/moderate hepatic impairment or severe 
renal impairment.
HER2-targeted Agents 
Several agents that target HER2 and prevent its activation or heterodimerization have been 
developed and marketed for the treatment of HER2-positive cancers. These include the mAbs 
trastuzumab (HERCEPTIN®) and pertuzumab (PERJETA®), the ADC T-DM1 (KADCYLA®), 
and EGFR- and HER1- and 2-associated TKIs, lapatinib (TYKERB®) and neratinib 
(NERLYNX®). 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 
congestive heart failure (CHF; New York Heart Association [NYHA] class II-IV) 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 

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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 drug-induced liver injury.
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.
Refer to Appendix H for toxicity management guidelines (TMGs) for T-DXd.
Topoisomerase I Inhibitors
MAAA-1181a is a derivative of exatecan (DX-8951f), a topoisomerase I 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 anti-cancer therapy.
The main risks associated with the use of topoisomerase I 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, which can be severe and lead to dehydration, have been associated with 

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topoisomerase I 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 topoisomerase I 
inhibitors, with hematological toxicities and gastrointestinal toxicities being the most 
significant groups of events.
2.3.2
Potential Benefits of T-DXd
T-DXd is under development for the treatment of HER2-expressing cancers and HER2-mutant 
tumors. Based on the clinical observations to date, T-DXd demonstrates antitumor activity in 
HER2-expressing cancers.
Initial evaluation of T-DXd in patients with HER2-positive (defined by ASCO/CAP guidelines 
as HER2 IHC 3+ or IHC 2+/ISH+), unresectable and/or metastatic breast cancer (studies 
DS8201-A-J101 [Phase 1] and DS8201-A-U201 [Phase 2; NCT03248492], both single-arm) 
demonstrated that T-DXd 5.4 mg/kg was associated with an ORR of 51.0% (95% confidence 
interval [CI]: 36.6, 65.2; n=51 patients) and 60.3% (95% CI: 52.9, 67.4; n=184 patients), 
respectively, in patients with multiple prior lines of therapy. In study DS8201-A-J101, in 
which the data are more mature (median follow-up of 15.5 months), the median duration of 
response as of 01 February 2019, was 12.7 months (95% CI: 6.7, not estimable) for the 
5.4 mg/kg dose. At the DCO date of 01 August 2019 (median follow-up of 11.1 months), 
study DS8201-A-U201 showed a median duration of response of 14.8 months (95% CI: 13.8, 
16.9). These data represent a substantial improvement over ORRs observed in similar settings, 
such as in the recent SOPHIA (NCT02492711) and NALA (NCT01808573) studies in which 
ORRs of approximately 30% were observed (Rugo et al 2019, Saura et al 2019).
In addition, evaluation of T-DXd in patients with HER2-low (defined as 
HER2 IHC 2+/ISH- or HER2 IHC 1+) advanced breast cancer refractory to or intolerant of 
standard treatment in the first-in-human Phase 1 Study DS8201-A-J101, demonstrated that the 
majority of patients experienced tumor shrinkage; durable responses were observed. Among 
the 54 patients with HER2-low breast cancer treated with either 5.4 mg/kg (n=21) or 
6.4 mg/kg q3w (n=33), confirmed ORR by independent central review (ICR) was 37.0% 
(95% CI: 24.3, 51.3). Median confirmed duration of response (DoR) by independent central 
review (ICR) was 10.4 months (95% CI: 8.8, not estimable). Median PFS by ICR was 
11.1 months (95% CI: 7.6, not estimable) and median OS was 29.4 months (95% CI: 12.9, 
29.4). In addition, data from 11 patients in study DS8201-A-J101 whose HER2 expression 
was locally reported as IHC 1+, 2+ or 3+ were categorized by a central laboratory as HER2 
IHC 0 as per ASCO/CAP guidelines 2018. Of these 11 patients, 5 had a tumor response 
(45.5%). In the Phase 2 DAISY study, patients with advanced breast cancer who had received 
at least one prior line of chemotherapy were treated with T-DXd. In 37 patients with HER2 

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IHC 0+, confirmed ORR was 29.7% and median PFS was 4.2 months (Diéras et al 2022). This 
compares favorably with historical data for chemotherapy that demonstrated ORR of 11.5% to 
15.5% (Baselga et al 2017, Kaufman et al 2015). Data from both study DS8201-A-J101 and 
the DAISY study suggest that the antitumor activity of T-DXd may extend to the population of 
patients with HER2 IHC < 1+.
The results from study DS8201-A-J101 (NCT02564900) comprise the primary data set to 
support initiation for this study and the DESTINY-Breast04 Phase 3 study (NCT03734029; 
DS8201-A-U303) (AstraZeneca 2022). The DESTINY-Breast04 study, compared to 
DESTINY-Breast06, has been initiated in later-line HER2-low, advanced or metastatic breast 
cancer patients for whom ET is no longer an option and who have received 1 to 2 lines of 
chemotherapy in the metastatic setting. Recently, this study has demonstrated that T-DXd
significantly improved PFS and OS compared to physician’s choice of chemotherapy.
2.3.3 Standard of Care (Investigator’s Choice Chemotherapy)
The risks associated with capecitabine, paclitaxel and nab-paclitaxel are described in the local 
prescribing information.
2.3.4 Overall Benefit/Risk Conclusion
The standard of care with single agent chemotherapy in a heterogenous metastatic breast 
cancer population leads to response rates of 10% to 30%, median PFS of 4-6 months and 
median OS of 15-25 months. Chemotherapy is also associated with significant AEs, including 
hematologic toxicities, nausea, vomiting, alopecia, and skin reactions; thus, additional 
effective treatment options are needed for this patient population.
In the Phase 1 DS8201-A-J101 clinical trial, T-DXd demonstrated promising antitumor 
activity in HER2-low tumors with a majority of patients experiencing tumor shrinkage. 
Among the 54 patients with HER2-low breast cancer treated with either 5.4 mg/kg (n=21) or 
6.4 mg/kg q3w (n=33), confirmed ORR by ICR was 37.0% (95% CI: 24.3, 51.3). Median 
confirmed DoR by ICR was 10.4 months (95% CI: 8.8, not estimable). Median PFS by ICR 
was 11.1 months (95% CI: 7.6, not estimable). Median OS was 29.4 months (95% CI: 12.9, 
29.4). In the Phase 2 DAISY study, T-DXd showed promising antitumor activity in 37 patients 
with HER2 IHC 0+ advanced breast cancer who had received at least one prior line of 
chemotherapy. Confirmed ORR was 29.7% and median PFS was 4.2 months. In the Phase 3 
DESTINY-Breast04 study in later line HER2-low, advanced or metastatic breast cancer 
patients for whom ET is no longer an option and who have received 1 to 2 lines of 
chemotherapy in the metastatic setting, treatment with T-DXd has led to significantly 
improved PFS and OS compared to physician’s choice of chemotherapy.
The safety profile of T-DXd in patients with HER2-low breast cancer was consistent with that 

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observed in HER2-positive breast cancer. In the 54 patients with HER2-low breast cancer in 
the DS8201-A-J101 clinical study, ≥Grade 3 treatment-emergent adverse events occurred in 
34 patients (63.0%) with neutrophil count decrease, white blood cell (WBC) count decrease, 
anemia, hypokalemia, platelet count decrease, AST increase, decreased appetite, febrile 
neutropenia, cellulitis and diarrhea occurring in ≥ 5% of patients. Three patients with 
HER2-low breast cancer receiving the 6.4 mg/kg dose died due to treatment-related AEs, 
which included 2 TEAEs of pneumonitis and 1 TEAE of ILD (Modi et al 2020). 
Several measures have been put in place to mitigate the incidence of pulmonary toxicities, 
including inclusion of eligibility criteria that prohibit patients with pre-existing pulmonary 
comorbidities from entering the study. In addition, baseline pulmonary function tests will be 
performed for all patients. For hematological toxicities, the use of growth factors is allowed, 
as per the Investigator’s discretion. Patients will be monitored closely throughout the study 
and clinical and laboratory assessments will be performed before every cycle. TMGs 
(Appendix H) are also provided to assist with the management of the most commonly seen 
AEs. 
ILD education is to be reemphasized in patients with moderate renal impairment. Physicians 
should consider more frequent patient contact in between visits (at least once in between 
cycles) in order to reinforce ILD education and the importance of prompt reporting of 
symptoms, until the investigator is confident the patient is familiar with the requirements.
The emergence of coronavirus 2019-nCoV (COVID-19) presents a potential safety risk for 
patients, therefore, several risk mitigation factors have been implemented 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 I. 
This study will also randomize approximately 150 HER2 IHC >0 <1+ patients. Given the 
available data for T-DXd in the HER2 IHC >0 <1+ patients, a futility analysis specific to the 
HER2 IHC >0 <1+ population is planned after the first 70 HER2 IHC >0 <1+ patients are 
randomized (i.e., approximately 35 HER2 IHC >0 <1+ patients per treatment arm; see 
Section 9.5 for further details).
Based on these considerations, T-DXd has the potential to provide meaningful clinical benefit 
and given the measures put in place for mitigation, the benefit/risk assessment supports the 
proposed study.

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3
OBJECTIVES AND ENDPOINTS
Table 7
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To assess the efficacy of T-DXd compared with 
investigator’s choice chemotherapy in terms of 
PFS by BICR in the HR+, HER2-low 
(IHC 2+/ISH- and IHC 1+) population.
•
PFS in the HR+, HER2-low population: Time 
from date of randomization until the date of 
objective radiological disease progression by 
BICR according to RECIST 1.1 or death (by any 
cause in the absence of progression)
Secondary
The key secondary objectives are:
•
To assess the efficacy of T-DXd compared with 
investigator’s choice chemotherapy in terms of 
OS in the HR+, HER2-low population
•
To assess the efficacy of T-DXd compared with 
investigator’s choice chemotherapy in terms of 
PFS by BICR and OS in the ITT population 
(HER2 IHC >0 <1+ and HER2-low)
The other secondary objectives:
•
To further assess the efficacy of T-DXd
compared with investigator’s choice 
chemotherapy in terms of PFS by Investigator 
assessment, ORR, and DoR by BICR and 
Investigator assessment in the HR+, HER2-low 
population
•
To further assess the efficacy of T-DXd
compared with investigator’s choice 
chemotherapy in terms of ORR and DoR by 
BICR and Investigator assessment in the ITT 
population
The key secondary endpoints are:
•
OS in the HR+, HER2-low population: Time 
from date of randomization until the date of 
death by any cause
•
PFS by BICR according to RECIST 1.1 in the 
ITT population (HER2 IHC >0 <1+ and 
HER2-low)
•
OS in the ITT Population 
The other secondary endpoints are:
•
ORR in the HR+, HER2-low population: The 
percentage of patients with at least 1 visit 
response of CR or PR by BICR and Investigator 
assessment according to RECIST 1.1
•
DoR in the HR+, HER2-low population: Time 
from date of first detection of objective response 
until the date of objective radiological disease 
progression by BICR and Investigator 
assessment according to RECIST 1.1 or death in 
the absence of progression
•
PFS by Investigator assessment according to 
RECIST 1.1 in the HR+, HER2-low population 
•
ORR and DoR by BICR and by Investigator 
assessment according to RECIST 1.1 in the ITT 
population (HER2 IHC >0 <1+ and HER2-low)

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Table 7
Objectives and Endpoints
Objectives
Endpoints
•
To compare the effect of T-DXd with 
investigator’s choice chemotherapy in terms of 
PFS2 according to Investigator assessment, time 
to first subsequent treatment or death (TFST) 
and time to second subsequent treatment or 
death (TSST) in the HR+, HER2-low population 
and the ITT population
•
PFS2 in the HR+, HER2-low population and the 
ITT population: time from randomization until 
second progression on next-line of treatment, as 
assessed by Investigator at the local site or death 
due to any cause
•
TFST in the HR+, HER2-low population and 
the ITT population: time from randomization to 
the start date of subsequent therapy after 
discontinuation of randomized treatment or 
death due to any cause
•
TSST in the HR+, HER2-low population and 
the ITT population: time from randomization to 
the start date of second subsequent therapy after 
discontinuation of randomized treatment or 
death due to any cause
•
To assess the safety and tolerability profile of 
T-DXd compared with investigator’s choice 
chemotherapy
•
AEs, changes from baseline in laboratory 
findings, ECHO/MUGA scans, ECGs and vital 
signs
•
To assess the PK of T-DXd
•
T-DXd total anti-HER2 antibody and 
MAAA-1181a concentrations in serum
•
To assess symptoms, functioning and HRQoL in 
patients treated with T-DXd compared with 
investigator’s choice single agent chemotherapy
The PROs include:
•
Change from baseline in EORTC QLQ-C30 and 
EORTC QLQ-BR45 scale scores
•
Time to deterioration in EORTC QLQ-C30 
scale scores
•
To investigate the immunogenicity of T-DXd
•
Number and percentage of patients who develop 
ADA for T-DXd
Exploratory a
•
To collect blood and tissue samples at 
pre-treatment, on-treatment and post-treatment 
for defining biological responses to T-DXd and 
to investigate predictive markers of response, 
acquired resistance and other markers that may 
correlate with likelihood of clinical benefit or 
tolerability; samples and generated data may be 
used to support diagnostic development
Biomarkers that include but are not limited to 
biomarkers of T-DXd sensitivity/resistance and 
immunological biomarkers are:
•
Protein expression (IHC and proteomic analysis 
including, but not limited to ERBB2, related 
family members and TOPO-1 expression)
•
Mutational profiling in tissue, blood and ctDNA
•
Plasma and blood analysis for ctDNA 
(exploration of genetic alterations in ctDNA and 
dynamic changes, including ctDNA clearance)
•
mRNA expression (exploration of gene 
expression, molecular subtype and gene 
expression changes following treatment) in 
tissue and blood

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Table 7
Objectives and Endpoints
Objectives
Endpoints
•
To explore the impact of treatment and disease 
state on health utility using the EQ-5D-5L
•
To assess patient-reported treatment tolerability 
•
To assess the patient’s overall impression of the 
severity of their cancer symptoms, change in 
condition since starting the study and 
benefit/risk assessment
•
To explore the impact of treatment and disease 
on health care resource use
•
The EQ-5D-5L health state utility index will be 
used to derive health state utility based on 
patient-reported data
•
Proportion of patients experiencing treatment-
related symptoms as measured by the 
PRO-CTCAE; patient perceived overall 
tolerability as measured by the PGI-TT
•
Proportion of patients reporting different levels 
of symptom severity as measured by the PGIS, 
change in condition as measured by the PGIC, 
and benefit/risk as measured by the PGI-BR.
•
Health care resource use will be captured, 
including inpatient admissions, intensive care 
unit admissions, and length of stay in hospital
•
To explore & optimize technologies for 
detection of HER2 protein expression
•
Exploration of IHC and non-IHC methods to 
determine tumoral HER2 expression
ADA = anti-drug antibody; AE = adverse events; BICR = blinded independent central review; CR = complete 
response; cfDNA = circulating free DNA; ctDNA = circulating tumor DNA; DoR = duration of response; 
ECG = electrocardiogram; ECHO/MUGA = echocardiogram/multigated acquisition; EORTC 
QLQ = European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire; 
EQ-5D-5L = European Quality of Life 5-Domain 5-Level Scale; ERBB =erythroblastic oncogene B; 
HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; HRQoL = health-related quality 
of life; IHC = immunohistochemistry; ISH = in situ hybridization; ITT = intent-to-treat; mRNA = messenger 
RNA; ORR = objective response rate; OS = overall survival; PFS = progression-free survival; PFS2 = time 
from randomization to second progression or death; PGI-BR = Patient Global Impression – Benefit/Risk; 
PGIC = Patient Global Impression–Change; PGIS = Patient Global Impression–Severity; PGI-TT = Patient 
Global Impression–Treatment Tolerability; PK = pharmacokinetics; PR = partial response; 
PRO = patient-reported outcome; PRO-CTCAE = Patient-reported outcomes version of the Common 
Terminology Criteria for Adverse Events; RECIST 1.1 = Response Evaluation Criteria In Solid Tumors, 
version 1.1; TFST = time to first subsequent treatment or death; TOPO = topoisomerase; TSST = time to 
second subsequent treatment or death
a
Patients randomized into the study in China will be excluded from exploratory objectives requiring the 
provision of additional tumor or blood samples, with the exception of samples for exploratory safety or 
clinical benefit analyses to identify candidate markers which may correlate with likelihood of clinical 
benefit/tolerability (see Section 8.7.1).

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4
STUDY DESIGN
4.1
Overall Design
The study is an open-label, multi-center, randomized study in HER2-low, HR+ breast cancer 
patients with disease progression on at least 2 lines of prior ET or within 6 months of first line 
ET + CDK4/6i in the metastatic setting. The primary purpose of the study is to determine the 
efficacy and safety of T-DXd compared with investigator’s choice single agent chemotherapy 
in the target population. Approximately 850 patients (700 patients with HER2 IHC 1+/2+ 
expression and 150 patients with HER2 IHC>0 <1+ expression) will be randomized 1:1 across 
approximately 300 centers globally to receive either 5.4 mg/kg T-DXd q3w or investigator’s 
choice single agent chemotherapy (paclitaxel, nab-paclitaxel or capecitabine) until RECIST 
1.1 defined progressive disease (PD), unless there is unacceptable toxicity, withdrawal of 
consent, or another criterion for discontinuation is met. See Figure 2 for details on study 
schema. To ensure adequate representation of each subgroup of the HER2-low population, at 
least 240 patients in each HER2 IHC group (IHC 1+ and IHC 2+/ISH-) across both treatment 
arms (approximately 120 patients per arm) will be randomized. The study will compare PFS, 
OS and other measures of efficacy between the study treatment groups and further 
characterize the safety and tolerability profile of T-DXd. 
The randomization will be stratified by:
!
prior CDK4/6 inhibitor use (Yes vs No)
!
HER2 IHC expression (IHC 2+/ISH- vs IHC 1+ vs IHC >0 <1+)
!
prior taxane use in the non-metastatic setting (Yes vs No) 
Stratification factor status must be known at the time of patient’s randomization to the study.
CDK4/6 inhibitors are being increasingly utilized as part of standard of care for patients with 
HR+ breast cancer. To ensure that majority of patients have received prior CDK4/6 inhibitor 
therapy in the HER2-low population, no more than 343 patients (49% of 700 patients) who 
have not received prior therapy with CDK 4/6 inhibitors (e.g., palbociclib, abemaciclib, or 
ribociclib) will be randomized; a similar proportion of patients who have not received prior 
CDK4/6 therapy will be randomized in the HER2 IHC >0 <1+ population as well.
RECIST 1.1 tumor assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis at screening (as baseline) with follow-ups at q6w ± 1 week from the date 
of randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48, until objective 
RECIST 1.1 disease progression by investigator assessment (see SoAs in Section 1.3). 
Patients who permanently discontinue study treatment for reasons other than objective 
RECIST 1.1 disease progression, withdrawal of consent, closure of study or death (regardless 
of whether subsequent anticancer therapy was started) should continue to have RECIST 1.1 

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scans performed as per schedule until RECIST 1.1 disease progression. Following 
investigator-determined RECIST 1.1 progression, it is mandatory to perform an additional 
imaging assessment (preferably within 4 to 6 weeks after investigator PD) for central review 
to support the primary endpoint of PFS by BICR. In addition, every attempt should be made to 
continue to collect and submit subsequent scans (completed per standard practice / as 
clinically indicated) for central review until the primary PFS analysis DCO, or until the 
Sponsor notifies the site to discontinue (whichever is earlier) regardless of whether the subject 
has started another anti-cancer therapy.
An intravenous (IV) contrast-enhanced brain MRI (preferred) or IV contrast-enhanced CT of 
the brain is to be acquired for all patients at baseline. Regularly scheduled follow-up brain 
scans (q6w ±1 week from the date of randomization for 48 weeks, and then q9w ±1 week, 
starting at Week 48 thereafter until RECIST 1.1 disease progression per investigator 
assessment) are mandatory for all patients who are enrolled with baseline stable brain 
metastases, while patients without brain metastases do not need additional brain scans for 
subsequent tumor assessments, unless clinically indicated. Following investigator determined 
RECIST 1.1 progression, subsequent imaging assessments as described above should include 
brain scans for patients who are enrolled with baseline stable brain metastases or if clinically 
indicated. 
For patients with bone-only disease that is non-measurable, X-ray may also be used in 
addition to the required CT or MRI of the chest, abdomen and pelvis. Any other areas of 
disease involvement or any other sites at which new metastatic disease is clinically suspected 
should be additionally imaged based on the signs and symptoms of individual patients. 
Digital copies of all scans performed during the conduct of this study must be retained at site 
as source data. Sites shall submit the digital copies electronically to the imaging contract 
research organization (iCRO) for centralized review by blinded independent central review 
(BICR). Submission via alternative method such as compact disc (CD)/digital versatile disc 
(DVD) may be accepted on discussion with the study team if electronic submission is not 
possible. Patients will be followed for OS, regardless of whether study treatment is 
discontinued or delayed, unless the patient withdraws consent or study closure, whichever 
occurs first. 
A mandatory formalin-fixed paraffin-embedded (FFPE) tumor sample obtained at the time of 
metastatic disease or later must be provided; the most recently collected pre-randomization 
tumor sample from the time of metastatic disease or later that meets the tissue requirements 
specified in Section 8.7.1 is required. If no archival specimens are available, a newly acquired 
biopsy specimen is acceptable. The tumor sample submitted should be of sufficient quantity to 
allow for assessment of HER2 status and for other exploratory biomarker analyses (for details 
of tumor tissue requirements see Section 8.7.1). Assessment of HER2 status will be performed 

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via a central laboratory.
Central testing of HER2 status will be conducted using a HER2 IHC assay, investigational for 
the IHC 2+, IHC 1+ and IHC >0 <1+ cut-offs. Tumor samples centrally confirmed to be 
HER2 IHC 2+ will be confirmed to be HER2 ISH negative using an approved HER2 ISH 
assay per manufacturers requirements. Testing will be carried out in a laboratory operating to 
GCP and with pathology staff fully trained by the diagnostic manufacturer to score 
reproducibly at all relevant HER2 IHC cut-offs (IHC >0 <1+ and IHC1+ and IHC 2+). In 
addition, an on-market assay will be used to centrally confirm ISH status according to the 
manufacturer’s guidelines.
4.1.1
Duration of the Study
Enrollment is planned to occur over approximately 18-25 months. For each patient there will 
be a 40-day (+7 days) follow-up visit after the last study treatment administration, followed by 
long-term/survival follow-up visits every 3 months (±14 days) until death, withdrawal of 
consent, or study closure, whichever occurs first. 
4.1.2
Duration of Patient Participation
The screening period is up to 28 days. Prior to the 28-day screening period, an optional 
pre-screen ICF may be signed by patients to permit a pre-screening period for tumor tissue 
sample collection for central HER2 status testing. For T-DXd, each cycle of treatment will be 
21 days. For capecitabine and paclitaxel, each cycle of treatment will be 21 days. For 
nab-paclitaxel, each cycle of treatment will be 28 days (see Table 2 for further details). The 
number of treatment cycles with T-DXd and the investigator’s choice chemotherapy 
(capecitabine, paclitaxel and nab-paclitaxel) is not fixed. Upon commencing study treatment, 
patients may continue receiving study treatment until RECIST 1.1 disease progression, 
withdrawal of consent or any of the discontinuation criteria as defined in Section 7.1.1 are 
met. Patients cannot switch between the investigator’s choice single agent chemotherapy 
control agents while on-treatment during the study.
After study treatment discontinuation, patients will be contacted for the 40-day (+7 days) 
follow-up visit, followed by long-term/survival follow-up visits every 3 months (±14 days) to 
obtain information about subsequent treatment(s) and survival status.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for T-DXd in HR+, HER2-low, Advanced or Metastatic 
Breast Cancer
Preclinical data have demonstrated that T-DXd inhibits tumor growth in a patient-derived 
HER2-low tumor xenograft model that is insensitive to T-DM1. Results from the 
first-in-human Phase 1 DS8201-A-J101 study in patients with HER2-low (defined by 

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ASCO/CAP guidelines as HER2 IHC 2+/ISH- or HER2 IHC 1+) advanced breast cancer, 
refractory to or intolerant of standard treatment, demonstrated that the majority of patients 
experienced tumor shrinkage; durable responses were observed.
Among the 54 patients with HER2-low breast cancer treated with either 5.4 mg/kg (n=21) or 
6.4 mg/kg q3w (n=33), confirmed ORR by ICR was 37.0% (95% CI: 24.3, 51.3). Median 
confirmed DoR by ICR was 10.4 months (95% CI: 8.8, not estimable). Median PFS by ICR 
was 11.1 months (95% CI: 7.6, not estimable) and median OS was 29.4 months (95% CI: 
12.9, 29.4; (Modi et al 2020).
Furthermore, DESTINY-Breast04, a Phase 3 study in later line HER2-low, advanced or 
metastatic breast cancer patients, for whom ET is no longer an option and who have received 
1 to 2 lines of chemotherapy in the metastatic setting, demonstrated that T-DXd significantly 
improved both PFS and OS (AstraZeneca 2022). 
4.2.2
Rationale for T-DXd in HR+, HER2 IHC >0 <1+, Advanced or 
Metastatic Breast Cancer 
In the DS8201-A-J101 study, patients were enrolled based on historical HER2 status. 
HER2 IHC was later assessed retrospectively by central laboratory testing of submitted 
archival samples via HercepTest™ at Mosaic Laboratories for IHC analysis, and by 
PathVysion HER-2 DNA Probe Kit at Mosaic Laboratories for the ISH analysis. Central 
confirmatory testing involved new HER2 IHC staining on the submitted archival samples. 
Based on central testing, there were 11 breast cancer patients treated at either 5.4 or 6.4 mg/kg 
whose HER2 expression was considered IHC 0 per ASCO/CAP guidelines. Among these 11 
patients, 5 had objective responses, suggesting that the antitumor activity of T-DXd may also 
extend to the population of patients with HER2 IHC 0. 
The on-market HER2 IHC assays are optimized to detect HER2 expression on tumor cell 
membrane above the basal level of HER2 expressed on epithelial cells. Current ASCO/CAP 
scoring guidelines for HER2 IHC 0 classification includes both patients whose tumors have no 
detectable HER2 expression (HER2 null) and those whose tumors have membrane staining 
that is incomplete and is faint/bare perceptible in greater than 0% and less than or equal to 
10% of tumor cells. Given the mechanism of action of T-DXd as a HER2-targeting agent, it is 
hypothesized that some detectable expression of HER2 above normal is necessary to allow 
T-DXd to induce death in tumor cells. Therefore, this study will focus on further evaluating 
the subset of the ASCO/CAP defined HER2 IHC 0 population that has some detectable HER2 
expression above normal; i.e., the HER2 IHC >0 <1+ population. 
In addition to the J101 study, the DAISY study has provided additional evidence for the 
activity of T-DXd in the IHC >0 <1+ population. The DAISY study (Diéras et al 2022) treated 
38 advanced breast cancer patients with HER2 IHC 0+ (defined as staining of  ≤10% HER2 

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cells according to American Society of Clinical Oncology 2018 and GEFPICS 
recommendations) expression. Of these 38 patients, 12 patients were HR-, 26 were HR+ and a 
great majority (86.8%) of patients received ≥2 prior lines of metastatic treatment before 
receiving T-DXd. All patients were required to have a biopsy prior to entering the study. In 37 
of these heavily pre-treated patients, T-DXd demonstrated a confirmed ORR of 29.7% and a 
median PFS of 4.2 months, providing further efficacy of T-DXd in HER2 expression below 
IHC 1+ in patients with advanced breast cancer. 
Given the available data for T-DXd in the HER2 IHC >0 <1+ patients, a futility analysis 
specific to the HER2 IHC >0 <1+ population is planned after the first 70 HER2 IHC >0 <1+ 
patients are randomized (i.e., approximately 35 HER2 IHC >0 <1+ patients per treatment arm; 
see Section 9.5 for further details).
4.2.3
Rationale for Efficacy Endpoints
The primary endpoint is 
!
PFS by BICR according to RECIST 1.1 in the HR+, HER2-low population.
PFS has been selected as the primary endpoint based on the following considerations: 
!
PFS is not confounded by subsequent therapies.
!
Several meta-analyses demonstrate a statistically significant correlation between hazard 
ratios of PFS and OS in metastatic breast cancer patients (Adunlin et al 2015, Lux et al 
2019).
!
PFS has been used as the primary endpoint in studies leading to the registration of 
recently approved treatments for breast cancer where the magnitude of effect was 
sufficient to establish clinical benefit. 
!
PFS provides the evidence of drug activity and the improvement in PFS is of clinical 
benefit to patients.
!
PFS is an acceptable primary endpoint as described in, for example, the EMA Guideline 
on the evaluation of anticancer medicinal products in man (EMA/CHMP/205/95 Rev.5) 
and the FDA Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer 
Drugs and Biologics (December 2018).
This is in line with the guidelines outlined by the National Cancer Institute Breast Cancer 
Steering Committee Working Group Report, which recommends that it is appropriate to have 
PFS as the primary endpoint (Seidman et al 2018) in HR+, HER2-negative disease in the first 
line setting of metastatic breast cancer. This recommendation was based on the expectation 
that post-progression survival is long and that subsequent therapies will have great influence 
on OS. 

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The Key secondary endpoints are:
!
OS in the HR+, HER2-low population
!
PFS by BICR according to RECIST 1.1 in the ITT population (HER2 IHC >0 <1+ and 
HER2-low)
!
OS in the ITT population (HER2 IHC >0 <1+ and HER2-low)
The additional secondary endpoints are:
!
ORR and DoR by BICR and Investigator assessment according to RECIST 1.1 in the 
HR+, HER2-low population
!
ORR and DoR by BICR and Investigator assessment according to RECIST 1.1 in the ITT 
population (HER2 IHC >0 <1+ and HER2-low)
!
PFS by Investigator assessment according to RECIST 1.1 in the HR+, HER2-low 
population
!
Time from randomization to second progression or death (PFS2), time to first subsequent
treatment or death (TFST) and time to second subsequent treatment or death (TSST) in 
the HR+, HER2-low and ITT population
The secondary endpoints are in line with the recommendations outlined in the National Cancer 
Institute Breast Cancer Steering Committee Working Group Report, where for 
HR+/HER2-negative breast cancer in the first line setting it is appropriate to have the 
following secondary endpoints: OS, response rate and patient-reported outcomes (PROs) 
(Seidman et al 2018).
Furthermore, PFS2, TFST and TSST will be examined to further evaluate the antitumor effect 
of T-DXd vs investigator’s choice chemotherapy as exploratory endpoints to complement the 
antitumor effect noted from other, conventional endpoints (e.g., PFS, ORR, DoR and OS).
4.2.4
Rationale for Other Study Endpoints
As part of the secondary endpoint assessment, blood samples will be taken to allow for 
research into the PK and immunogenicity of T-DXd.
The secondary patient-reported symptoms, functioning and overall health-related quality of 
life (HRQoL) endpoints, assessed using the European Organisation for Research and 
Treatment of Cancer (EORTC) 30 Core Quality of Life Questionnaire and Breast 
Cancer-Specific Module, (QLQ-C30 and QLQ-BR45) 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. The EQ-5D-5L, developed by the EuroQol Group, 
is a generic questionnaire that provides a simple descriptive profile of health and a single 

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index value for health status for economic appraisal by payers. These PRO questionnaires are 
well-established instruments that have been previously included in cancer clinical studies.
Biological samples will be used to explore potential biomarkers in tumor, plasma, and/or 
serum, which may predict the progression of cancer (and associated clinical characteristics) 
and/or tumor response.
4.3
Justification for Dose
T-DXd, and 3 investigator’s choice of single agent chemotherapy are used in the study. 
The justification for dose for each of these interventions are provided below.
4.3.1
T-DXd Dose Rationale
Based on all available information, a T-DXd dose of 5.4 mg/kg q3w has been chosen for this 
study. Doses including 5.4 mg/kg and 6.4 mg/kg T-DXd monotherapy have been tested in 
clinical studies and the maximum tolerated dose (MTD) was not reached in the dose 
escalation phase of the DS8201-A-J101 study. Both doses showed efficacy in different tumor 
types; efficacy was only marginally better at 6.4 mg/kg over 5.4 mg/kg. A numerically higher 
incidence of AEs ≥Grade 3 (overall and causally related), serious adverse events (SAEs; 
including causally related), AEs leading to drug withdrawal (overall and causally related), AEs 
leading to dose reduction (overall and causally related) and ILD/pneumonitis was observed 
with 6.4 mg/kg compared to 5.4 mg/kg. Therefore, 5.4 mg/kg dose of T-DXd was chosen 
instead of the 6.4 mg/kg dose because of its superior benefit/risk profile.
For additional details on the nonclinical and clinical data on T-DXd, see the T-DXd IB.
For information on dose modifications for T-DXd, see Section 6.6.
4.3.2
Chemotherapy Dose Rationale
Three chemotherapy options were chosen for the proposed study based on the strength of the 
efficacy data in the first line setting, previously approved indications, and the responses 
obtained in feasibility questionnaires (completed by AstraZeneca Clinical representatives in 
34 countries [including the US] following outreach to sites in their respective region). The 
chosen options are capecitabine, paclitaxel, and nab-paclitaxel. 
In addition, the decision to limit the investigator’s choice comparator treatment to 3 options 
was taken to also limit the heterogeneity of the comparator arm without limiting effective 
treatment choices. 
The rationale for the dose of each chemotherapy agent is provided below. All regimens 
proposed are based on standard practice and the National Comprehensive Cancer Network 
(NCCN) guidelines for HER2-negative recurrent or Stage IV breast cancer.

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!
Paclitaxel: Paclitaxel will be administered at a standard of care dose of 80 mg/m2 every 
week as opposed to the United States Prescribing Information (USPI) labelled paclitaxel 
dose of 175 mg/m2 q3w. In a meta-analysis of randomized, controlled studies in advanced 
breast cancer (5 studies, 1471 patients), which compared weekly administration of 
paclitaxel with q3w administration, the analysis concluded that there was an improvement 
in OS with weekly paclitaxel (pooled hazard ratio, 0.78; 95% CI: 0.67 to 0.89; p=0.001). 
Additionally, the incidence of neutropenia, neutropenic fever, peripheral neuropathy, and 
other SAEs was significantly lower with weekly paclitaxel compared with paclitaxel q3w 
(Mauri et al 2010). Based on this meta-analysis and to be aligned to standard practice 
among breast cancer clinicians, the weekly regimen of 80 mg/m2 is proposed for this 
study. 
!
Nab-paclitaxel: The q3w labelled dose of nab-paclitaxel (260 mg/m2), established from 
the Phase 3 study comparing paclitaxel with nab-paclitaxel (Gradishar et al 2005) is not 
generally used in current clinical practice. Instead, weekly administration of 
nab-paclitaxel at a dose of 100 mg/m2 is the most commonly utilized schedule given the 
better tolerability and suggestions of increased efficacy of weekly dosing compared with 
q3w dosing. The superiority of the weekly regimen of nab-paclitaxel was first 
demonstrated in a randomized, Phase 2 study conducted in patients with previously 
untreated metastatic breast cancer (Gradishar et al 2009). In this study, the ORR and PFS 
by independent radiologist assessment were higher for the weekly regimens of 
nab-paclitaxel vs q3w administration. The differences in PFS and ORR between the 100 
and 150 mg/m2 weekly dose levels of nab-paclitaxel were not statistically significant, but 
patients receiving the higher dose experienced a greater incidence of Grade 3 or 4 
neutropenia (44% vs 25%) and Grade 3 sensory neuropathy (14% vs 8%). Subsequent 
clinical studies have not clearly demonstrated that weekly doses of nab-paclitaxel greater 
than 100 mg/m2 are more efficacious. Therefore, for this study AstraZeneca proposes that 
patients receive 100 mg/m2 nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle. 
!
Capecitabine: The approved labelled dose of 1250 mg/m2 twice daily on Days 1 to 14 
followed by a 7-day rest period has demonstrated efficacy in ORR and PFS. However, 
26% to 65% of patients had their dose reduced by at least 20% in these trials (Miller et al 
2005, Pallis et al 2012). The main treatment-limiting toxicities at the labelled dosage were 
hand and foot syndrome (HFS) and diarrhea. Based on this experience, a number of 
Investigators have evaluated capecitabine at a lower starting dose (1000 mg/m2 twice 
daily) and demonstrated similar efficacy to the approved dose and a more favorable safety 
profile with an incidence of dose reduction, ranging from 16% to 34% in Phase 2 studies 
(Baselga et al 2012, El-Helw and Coleman 2005). These results are further supported by a 
meta-analysis of data from 34 studies comprising of 4833 patients. The results showed a 
significantly lower incidence of dose reduction (15.9% vs 39.0%; p=0.007), high-grade 
HFS (12.0% vs 19.0%; p=0.01), diarrhea (5.3% vs 9.1%; p=0.01), and neutropenia (1.8% 
vs 7.3%; p<0.01) and all-grade neutropenia (5.8% vs 25.4%; p=0.01) for capecitabine 

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1000 mg/m2 compared with 1250 mg/m2 (Nishijima et al 2016). Therefore, for this study, 
AstraZeneca proposes that patients have the option, based on Investigator’s choice, to 
receive either the 1250 mg/m2 dose as indicated in the label or the 1000 mg/m2 dose.
For information on dose modifications for paclitaxel, nab-paclitaxel and capecitabine, see 
Section 6.6.1 and the respective local prescribing information.
4.4
End of Study Definition
For the purpose of Clinical Trial Transparency (CTT), the definition of the end of the study 
differs under FDA and EU regulatory requirements: 
!
European Union requirements define study completion as the last visit of the last 
subject for any protocol-related activity.
!
Food and Drug Administration requirements defines 2 completion dates:
o
Primary Completion Date – the date that the final patient is examined or receives 
an intervention for the purposes of final collection of data for the primary 
outcome measure, whether the clinical study concluded according to the pre-
specified protocol or was terminated. In the case of clinical studies with more 
than one primary outcome measure with different completion dates, this term 
refers to the date on which data collection is completed for all of the primary 
outcomes.
o
Study Completion Date – the date the final patient is examined or receives an 
intervention for purposes of final collection of data for the primary and secondary 
outcome measures and AEs (for example, last patient’s last visit), whether the 
clinical study concludes according to the pre-specified protocol or is terminated.
A patient is considered to have completed the study if they have completed all phases of the 
study, including the last scheduled procedure shown in the SoA.
Patients must be withdrawn from the study if the study itself is stopped. The study may be 
stopped if, in the judgement of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings. The study may be terminated at individual centers if the study 
procedures are not being performed according to ICH GCP or if recruitment rate does not 
allow to complete study in the planned timeframe.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and randomization criteria, also 
known as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 

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study in order to be randomized to a study treatment. Under no circumstances can there be 
exceptions to this rule. Patients who do not meet the entry requirements are screen failures; 
refer to Section 5.4.
In this protocol, enrolled patients are defined as those who sign informed consent including 
the pre-screening ICF. Randomized patients are defined as those who undergo randomization 
and receive a randomization number. For procedures for withdrawal of incorrectly 
randomized patients see Section 6.3.2.
The study population for this study will include pathologically documented advanced or 
metastatic HR+, HER2-low breast cancer patients whose disease has progressed on at least 2 
lines of prior ET or within 6 months of first line ET + CDK4/6i in the metastatic setting. 
Patients must be ≥18 years of age, RECIST 1.1 evaluable, have an Eastern Cooperative 
Oncology Group (ECOG) performance status of 0 or 1, and have not received chemotherapy 
for metastatic disease.
5.1
Inclusion Criteria
Patients must meet the following criteria at screening:  
1
Male or female patients ≥ 18 years of age.
2
Pathologically documented breast cancer that: 
(a) Is advanced or metastatic
(b) Has a history of HER2-low or negative expression, defined as IHC 2+/ISH- or 
IHC 1+ (ISH- or untested) or IHC 0 (ISH- or untested) with a validated assay
(c) Has HER2-low expression or HER2 IHC >0 <1+ expression as determined by the 
central laboratory result from a metastatic setting (see inclusion criterion #3). 
(d) Was never previously reported as HER2-positive (IHC 3+ or ISH+) as per 
ASCO/CAP guidelines.
(e) Is documented as HR+ (either ER and/or PgR positive [ER or PgR ≥1%]) per 
ASCO/CAP guidelines (Allison et al 2020) in the metastatic setting. If a patient has 
had multiple ER/PgR results after metastatic disease, the most recent test result will 
be used to confirm eligibility.
3
Must have an adequate tumor tissue sample available for assessment of HER2 by central 
laboratory and other exploratory biomarker analyses and is preferred in FFPE blocks 
based on a mandatory FFPE tumor sample obtained at the time of metastatic disease or 
later; the most recently collected pre-randomization tumor sample from the time of 
metastatic disease or later that meets the tissue requirements specified in Section 8.7.1 is 
required. If no archival specimens are available, a newly acquired biopsy specimen is 
acceptable. (see Section 8.7.1 and the laboratory manual for additional details).

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4
ECOG performance status of 0 or 1
5
Radiologic or objective evidence of disease progression on or after the last systemic 
therapy prior to starting study treatment 
6
Must have had either:
(a) Disease progression on endocrine therapy + CDK4/6 inhibitor within 6 months of 
starting first line treatment for metastatic disease and considered appropriate for 
chemotherapy as the next treatment by the investigator, OR
(b) Disease progression on at least 2 previous lines of ET with or without a targeted 
therapy (such as CDK4/6, mTOR or PI3-K inhibitors) administered for the treatment 
of metastatic disease. 
Of note with regards to the ≥2 lines of previous ET requirement:
∀
Single agent anti-CDK4/6 therapy for the treatment of metastatic disease is 
considered a line of therapy 
∀
Disease recurrence while on the first 24 months of adjuvant ET, will be considered a 
line of therapy; these patients will only require 1 line of ET in the metastatic setting
∀
Any progression after discontinuing or completing a course of adjuvant ET will not 
be considered a line of therapy
∀
Single agent PARP inhibitor therapy is not considered a line of ET
∀
Changes in dosing schedules, or discontinuations/re-starting of the same drugs or the 
addition of a targeted therapy to an ET without progression (e.g., adding a CDK4/6 
to a current aromatase inhibitor regimen) will not be considered separate lines of 
therapy.
7
No prior chemotherapy for advanced or metastatic breast cancer. Patients who have 
received chemotherapy in the neo-adjuvant or adjuvant setting are eligible, as long as they 
have had a disease-free interval (defined as completion of systemic chemotherapy to 
diagnosis of advanced or metastatic disease) of >12 months.
8
Life expectancy ≥12 weeks at screening
9
At least 1 lesion, not previously irradiated, that can be measured accurately at baseline as 
≥10 mm in the longest diameter (except lymph nodes which must have short axis 
≥15 mm) with CT or MRI which is suitable for accurate repeated measurements, or 
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; patients with sclerotic/osteoblastic 
bone lesions only in the absence of measurable disease are not eligible. 
10 LVEF ≥ 50% within 28 days before randomization.

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11 Adequate organ and bone marrow function within 14 days before randomization. For all 
parameters listed below, the most recent results available must be used to meet the 
inclusion criteria:
(a) Hemoglobin ≥ 9 g/dL Note: Patients requiring ongoing transfusions or growth factor 
support to maintain hemoglobin ≥ 9 g/dL are not eligible. (Red blood cell transfusion 
is not allowed within 1 week prior to screening assessment)
(b) Absolute neutrophil count ≥ 1500/mm3. (granulocyte-colony stimulating factor 
[G-CSF] administration is not allowed within 1 week prior to screening assessment)
(c) Platelet count ≥ 100000/mm3. (Platelet transfusion is not allowed within 1 week prior 
to screening assessment)
(d) Total bilirubin (TBL) ≤ 1.5 × upper limit of normal (ULN) if no liver metastases or 
< 3 × ULN in the presence of documented Gilbert’s Syndrome (unconjugated 
hyperbilirubinemia) or liver metastasis at baseline.
(e) ALT and AST ≤ 3 ×ULN, < 5 ×ULN in patients with liver metastasis.
(f) Serum albumin ≥ 2.5 g/dL
(g) Creatinine clearance ≥ 30 mL/min (as calculated using the Cockcroft and Gault 
equation)
Cockcroft-Gault equation: 
CLcr (mL/min) =
[ — 	
 (	)] × 
 (
)
 ×  	 (
/ )
{× 0.85 for females}
(h) International normalized ratio (INR) or prothrombin time (PT) and either partial 
thromboplastin or activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN
12 Adequate treatment washout period before randomization, defined as:
(a) Major surgery: ≥ 4 weeks
(b) Radiation therapy including palliative stereotactic radiation therapy to chest: 
≥4 weeks (palliative stereotactic radiation therapy to other areas ≥ 2 weeks).
(c) Hormonal therapy: ≥ 3 weeks 
(d) Immunotherapy (non-antibody based therapy): ≥ 3 weeks
(e) Small molecule targeted agents: ≥ 2 weeks or 5 half-lives, whichever is longer
(f) Antibody-based anti-cancer therapy: ≥ 4 weeks with the exception of receptor 
activator of nuclear factor kappa-B ligand (RANKL) inhibitors (e.g., denosumab for 
the treatment of complications resulting from bone metastases)
(g) Chloroquine/Hydroxychloroquine: ≥ 14 days 
13 Evidence of post-menopausal status (Section 5.3) or negative serum pregnancy test for 
females of childbearing potential who are sexually active with a non-sterilized male 
partner. For women of childbearing potential, a negative result for serum pregnancy test 

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(test must have a sensitivity of at least 25 mIU/mL) must be available at the screening 
visit and urine beta-human chorionic gonadotropin (β-HCG) pregnancy test prior to each 
administration of study treatment. 
Women of childbearing potential are defined as those who are not surgically sterile (i.e. 
underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal.
14 Female patients of childbearing potential who are sexually active with a non-sterilized 
male partner must use at least one highly effective method of contraception (Table 8) 
from the time of screening and must agree to continue using such precautions for 
7 months after the last dose of study treatment. Not all methods of contraception are 
highly effective. Female patients must refrain from egg cell donation and breastfeeding 
while on study treatment and for at least 7 months after the last dose of study treatment. 
Abstinence is acceptable only as true abstinence when this is in line with the preferred 
and usual lifestyle of the patient for the duration of the study treatment and the drug 
washout period (7 months). Periodic abstinence (e.g., calendar ovulation, symptothermal, 
post-ovulation methods), the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.
15 Non-sterilized male patients who are sexually active with a female partner of childbearing 
potential must use a condom with spermicide from screening and throughout the duration 
of the study treatment and the washout period (4 months after the last dose of T-DXd, 6 
months after the last dose of paclitaxel or nab-paclitaxel, and 3 months after the last dose 
of capecitabine). Abstinence is acceptable only as true abstinence when this is in line with 
the preferred and usual lifestyle of the patient for the duration of the study treatment and 
the drug washout period. Periodic abstinence (e.g., calendar ovulation, symptothermal, 
post-ovulation methods), the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. It is strongly recommended for the female partners 
of a male patient also use at least one highly effective method of contraception throughout 
this period, as described Table 8. In addition, male patients should refrain from fathering 
a child or donating sperm throughout the duration of the study and the washout period 
(4 months after the last dose of T-DXd, 6 months after the last dose of paclitaxel or 
nab-paclitaxel, and 3 months after the last dose of capecitabine). Preservation of sperm 
should be considered prior to randomization in this study.
16 Female patients 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 
last dose of study treatment. They should refrain from breastfeeding throughout this time.
Preservation of ova may be considered prior to randomization in this study.

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5.2
Exclusion Criteria 
Patients must NOT meet the following criteria at screening:
1
Ineligible for all options in the investigator’s choice chemotherapy arm. Patients with 
contraindications to capecitabine, paclitaxel, and nab-paclitaxel treatment, per local 
prescribing information, cannot be enrolled to the study.
2
Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, 
uncontrolled or significant cardiovascular disease, serious chronic gastrointestinal 
conditions associated with diarrhea, or psychiatric illness/social situations that would 
limit compliance with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed consent. 
3
Uncontrolled or significant cardiovascular disease includes any of the following: 
(a) Patients with a medical history of myocardial infarction within 6 months before 
randomization or symptomatic CHF (NYHA Class II to IV). Patients with troponin 
levels above ULN at screening (as defined by the manufacturer), and without any 
myocardial infarction related symptoms, should have a cardiologic consultation 
before randomization to rule out myocardial infarction.
(b) Uncontrolled hypertension
(c) Uncontrolled and/or clinically important cardiac arrhythmias
(d) Corrected QT interval by Fredericia’s method (QTcF) prolongation to >470 ms 
(females) or >450 ms (male) based on average of screening triplicate 12-lead 
electrocardiogram (ECG)
4
Has as a 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.
5
Patients with prior use of immunosuppressive medication within 14 days prior to first 
study dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at 
doses less than 10 mg/day of prednisone/prednisolone or equivalent. 
6
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any 
underlying pulmonary disorder (i.e., pulmonary emboli within three months prior to study 
randomization, severe asthma, severe chronic obstructive pulmonary disorder [COPD], 
restrictive lung disease, significant pleural effusion etc.), and any autoimmune, 
connective tissue or inflammatory disorders with pulmonary involvement (i.e., 
rheumatoid arthritis, Sjogren’s syndrome, sarcoidosis etc.), and/or prior pneumonectomy 
(complete).
7
Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
8
Has spinal cord compression or clinically active central nervous system metastases, 
defined as untreated and symptomatic, or requiring therapy with corticosteroids or 

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anticonvulsants to control associated symptoms. Subjects with clinically inactive brain 
metastases may be included in the study. Subjects with treated brain metastases that are 
no longer symptomatic and who require no treatment with corticosteroids or 
anticonvulsants may be included in the study if they have recovered from the acute toxic 
effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of 
whole brain radiotherapy and study randomization. 
9
Active primary immunodeficiency, known human immunodeficiency virus (HIV) 
infection, or active hepatitis B or C infection. Patients positive for hepatitis C antibody 
are eligible only if polymerase chain reaction is negative for HCV RNA. Participants 
should be tested for HIV prior to randomization if required by local regulations or by the 
IRB/IEC.
10 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 study 
treatment. Note: Patients, if enrolled, should not receive live vaccine during the study and 
up to 30 days after the last dose of study treatment. 
11 Has 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 enrollment and managed with 
standard of care treatment) that the investigator deems related to previous anticancer 
therapy, such as:
!
Chemotherapy-induced neuropathy
!
Fatigue
!
Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies 
which may include:
(a) Hypothyroidism/hyperthyroidism
(b) Type 1 diabetes
(c) Hyperglycaemia
(d) Adrenal insufficiency
(e) Adrenalitis
(f) Skin hypopigmentation (vitiligo)
12 Pregnant or breastfeeding female patients, or patients who are planning to become 
pregnant.
13 Patients with a known hypersensitivity to either the drug substances, inactive ingredients 
in the drug product or to other monoclonal antibodies
14 History of another primary malignancy within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in situ disease, other solid tumors curatively 
treated, or contralateral breast cancer.

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15 Previous treatment with anti-HER2 therapy 
16 Prior treatment with antibody drug conjugate that comprised an exatecan derivative that is 
a topoisomerase I inhibitor
17 Prior randomization or treatment in a previous T-DXd study regardless of treatment 
assignment.
18 Participation in another clinical study with a study treatment administered in the last 
30 days prior to first dose of study treatment or concurrent enrollment in another clinical 
study, unless it is an observational (non-interventional) clinical study or during the 
follow-up period of an interventional study. Of note, pre-screening for this study while a 
patient is on treatment in another clinical study is acceptable. 
19 Has substance abuse or any other medical conditions such as psychological conditions, 
that may, in the opinion of the Investigator, interfere with the patient’s participation in the 
clinical study or evaluation of the clinical study results.
5.3
Lifestyle Considerations
The safety-specific restrictions of T-DXd are listed below and also in Section 6.5. 
!
Patients must be instructed not to take any medications, including over-the-counter 
products, during the treatment period and 40 days (+7 days) after the last study treatment, 
without first consulting with the Investigator.
!
Patients, if enrolled, should not receive 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 study treatment will be excluded.
!
Females of childbearing potential (defined as those who are not surgically sterile [i.e., 
bilateral oophorectomy, or complete hysterectomy] or post-menopausal) who are sexually 
active with a non-sterilized male partner must use at least one highly effective method of 
contraception (Table 8) from the time of screening and must agree to continue using such 
precautions for 7 months after the last dose of study treatment; cessation of birth control 
after this point should be discussed with a responsible physician. Female patients must 
not donate, or retrieve for their own use, ova from the time of screening and throughout 
the study treatment period, and for at least 7 months after the final study drug 
administration. Women will be considered post-menopausal if they have been 
amenorrheic for 12 months without an alternative medical cause (treatment with anti-
hormonal therapies is considered an alternative medical cause). The following age-
specific requirements apply: 
!
Women <50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy and if they have luteinizing hormone and follicle-stimulating hormone levels in 
the post-menopausal range for the institution.

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!
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all hormonal replacement 
therapy, or had radiation-induced menopause with last menses >1 year ago, or had 
chemotherapy-induced menopause with last menses >1 year ago
A highly effective method of contraception is defined as one that results in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly and are described in Table 8. 
Note that some contraception methods are not considered highly effective (e.g., male or 
female condom with or without spermicide; female cap, diaphragm or sponge with or without 
spermicide; non-copper containing intrauterine device; progesterone-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).
All patients should also follow the local prescribing information relating to contraception, the 
time limits for such precautions, and any additional restrictions for paclitaxel, capecitabine 
and nab-paclitaxel.
Table 8
Highly Effective Methods of Contraception( < 1% failure rate)
Barrier/intrauterine methods
Hormonal methods (female partners [of 
childbearing potential] 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)
•
Copper T intrauterine device 
•
Progesterone T intrauterine device 
•
Levonorgestrel-releasing intrauterine system (e.g., 
Mirena®) a
Injection: Medroxyprogesterone injection 
(e.g., Depo-Provera®) b
Levonorgestrel-releasing intrauterine system 
(e.g., Mirena®) b
Implants: Etonogestrel-releasing implants 
(e.g., Implanon® or Norplant®)
Intravaginal Devices: 
Ethinylestradiol/etonogestrel-releasing intravaginal 
devices (e.g., NuvaRing®)
Combined pill: Normal and low dose combined oral 
contraceptive pill
Minipill: Progesterone-based oral contraceptive pill 
using desogestrel: Cerazette® is currently the only 
highly effective progesterone-based pill
Patch: Norelgestromin/ethinylestradiol-releasing 
transdermal system (e.g., Ortho Evra®)
a
Also considered a hormonal method
b
Hormonal contraception associated with inhibition of ovulation.
!
Male patients with a female partner of childbearing potential
∀
Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential must use a male condom plus 

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spermicide from the time of screening throughout the total duration of the study 
treatment and the washout period (4 months after the last dose of T-DXd, 6 months 
after the last dose of paclitaxel or nab-paclitaxel, and 3 months after the last dose of 
capecitabine). Periodic abstinence, the rhythm method, and the withdrawal method 
are not acceptable methods of contraception. Male patients should refrain from 
fathering a child or donating sperm during the study treatment and during the 
washout period (4 months after the last dose of T-DXd, 6 months after the last dose 
of paclitaxel or nab-paclitaxel, and 3 months after the last dose of capecitabine) after 
the last dose of study treatment. 
∀
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 8).
!
Due to the possibility of paclitaxel, nab-paclitaxel, and capecitabine chemotherapy 
causing irreversible infertility/testicular damage, men are advised to seek counselling on 
sperm storage before starting treatment, and preservation of sperm should be considered 
prior to randomization in this study. 
Restrictions relating to concomitant medications are described in Section 6.5.
5.4
Screen Failures
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be randomized. These patients should have the reason for study withdrawal recorded 
as “eligibility criteria not fulfilled” (i.e., patient does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures (i.e., not 
randomized patients). Patients may be rescreened a single time, but they may not be 
re-randomized to treatment. In addition, patients who are pre-screened may also be rescreened 
one single time, and may enter pre-screening on rescreen. Rescreened patients should be 
assigned the enrollment number as for the initial screening. Rescreening should be 
documented so that its effect on study results, if any, can be assessed.
Of note, patients who previously screen failed due to having the local HER2 test result not 
confirmed by central HER2 testing (inclusion criterion #2[c] of CSP version 3.0) can be 
rescreened once, as long as they have not been previously rescreened and they were not HER2 
positive by central HER2 test. Patients who screen failed because of having a central HER2 
test of HER2 IHC 0 cannot be rescreened unless a strong rationale can be provided to allow 
for HER2 retesting (e.g., patient received a subsequent line of therapy). In the event 
Investigators would like to rescreen patients who have screen failed due to having a central 
HER2 test result of HER2 IHC 0, the rationale must be documented and a discussion with the 
AstraZeneca Study Physician is required.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure patients to meet the Consolidated Standards of Reporting Trials (CONSORT) 

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publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, local HER2 testing 
results, details about sample sent for central HER2 testing and any SAE for screen failures 
including patients who are identified in the pre-screening phase as not eligible.
6
STUDY INTERVENTIONS (TREATMENTS) 
Study intervention or study treatment is defined as any investigational intervention/treatment 
(including marketed product comparator and placebo) or medical device(s) intended to be 
administered to a patient according to the study protocol. Study treatment in this study refers 
to T-DXd and investigator’s choice chemotherapy (paclitaxel, nab-paclitaxel and 
capecitabine). 
6.1
Study Interventions (Treatments) Administered
6.1.1
Study Treatments
The study treatments to be administered in this study are shown in Table 9.

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Table 9
Study Treatments
Study 
treatment 
name
Dosage Presentation
Unit Dose Strength
Dosage level
Route of 
administration
Packaging and labeling
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 
100 mg vials. Each vial 
will be labelled in 
accordance with GMP 
Annex 13 and per country 
regulatory requirement a
Provided 
centrally by 
AstraZeneca
Paclitaxel
Vial
Variable
80 mg/m2
IV
If centrally sourced b, 
product will be provided 
in vials. Each vial will be 
labelled in accordance 
with GMP Annex 13 and 
per regulatory country 
requirements. 
Sourced 
locally by 
site b
Capecitabine
Tablet
Capecitabine 500 mg 
film-coated tablets 
and
Capecitabine 150 mg 
film-coated tablets
1000 or 1250 mg/m2
Oral
If centrally sourced b, 
product will be provided 
either in blister packs in 
carton, bottles or in a 
wallet.
If applicable, the blister 
pack and carton, or bottle, 
will be labeled. If 
provided in a wallet, only 
the wallet will be labelled. 
All labels will be labelled 
in accordance with GMP 
Annex 13 and per country 
requirements.
Sourced 
locally by 
site b

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Table 9
Study Treatments
Study 
treatment 
name
Dosage Presentation
Unit Dose Strength
Dosage level
Route of 
administration
Packaging and labeling
Sourcing
Nab-paclitaxel
Vial
Variable
100 mg/m2 
IV
If centrally sourced b, 
product will be provided 
in vials. Each vial will be 
labelled in accordance 
with GMP Annex 13 and 
per regulatory country 
requirements.
Sourced 
locally by 
site b
GMP = good manufacturing practice; IV = intravenous
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.
b
Under certain circumstances when local sourcing is not feasible, paclitaxel/nab-paclitaxel/capecitabine may be supplied centrally through AstraZeneca

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6.1.2
T-DXd
T-DXd will be supplied by AstraZeneca as a 100 mg lyophilized powder for infusion after 
reconstitution and dilution. The reconstituted 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 5.0 mL.
The reconstituted drug product is a clear to opalescent, colorless to yellow liquid and 
practically free from visible particles.
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Investigational product should be kept in original packaging until use to prevent prolonged 
light exposure.
6.2
Preparation/Handling/Storage/Accountability of Study 
Treatments
!
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are 
reported and resolved before use of the study treatments.
!
Only patients randomized in the study will receive study treatment and only authorized 
site staff will supply or administer study treatment. All study drugs must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labelled storage conditions with access limited to the Investigator and 
authorized site staff.
!
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records).
!
Further guidance and information for the final disposition of unused study treatments are 
provided in the Pharmacy Manual.
The study treatments provided for this study will be used only as directed in this protocol and 
the Pharmacy Manual. The study site staff will account for all study treatments dispensed to 
and returned from the patient. The study site staff will account for all study treatments 
received at the site, unused study treatments and for appropriate destruction of all unused 
study treatments. Certificates of delivery and destruction should be signed and filed in the 
study documentation. 
6.2.1
T-DXd (DS-8201a)
T-DXd will be administered at room temperature by controlled infusion into a peripheral or 
central vein. The standard infusion time for T-DXd is approximately 90 minutes ±10 minutes 

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for the first infusion. If the first infusion is well tolerated and the participant does not 
experience an infusion-related reaction, then the minimum infusion time for subsequent cycles 
is 30 minutes. However, if there are interruptions during the infusion, the total time should not 
exceed 3 hours at room temperature.
Patients will receive a dose of 5.4 mg/kg q3w. The number of treatment cycles with T-DXd is 
not fixed. Upon commencing study treatment, patients will continue receiving T-DXd until 
RECIST 1.1 disease progression, withdrawal of consent or any of the discontinuation criteria 
are met. 
The patient’s weight at screening will be used to calculate the initial dose. If, during the 
course of treatment, the patient’s weight has changed by ≥± 10%, the patient’s dose will be 
recalculated based on the patient’s updated weight. However, sites can modify the dosage if 
the weight changes after screening and if the site’s local practice is more conservative than the 
10% threshold for dose adjustment (e.g., dose adjustment if 5% variance in the patient’s 
weight).
Do not co-administer other drugs through the same infusion line.
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. If either preparation time or infusion time exceeds the time limit a new dose must 
be prepared from new vials. T-DXd does not contain preservatives, and any unused portion 
must be discarded. 
Refer to the Pharmacy Instructions for detailed information about preparation and 
administration of T-DXd. 
6.2.2
Paclitaxel, Capecitabine and Nab-paclitaxel
Patients will receive the investigator’s choice chemotherapy in doses specified in Table 9. 
Refer to the local label for details on handling. The investigator’s choice of chemotherapy 
should be predefined, prior to randomization. The investigator’s choice chemotherapies, 
paclitaxel, capecitabine and nab-paclitaxel, will either be locally sourced or centrally supplied 
by AstraZeneca and will be administered according to local prescribing information or 
treatment guidance in general use by the investigation site or drug label for centrally sourced 
medications. The number of treatment cycles for the investigator’s choice chemotherapy is not 
fixed. 

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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Patient Enrollment and Randomization
All patients will be randomly assigned to an arm using IRT. Before the study is initiated, the 
login information and directions for the IRT will be provided to each site. 
If a patient withdraws from the study, then his/her randomization code cannot be reused. 
Withdrawn patients will not be replaced.
Investigators should keep a record of patients (i.e., the patient screening log) who entered 
screening and/or pre-screening. 
At screening/baseline (Days -28 to -1), the Investigators or suitably trained delegate will do 
the following:
!
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 patient. However, 
all screening laboratory and imaging results must have been obtained within 28 days of 
randomization. For patients with a single target lesion (TL), if screening biopsy is 
collected prior to screening imaging for baseline tumor assessment, allow approximately 
2 weeks before imaging scans are acquired. An optional pre-screen ICF may 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 (e.g., medical history, availability of required 
number of slides for study). Patients who signed the pre-screening ICF will be considered 
enrolled.
!
Obtain a unique 7-digit enrollment number (E-code) at pre-screening or screening, 
through IRT in the following format: ECCNNXXX (CC being the country code, NN 
being the center number, and XXX being the patient enrollment code at the center). This 
number is the patient’s unique identifier and is used to identify the patient on the 
electronic case report forms (eCRFs).
!
Obtain tumor sample and send for centralized HER2 testing. A mandatory FFPE tumor 
sample obtained at the time of metastatic disease or later must be provided; the most 
recently collected pre-randomization tumor sample from the time of metastatic disease or 
later that meets the tissue requirements specified in Section 8.7.1 is required. If no 
archival specimens are available, a newly acquired biopsy specimen is acceptable. 
Obtaining the tumor sample should be given very high priority and as such, an optional 
pre-screen ICF may be signed for patients to permit for sample collection and testing 
prior to the 28-day screening window in order to permit for analysis in a timely manner. 

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Screening procedures may be carried out while HER2 status is being tested, however it is 
recommended that the main ICF and other study procedures not be started until the 
sample submitted for HER2 testing is accepted for central laboratory testing. 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 patient eligibility (see Sections 5.1 and 5.2).
!
Obtain signed informed consent for genetic research study (optional).
If the patient is ineligible and not randomized, such a patient should be recorded by site 
personnel in the IRT system as “screen-failure” and the IRT should be contacted to terminate 
the patient in the system.
The day patients receive the first dose of study treatment is Cycle 1 Day 1. Every effort should 
be made to minimize the time between randomization and dosing. Dosing should occur no 
more than 3 days after randomization. If it is anticipated that dosing cannot occur within 
3 days, a discussion with the AstraZeneca Study Physician is required. Patients must not be 
randomized and must not receive study treatment unless all eligibility criteria have been met. 
6.3.2
Procedures for Handling Incorrectly Randomized Patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. There can be no exceptions to this rule. Patients who 
are enrolled but subsequently found not to meet all the eligibility criteria must not be 
randomized to treatment, and they must be withdrawn from the study.
When a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient from 
treatment. The AstraZeneca Study Physician must ensure all decisions are appropriately 
documented and that the potential benefit/risk profile remains positive for the patient. 
6.3.3
Methods for Assigning Treatment Groups (Randomization)
The actual treatment given to patients will be determined by the randomization scheme in the 
IRT. The randomization scheme will be produced by a computer software program that 
incorporates a standard procedure for generating randomization numbers. One randomization 
list will be produced for each of the randomization stratum. A blocked randomization will be 
generated, and all centers will use the same list in order to minimize any imbalance in the 
number of patients randomized to each treatment group. 
Randomization codes will be assigned strictly sequentially, within each stratum (refer to the 3 

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stratification factors in Section 4.1), as patients become eligible for randomization. When 
medication is provided centrally by AstraZeneca, the IRT will allocate kit identification 
numbers at each treatment visit. If medication is provided locally, IRT will not provide kit 
numbers.
6.3.4
Methods for Ensuring Blinding
This is an open-label study for the personnel at study sites; however, the trial will be 
conducted as “sponsor-blind” and the specific treatment to be taken by a patient will be 
assigned using an IRT (see Section 6.3.3 for details). To maintain the integrity of the study, 
AstraZeneca personnel directly involved in the study conduct will not undertake or have 
access to efficacy data aggregated by treatment arm prior to final data readout for the primary 
endpoint. Before the first patient is randomized, a Trial Integrity Document will be generated 
in which data access levels for relevant AstraZeneca personnel will be pre-specified.
6.4
Study Treatment Compliance
When patients are dosed at the site, they will receive study treatment directly from the 
Investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study treatment and study patient identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
treatment. Study treatment start and stop dates, including any changes from the dosing 
schedule, dose interruptions, dose reductions, and dose discontinuations should be recorded in 
the eCRF. The reason should also be documented. The Investigator or pharmacist must retain 
records of all study treatments administered at the site. The Study Monitor will check these 
records to confirm compliance with the protocol administration schedule.
Capecitabine is the only oral intervention in this study and will be self-administered by the 
patients at home. Patients will be instructed to bring capecitabine dosing diaries and all blister 
packs, bottles, or wallets of capecitabine (empty, partially empty, or full) to the clinic for each 
study visit. For each cycle, participants should return all unused tablets during the 
dispensation visit of the subsequent cycle, at which point a new set of tablets will be dispensed 
to the participants. In this case, the compliance will be assessed at each visit. Compliance will 
be assessed by direct questioning and counting returned tablets during the site visits and 
documented in the source documents and eCRF. Deviation(s) from the prescribed dosage 
regimen should be recorded in the eCRF. Accountability records should be maintained by the 
site staff and should be current and up to date. In case of low compliance, participants should 
be retrained by the site staff, and the retraining should be documented.
6.5
Concomitant Therapy
The Investigator must be informed as soon as possible about any medication taken from the 

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time of screening (signing main ICF) until the end of the clinical treatment phase of the study 
including the 40-day (+7 days) follow-up period following the last dose of study treatment. 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with the following:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose, unit and frequency
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. Concomitant use of dietary supplements, 
medications not prescribed by the Investigator, and alternative/complementary treatments is 
discouraged, but not prohibited.
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables (Table 10 and Table 11) and apply to all treatment arms. Refer also to the dosing 
modification (Section 6.6) and TMGs (see Appendix H). Refer to the local prescribing 
information for capecitabine, paclitaxel and nab-paclitaxel, with regards to warnings, 
precautions, contraindications and prohibited medications during treatment.
Table 10
Prohibited Concomitant Medications 
Prohibited medication/class of drug
Usage
Any investigational anticancer therapy other than 
those under investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment
mAbs against HER2 other than those under 
investigation in this study
Should not be given concomitantly whilst the patient is 
on study treatment

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Table 10
Prohibited Concomitant Medications 
Prohibited medication/class of drug
Usage
Any concurrent chemotherapy, targeted therapy, 
radiotherapy, immunotherapy, or biologic or 
hormonal therapy for cancer treatment other than 
those under investigation in this study
•
Should not be given concomitantly whilst the 
patient is on study treatment. (Concurrent use of 
hormones for non-cancer-related conditions 
[e.g., insulin for diabetes and hormone replacement 
therapy] is acceptable). 
•
For T-DXd treatment, palliative radiotherapy to the 
chest area is prohibited. 
•
For both treatment arms, palliative radiotherapy 
(outside of palliative radiotherapy to the chest area) 
is permitted after consultation with the Study 
Physician. The lesions must be known to be present 
at the time of study entry and the Investigator 
clearly documents that the need for palliative 
radiotherapy is not indicative of disease 
progression. For patients with bone involvement, it 
is suggested to institute palliative radiotherapy 
before study initiation if possible and clinically 
appropriate (e.g., lesions at risk for spontaneous 
micro-fractures or painful lesions). 
Live attenuated vaccines 
Should not be given during the study and up to 30 days 
after the last dose of study treatment.
Immunosuppressive medications 
T-DXd cannot be administered when the patient is taking 
immunosuppressive medications, including 
corticosteroids with the exception of:
•
Short-term courses (< 2 weeks)
•
Low to moderate dose (less than 10 mg/day of 
prednisone/prednisolone or equivalent)
•
Long-term, alternate-day treatment with 
short-acting preparations; maintenance physiologic 
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.
Corticosteroids used as premedication for the prevention 
of nausea and vomiting is allowed.
A temporary period of steroid treatment will be allowed 
for different indications after discussion with the Study 
Physician (e.g., chronic obstructive pulmonary disease, 
radiation, nausea, etc.). 
Patients with bronchopulmonary disorders who require 
intermittent use of bronchodilators (such as albuterol) 
will not be excluded from this study. 
Use of immunosuppressive medications for the 
management of treatment-related AEs or in patients with 
contrast allergies is acceptable.

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Table 10
Prohibited Concomitant Medications 
Prohibited medication/class of drug
Usage
Immunosuppressive medications also include drugs like 
methotrexate, azathioprine, and tumor necrosis 
factor-alpha blockers.
Chloroquine/hydroxychloroquine
Concomitant treatment with chloroquine or 
hydroxychloroquine is not allowed during the study 
treatment. 
AE = adverse event; HER2 = human epidermal growth factor receptor 2; mAb = monoclonal antibody
Table 11
Supportive Medications
Supportive medication/class of drug
Usage
Anti-emetic agents including 
5-hydroxytryptamine receptor (5-HT3) 
antagonists, Neurokinin-1 (NK1) receptor 
antagonists and steroids (e.g., dexamethasone)
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 
two or three medicinal products (e.g., 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.
Concomitant medications or treatments 
(e.g., acetaminophen or diphenhydramine) 
deemed necessary to provide adequate 
prophylactic or supportive care, except for those 
medications identified as “prohibited,” as listed 
above 
To be administered as prescribed by the Investigator
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic 
disorders, optimal symptom control, and pain 
management [including palliative radiotherapy to 
non-target lesions, etc.])
Should be used, when necessary, for all patients
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
Coumadin anticoagulants
Permitted
Hematopoietic growth factors
Hematopoietic growth factors may be used for 
prophylaxis or treatment based on the clinical judgment 
of the Investigator
6.5.1
Other Concomitant Medications
Other medications other than that described above, which is considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.

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6.5.2
Restrictions on Concomitant Medications/Therapies
Patients with prior use of immunosuppressive medication within 14 days prior to first study 
dose, except for intranasal and inhaled corticosteroids or systemic corticosteroids at doses less 
than 10 mg/day of prednisone/prednisolone 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, 
anti-cancer IP 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. Concurrent use of hormones for 
noncancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is 
acceptable. 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. 
6.6
Dose Modification
6.6.1
Individual Patient Dose Modifications
6.6.1.1
T-DXd
The following dose modifications apply to toxicities that are attributable to T-DXd:
!
Dose delays are permitted for T-DXd therapy. In instances for delays in dosing, the 
dosing interval for the next T-DXd cycle may be shortened as clinically feasible to 
gradually align with the schedule of tumor efficacy assessment. Two consecutive doses 
must be administered at least 19 days apart. 
!
Every effort should be made to limit T-DXd delay, however in circumstances of AE 
management or medical intervention, T-DXd can be held up to 18 weeks (126 days) from 
the last T-DXd dose. During this time scheduled CT/MRI scans should continue as per 
protocol, and patients should fulfil all of the following criteria: 
∀
T-DXd 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 scan must be done within 6 weeks prior to restarting the 
study drug.
∀
T-DXd is restarted within the guidance of the TMGs for T-DXd.
∀
No prohibited concomitant medications have been administered since the last dose of 
T-DXd.
!
For management of dose delays due to T-DXd-related events, the TMGs (Appendix H) 
should be followed, as applicable.
In summary, if a patient experiences a clinically significant and/or unacceptable toxicity, 
dosing will be interrupted (or discontinued) or supportive therapy administered as required.

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Dose Modification for ILD/Pneumonitis Cases
!
ILD/pneumonitis Grade 1: If ILD/pneumonitis resolves before 28 days from day of event 
onset, T-DXd may be resumed at the same dose. If ILD/pneumonitis resolves after 28 
days, T-DXd will be resumed at a lower dose as instructed in Table 16.
!
ILD/pneumonitis Grade 2 and higher: Permanently discontinue T-DXd. Follow-up 
assessments should be completed as described in the SoA (Section 1.3).
See Section 8.2.10.1 for tests required if ILD/pneumonitis is suspected.
Any Grade 4 hematological toxicity with significant clinical symptoms that do not resolve 
with treatment within 4 weeks: resuming T-DXd will be possible if the toxicity resolves, and 
in consultation with the AstraZeneca Study Physician.
Dose Modification Criteria for Suspected or Confirmed COVID-19
Please see Appendix I for dose modification and management plan for patients with confirmed 
or suspected COVID-19 who are being treated with T-DXd.
6.6.1.2
Investigator’s Choice Chemotherapy
Investigators should follow the local prescribing information and standard clinical practice 
regarding management of paclitaxel, nab-paclitaxel and capecitabine-related toxicities. The 
investigator’s choice chemotherapy treatment can be interrupted for up to 28 days from the 
planned date of administration. If a patient requires a dose delay longer than 28 days, 
resumption of treatment should be discussed with the AstraZeneca Study Physician. The 
investigator’s choice of chemotherapy should be predefined, prior to randomization. 
Prophylactic therapy, supportive care prior to and after chemotherapy treatment should be 
given as needed on a prophylactic and treatment basis in compliance with institutional 
standards. Hematopoietic growth factors may be used for prophylaxis or treatment based on 
the clinical judgment of the Investigator in compliance with the standards of the center (see 
also Table 11). 
6.7
Intervention after the End of the Study
No intervention is planned after the end of the study. After the final analysis, AstraZeneca will 
continue to supply open-label drug to patients receiving T-DXd and to patients receiving 
centrally supplied capecitabine, paclitaxel, and nab-paclitaxel up to the time that they 
discontinue the treatment for whatever reason.
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patients currently receiving 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 

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ensure treatment continuation with visits and assessments per its protocol. Any patient who 
would be proposed to move to such a study would be asked to sign a new ICF.
7
DISCONTINUATION OF STUDY TREATMENT AND 
PATIENT DISCONTINUATION/WITHDRAWAL
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
treatment and follow-up and for any further evaluations that need to be completed.
7.1.1
Permanent Discontinuation of Study Treatment
Patients may be discontinued from study treatment in the following situations. Note that 
discontinuation from study treatment is NOT the same as a complete withdrawal from the 
study. Patients who permanently discontinue study treatment will continue to have follow-up 
assessments per the protocol. Patients will be permanently discontinued from the treatment if 
the following criteria are met: 
!
Withdrawal of consent by patient. The patient is, at any time, free to discontinue 
treatment, without prejudice to further treatment. A patient who discontinues study 
treatment is normally expected to continue to participate in the study (e.g., for safety and 
survival follow-up) unless they specifically withdraw their consent to all further 
participation in any study procedures and assessments (see Section 1.3).
!
Occurrence of any AE that, in the opinion of the Investigator or AstraZeneca, 
contraindicates further dosing
!
Occurrence of any AE that meets the criteria for permanent discontinuation as defined in 
TMGs for T-DXd (Appendix H) or as defined in the local prescribing information for 
paclitaxel, nab-paclitaxel and capecitabine
!
Pregnancy or intent to become pregnant
!
Severe non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from study treatment (e.g., refusal to adhere to 
scheduled visits)
!
When a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study 
Physician immediately, and a discussion should occur between the AstraZeneca Study 
Physician and the Investigator regarding whether to continue or discontinue the patient 
from treatment. (Section 6.3.2). The AstraZeneca Study Physician must ensure all 
decisions are appropriately documented. The Investigator should make documentation in 
the medical record as appropriate. 
!
Initiation of alternative anticancer therapy including another investigational agent
!
Objective progressive disease, as determined by the investigator per criteria set forth in 
RECIST 1.1 (refer to Appendix G) 

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!
Death
!
Study terminated by AstraZeneca
!
Lost to follow-up
All patients who are discontinued from study treatment should complete protocol-specified 
procedures for discontinuation of study treatment (details in Section 7.1.2) and follow-up 
procedures (details in Section 1.3). Discontinued patients will be followed for survival, either 
through direct contacts or by collecting public records (e.g., death certificates) as allowed by 
local laws.
The EOT visit should be performed as soon as the patient is permanently discontinued from 
study treatment (Table 4). The reason for discontinuation should be documented in the source 
document and the appropriate section of the eCRF.
7.1.2
Procedures for Discontinuation of Study Treatment
Discontinuation of study treatment does not impact the patient’s participation in the study. A 
patient who decides to discontinue the study treatment will always be asked about the 
reason(s) for discontinuation and the presence of any AE. The patient should continue 
attending subsequent study visits, and data collection should continue according to the study 
protocol. If the patient does not agree to continue in-person study visits, a modified follow-up 
must be arranged to ensure the collection of endpoints and safety information. This follow-up 
could be a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study.
Patients who are permanently discontinued from further receipt of study treatment, regardless 
of the reason, will be identified as having permanently discontinued treatment. Patients who 
are permanently discontinued will enter follow-up (for details, see Section 1.3). Patients who 
have permanently discontinued from further receipt of study treatment will need to be 
recorded in the IRT.
Patients who permanently discontinue study treatment for reasons other than objective 
RECIST 1.1 disease progression, withdrawal of consent, closure of study or death (regardless 
of whether subsequent anticancer therapy was started) should continue to have RECIST 1.1 
scans performed q6w ±1week for the first 48 weeks from randomization, and then 
q9w ±1week (starting at Week 48) thereafter until RECIST 1.1 disease progression by 
investigator assessment. Following investigator-determined RECIST 1.1 progression, it 
ismandatory to perform an additional imaging assessment (preferably within 4 to 6 weeks 
after investigator PD) for central review to support the primary endpoint of PFS by BICR. In 
addition, every attempt should be made to continue to collect and submit subsequent scans 

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(completed per standard practice / as clinically indicated) for central review until the primary 
PFS analysis DCO, or until the Sponsor notifies the site to discontinue (whichever is earlier) 
regardless of whether the subject has started another anti-cancer therapy.  Scans following 
investigator determined RECIST 1.1 progression should include brain scans for patients who 
are enrolled with baseline stable brain metastases or if clinically indicated.
All patients will be followed for survival until the end of the study. Survival information may 
be obtained via telephone contact with the patient, patient’s family, or by contact with the 
patient’s current physician. Patients who decline to return to the site for evaluations should be 
contacted by telephone, following the timing and procedures indicated in the SoAs (see 
Section 1.3), as an alternative. 
7.2
Patient Withdrawal from the Study
!
A patient 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. 
!
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g., telephone contact, a contact with a relative or 
treating physician, or information from medical records).
!
At the time of withdrawal from the study, if possible, an EOT visit should be conducted, 
as shown in the SoA (Table 5) and for data to be collected at the time of study withdrawal 
and follow-up (Table 5) and for any further evaluations that need to be completed.
∀
The patient will discontinue the study treatment and be withdrawn from the study at 
that time.
!
If the patient withdraws consent for disclosure of future information, AstraZeneca may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a patient withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried in line with what was stated in the informed consent and local regulation. The 
Investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
7.3
Lost to Follow up
Patients will be considered lost to follow-up only if no contact has been established by the 
time the study is completed (see Section 4.4) and there is insufficient information to determine 
the patient’s vital status at that time. The following actions must be taken if a patient fails to 
return to the clinic for a required study visit:

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!
The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the patient wishes to and/or should continue in the 
study.
!
Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, if 
necessary, a certified letter to the patient’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the patient’s medical record.
!
Efforts to reach the patient should continue until the end of the study. Should the patient 
continue to be unreachable, he/she will be considered to have withdrawn from the study. 
Site personnel, or an independent third party, will attempt to collect the vital status of the 
patient within legal and ethical boundaries for all patients randomized, including those 
who did not get study treatment. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
patient will not be considered lost to follow-up. AstraZeneca 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.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the SoAs (see Section 1.3)
!
The Investigator will ensure that data are recorded on the eCRFs. The RAVE Web Based 
Data Capture system will be used for data collection and query handling.
!
The Investigator ensures the accuracy, completeness, and timeliness of the data recorded 
and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed 
eCRFs will be archived at the study site.
!
Immediate safety concerns should be discussed with AstraZeneca immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
!
Adherence to the study design requirements, including those specified in the SoAs (see 
Section 1.3), is essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential 
patients meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
!
Procedures conducted as part of the patient’s routine clinical management (e.g., blood 
count and imaging assessments) and obtained before signing of the ICF may be utilized 

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for screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
!
Data management will be performed by AstraZeneca or a delegate according to the Data 
Management Plan.
!
Aes and medical/surgical history will be classified according to the terminology of the 
latest version of MedDRA. Medications will be classified according to the World Health 
Organization (WHO) Drug. Classification coding will be performed by AstraZeneca or a 
delegate. The data collected through third party sources will be obtained and reconciled 
against study data.
!
Data queries will be raised for inconsistent, impossible, or missing data. All entries to the 
study database will be available in an audit trail. The data will be validated as defined in 
the Data Management Plan. Quality control procedures will be applied to each stage of 
data handling to ensure that all data are reliable and have been processed correctly. The 
Data Management Plan will also clarify the roles and responsibilities of the various 
functions and personnel involved in the data management process.
!
When all data have been coded, validated, signed, and locked, a clean file will be 
declared.
!
SAE reconciliation reports are produced and reconciled with the Patient Safety database 
and/or the investigational site.
8.1
Efficacy Assessments
8.1.1
RECIST 1.1 Assessments
RECIST 1.1 tumor assessments will be performed using CT or MRI scans of the chest, 
abdomen and pelvis at screening (as baseline) with follow-ups at q6w ± 1 week from the date 
of randomization for 48 weeks, and then q9w ± 1 week, starting at Week 48, until objective 
RECIST 1.1 disease progression by investigator assessment (see SoAs in Section 1.3). 
Patients who permanently discontinue study treatment for reasons other than objective 
RECIST 1.1 disease progression, withdrawal of consent, closure of study or death (regardless 
of whether subsequent anticancer therapy was started) should continue to have RECIST 1.1 
scans performed as per schedule until RECIST 1.1 disease progression. Following 
investigator-determined RECIST 1.1 progression, it is mandatory to perform an additional 
imaging assessment (preferably within 4 to 6 weeks after investigator PD) for central review 
to support the primary endpoint of PFS by BICR. In addition, every attempt should be made to 
continue to collect and submit subsequent scans (completed per standard practice / as 
clinically indicated) for central review until the primary PFS analysis DCO, or until the 
Sponsor notifies the site to discontinue (whichever is earlier) regardless of whether the subject 
has started another anti-cancer therapy.
For patients with bone-only disease that is non-measurable, RECIST 1.1 tumor assessments 

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may be performed using X-ray in addition to the required CT or MRI scans of the chest, 
abdomen and pelvis. 
In addition, an IV contrast-enhanced MRI (preferred) or IV contrast-enhanced CT of the brain 
is to be included for all patients at screening/baseline. Regularly scheduled follow-up brain 
scans (q6w ±1 week from the date of randomization for 48 weeks, and then q9w ±1 week, 
starting at Week 48 and continuing until RECIST 1.1 disease progression per investigator 
assessment) are mandatory for all patients who were enrolled with baseline stable brain 
metastases, while patients without brain metastases do not need additional brain scans for 
subsequent tumor assessments, unless clinically indicated. Following investigator determined 
RECIST 1.1 progression, subsequent imaging assessments as described above should include 
brain scans for patients who are enrolled with baseline stable brain metastases or if clinically 
indicated. 
The on-study imaging schedule MUST be followed regardless of any delays in dosing. 
Additional anatomy should be imaged based on signs and symptoms of individual patients at 
baseline and follow-up. If an unscheduled assessment was performed (e.g., to investigate 
clinical signs/symptoms of progression) and the patient has not progressed, every attempt 
should be made to perform the subsequent imaging at their next regularly scheduled visit. 
A bone scan (scintigraphy) will be performed for all patients at baseline and subsequent scans 
will be performed as clinically indicated. During study treatment, response assessment scans 
must be reviewed for evidence of disease progression and ILD/pneumonitis prior to 
administration of the next scheduled dose of study treatment.
Guidelines on valid imaging modalities, image acquisition, and tumor evaluation using 
RECIST 1.1 are provided in Appendix G.
8.1.1.1
Central Reading of Scans
All images, including unscheduled visit scans, will be collected on an ongoing basis and sent 
to an AstraZeneca-appointed iCRO for quality control (QC), storage, and for BICR. 
Guidelines for image acquisition, de-identification, storage of digital copies at the 
investigative site as source documents, and electronic transfer to the iCRO will be provided in 
a separate document. A BICR of images will be performed at the discretion of AstraZeneca. 
Results of these independent reviews will not be communicated to Investigators, and results of 
Investigator RECIST 1.1 assessments will not be shared with the central reviewers. The 
management of patients will be based upon the results of the RECIST 1.1 assessment 
conducted by the Investigator. Further details of the BICR will be documented in the 
Independent Review Charter (IRC).
8.1.2
Overall Survival (OS)
Assessments for survival must be made every 3 months (±14 days) from the date of 40-day 

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(+7 days) follow-up visit, until death, withdrawal of consent, or study closure, whichever 
occurs first. Survival information may be obtained via telephone contact with the patient or 
the patient’s family, or by contact with the patient’s current physician. The details of first and 
subsequent therapies for cancer, after discontinuation of treatment, will be collected. 
In addition, patients on treatment or in survival follow-up will be contacted following the 
DCO for the final PFS analysis and all subsequent survival analyses to provide complete 
survival data. These contacts should generally occur within 7 days of the DCO.
8.1.3
PFS2
PFS2 is defined as time from randomization 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 Investigator according to RECIST 1.1 
assessment, patients will continue to be followed at the 40-day (+7 days) follow-up visit, and 
every 3 months (± 14 days) thereafter for documentation of progression on subsequent 
anticancer therapy. 
8.1.4
Patient-Reported Outcome (PRO) Measures
PRO measures will be used to examine the impact of treatment on symptoms, functioning, 
HRQoL and overall health status, patient-perceived treatment tolerability, and benefit/risk 
from the patients’ perspective. PROs have become increasingly important in evaluating the 
efficacy and tolerability of study treatments in clinical studies as part of the overall 
benefit/risk evaluation (Kluetz et al 2018). The PROs included in this study are as follows and 
will be administered in this order:
!
EORTC QLQ-C30
!
EORTC QLQ-BR45
!
EQ-5D-5L
!
Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE)
!
Patient Global Impression–Severity (PGIS)
!
Patient Global Impression–Change (PGIC)
!
Patient Global Impression–Treatment Tolerability (PGI-TT)
!
Patient Global Impression – Benefit/Risk (PGI-BR)
The PROs will be assessed in accordance with the SoA (see Section 1.3). The individual 
questionnaires are provided in Appendix J.

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8.1.4.1
EORTC QLQ-C30
The EORTC QLQ-C30 was developed by the EORTC Quality of Life Group to assess 
HRQoL, functioning, and symptoms in cancer clinical trials (see Appendix J). It has 
undergone extensive testing and validation as well as detailed cross-cultural testing and 
validation (Aaronson et al 1993). It is a 30-item self-administered questionnaire for all cancer 
types. Questions are grouped into 5 multi-item functional scales (physical, role, emotional, 
cognitive, and social), 3 multi-item symptom scales (fatigue, pain, and nausea/vomiting), a 
2-item global QoL scale, 5 single items assessing additional symptoms commonly reported by 
cancer patients (dyspnea, loss of appetite, insomnia, constipation, and diarrhea), and 1 item on 
the financial impact of the disease. All but 2 questions have 4-point scales: “Not at All,” “A 
Little,” “Quite a Bit,” and “Very Much.” The 2 questions concerning global health status and 
QoL have 7-point scales with responses ranging from “Very poor” to “Excellent.” For each of 
the 15 domains, final scores are transformed such that they range from 0 to 100, where higher 
scores indicate better functioning, better HRQoL, or greater level of symptoms (Aaronson et 
al 1993).
8.1.4.2
EORTC QLQ-BR45
The EORTC QLQ-BR45 is an updated version of the BR23, a validated breast cancer-specific 
module used in conjunction with the core QLQ-C30 to assess breast cancer-specific HRQoL 
(Bjelic-Radisic et al 2020, Sprangers et al 1996) (see Appendix J). New breast cancer 
treatments and diagnostics prompted the update of the QLQ-BR23 to include an additional 22 
items. The self-administered instrument includes the original 23-items yielding 5 multi-item 
scores (body image, sexual functioning, arm symptoms, breast symptoms, and systemic 
therapy side effects). The additional 22 items yield four additional multi-item scales (breast 
satisfaction, endocrine therapy symptoms, skin mucosis symptoms, and endocrine sexual 
symptoms). In addition, single items assess sexual enjoyment, future perspective and being 
upset by hair loss. Items are scored on a 4-point verbal rating scale: “Not at All,” “A Little,” 
“Quite a Bit,” and “Very Much.” Scores are transformed to a 0 to 100 scale, where higher 
scores for functioning scales or items indicate better functioning, whereas higher scores for 
symptom scales or items represent a higher level of symptoms. The free text item in the 
EORTC QLQ-BR45 instrument is not included in the study, as the utility of this information 
and the analysis method have not been established.
8.1.4.3
EQ-5D-5L
The EQ-5D-5L will be used to explore the impact of treatment and disease state on health 
state utility. The EQ-5D-5L, developed by the EuroQol Group, is a generic questionnaire that 
provides a simple descriptive profile of health and a single index value for health status for 
economic appraisal (van Reenen et al 2014) (see Appendix J). The questionnaire comprises 
six questions that cover five dimensions of health (mobility, self-care, usual activities, 

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pain/discomfort and anxiety/depression). Respondents also assess their health today using the 
EQ-VAS (visual analogue scale), which ranges from 0 (worst imaginable health) to 100 (best 
imaginable health).
8.1.4.4
PGIS
The PGIS item is included to assess how a patient perceives the overall severity of cancer 
symptoms over the past week. This is a single-item questionnaire (Appendix J), and patients 
will choose the response that best describes the severity of their overall cancer symptoms with 
options ranging from “No Symptoms” to “Very Severe.”
8.1.4.5
PGIC
The PGIC item is included to assess how a patient perceives their overall change in health 
status since the start of study treatment. This is a single-item questionnaire (Appendix J), and 
patients will choose from response options ranging from “Much Better” to “Much Worse.”
8.1.4.6
PGI-TT
The PGI-TT item is included to assess how a patient perceives the overall tolerability of the 
study treatment. This is a single-item questionnaire (Appendix J), and patients will rate the 
bother associated with any treatment-related symptoms using response options ranging from 
“Not at all” to “Very much.”
8.1.4.7
PGI-BR
The PGI-BR is a 5-item questionnaire assessing the patient’s perception of the overall benefits 
and risks of treatment (Appendix J). The 5 items assess: overall trial experience, efficacy, side 
effects, convenience and overall assessment of the benefits and harms of treatment. Items are 
rated on 5- or 6-point verbal rating or Likert-type scales.
8.1.4.8
PRO-CTCAE
The PRO-CTCAE, developed by the NCI is included to address tolerability from the patients’ 
perspective (Appendix J). The PRO-CTCAE will only be administered in those countries 
where a linguistically validated version is available. All applicable translations available 
during the study will be used. PRO-CTCAE is an item library of symptoms experienced by 
patients while undergoing treatment of their cancer. The items pre-selected for this study are 
based on a review of the treatment-related symptoms of T-DXd, capecitabine, paclitaxel and 
nab-paclitaxel and in consideration of symptoms that are already captured in the other PRO 
instruments with a view to minimize burden. The free text item in the PRO-CTCAE 
instrument is not included in the study, as the utility of this information and the analysis 
method have not been established.

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8.1.4.9
Administration of Patient-Reported Outcome Measures
The PRO measures will be self-administered by patients using a handheld electronic device in 
accordance with the SoA (see Section 1.3). In case of handheld device failure, patients may 
complete the PRO measures using a web-based version or an appropriate back-up option may 
be considered with prior approval from AstraZeneca. PROs will be provided in the language 
of the country in which it will be administered. However, the PRO-CTCAE will only be 
administered in the languages where a linguistically validated version is already available. 
Patients will complete PRO assessments at home or at the study sites if the assessment 
timepoint coincides with a scheduled site visit. Similarly, during the follow-up period, patients 
will complete PROs at home or at the study site if a scheduled visit coincides with the 
timepoint. If patients have had scans or other tests at an outside facility or missed a scheduled 
data collection site visit, PRO questionnaires should still be completed by patients at home 
according to the PRO completion schedule. 
While PROs may be completed at home or site visits, patients should always bring the 
handheld electronic device to all site visits. It will take approximately 20 to 30 minutes for 
patients to complete the questionnaires. 
The following instructions should be followed when collecting PRO data via an electronic 
device:
!
The research nurse or appointed site staff must explain to patients the value and relevance 
of study participation and inform them that these questions are being asked to find out, 
directly from them, how they feel. The research nurse or appointed site staff should also 
stress that the information is not routinely shared with study staff. Therefore, if patients
have any medical problems, they should discuss them with the doctor or research nurse 
separately from the PRO assessment.
!
The research nurse or appointed site staff must train the patient on how to use the PRO 
device, using the materials and training provided by the PRO vendor, and provide 
guidance on whom to call if there are problems with the device if the patient is 
completing the PRO at home. 
!
It is vital that the PRO reporting is initiated at the baseline visit (Cycle 1, Day 1), as 
specified in the SoA (Section 1.3) to capture the effect of study treatment. The handheld 
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.
!
All questionnaires must be completed using an electronic device; paper questionnaires are 
not allowed in this study. It is therefore very important to set up the device in advance of 
the patient’s first treatment visit, ideally at least the day before, to ensure the device is 
functioning properly and to identify and address any technical issues prior to the visit.

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!
Study sites must ensure that patients complete baseline questionnaires before revealing 
the treatment arm allocated to the patient.
!
PRO questionnaires completed at site visits must be completed before treatment 
administration and ideally before any discussions of health status to avoid biasing the 
patient’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.
!
For PROs collected at site visits, PRO questionnaires must be completed by the patient in 
a quiet and private location and the patient given enough time to complete the PRO 
questionnaires at their own speed.
!
The research nurse or appointed site staff must remind patients that there are no right or 
wrong answers and avoid introducing bias by not interpreting or clarifying items.
!
The patient should not receive help from relatives, friends, or clinic staff to answer the 
PRO questionnaires. If a patient uses visual aids (e.g., glasses or contact lenses) for 
reading and does not have them when he or she visits the site, the patient will be 
exempted from completing the PROs at the visit.
!
Site staff must not read the PRO questionnaires on behalf of the patient. If the patient is 
unable to read the questionnaire (e.g., is blind, illiterate or not fluent in the available 
language), that patient should be 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 available language, the 
AstraZeneca study team must be contacted to determine if they can be exempted. Patients 
exempted in this regard should be flagged appropriately by the site staff in the source 
documents and the Review of PRO/Questionnaire/Diary eCRF.
!
Site staff must administer questionnaires available in the language that the patient speaks 
and understands. Questions should not be read in an available language and translated 
into another language for the patient.
!
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 patient could not 
complete assessments in the eCRF. The research nurse or appointed site staff must 
monitor compliance since minimizing missing data is a key aspect of study success. 
Compliance must be checked at each study visit and should be checked more frequently 
to identify problems early. If the site receives an email notification regarding the patient’s 
compliance, a check-in call from the study site to ask the patient if they have any 
difficulties is highly recommended. A solution to enhance/resolve compliance should be 
discussed with the patient. Discussions and compliance review should be reflected in 
source documents.

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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Informed Consent
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. All patients will be required to provide consent to supply a sample of their tumor 
for entry into this study. This consent is included in the main patient ICF. 
An optional pre-screen ICF may be signed for 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 a candidate for this study based on available information (e.g., medical 
history, availability of required number of slides for study). The collection of additional 
biopsies upon progression is strongly encouraged. 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 patient. However, all results from the screening assessments 
must have been obtained within 28 days of randomization 
Optional genetic sample will not be collected in China.
8.2.2
Physical Examinations
Physical examinations will be performed according to the assessment schedules (see 
Section 1.3). Full physical examinations will include assessments of the head, eyes, ears, nose, 
and throat and the respiratory, cardiovascular, gastrointestinal, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be 
measured at screening only. Situations in which physical examination results should be 
reported as AEs are described in Section 8.3.5.
8.2.3
Vital Signs
Vital signs (blood pressure [BP], pulse rate, temperature, and respiration rate) will be 
evaluated according to the SoAs (see Section 1.3). Body weight is recorded at Day 1 of each 
Cycle, at EOT and at the 40-day (+7 days) follow-up visit.
Vital signs will be evaluated and recorded in eCRF at baseline, before infusion, end of 
infusion on Day 1 and before infusion on Day 8 and Day 15 of the first cycle; they will be 
collected before infusion and end of infusion on Day 1 of Cycles 2 and 3; starting from 
Cycle 4, they will be evaluated only before infusion on Day 1 of each cycle until the end of 
treatment. Vital signs will be evaluated at the 40-day (+7 days) follow-up visit as well.

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Standard infusion time for T-DXd is over 90 minutes for first infusion and over 30 minutes 
thereafter if the first infusion was well tolerated; however, if there are interruptions during 
infusion, the total allowed infusion time should not exceed 3 hours at room temperature. 
Based on a 90-minute infusion period, BP and pulse rate will be collected before infusion and 
at the end of infusion: 
!
Prior to the beginning of the infusion (measured once from approximately 30 minutes 
before up to 0 minutes [i.e., the beginning of the infusion])
!
At the end of the infusion (after approximately 90 minutes ±5 minutes)
The time windows above (before infusion and at end of infusion) apply to both T-DXd and 
chemotherapy infusions.
If the infusion takes longer than 90 minutes, then BP and pulse measurements should follow 
the principles as described above or be taken more frequently if clinically indicated. An 1-hour 
observation period is recommended after the first infusion of T-DXd and the chemotherapy 
drugs that are administered intravenously. 
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.
8.2.4
Electrocardiograms
At screening, ECGs will be obtained in triplicate . Subsequent ECGs will be performed in 
triplicate only if an abnormality is noted. During the treatment period, ECGs are performed 
within 3 days prior to dosing (see Section 1.3). ECGs will be taken while the patient is in a 
supine/semi-recumbent position. Twelve-lead ECGs will be performed, and standard ECG 
parameters will be measured, including RR, PR, QTcF intervals, and QRS duration. All ECGs 
must be evaluated by Investigator or delegated physician for the presence of abnormalities. 
Whether or not measurement is performed, date performed, results, and findings for each 
parameter is to be recorded in the eCRF. 
At each time point at which a triplicate ECG is required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. The full set of triplicates should be 
completed within 5 minutes. ECGs will be obtained after the patient has been resting. All 
ECGs should be recorded with the patient in the same physical position. A standardized ECG 
machine should be used, and the patient should be examined using the same machine 
throughout the study, where feasible. After ECGs have been recorded, the Investigator or 
designated physician will review each of the ECGs and may refer to a local cardiologist if 
appropriate. A paper copy should be filed in the patient’s medical records. If an abnormal 
ECG finding at screening or pre-dose is considered to be clinically significant by the 

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Investigator, it should be reported as a concurrent condition. For all ECGs, details of rhythm, 
ECG intervals and an overall evaluation will be recorded. Any clinically significant 
abnormalities detected require a confirmatory ECG.
8.2.5
Clinical Safety Laboratory Assessments
Blood samples for determination of clinical chemistry, coagulation, hematology, and urine 
samples for urinalysis will be taken at the times indicated in the assessment schedules and as 
clinically indicated (see Section 1.3).
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a 
licensed clinical laboratory according to local standard procedures. Sample tubes and sample 
sizes may vary depending on the laboratory method used and routine practice at the site. For 
women of childbearing potential, a negative result for serum pregnancy test must be available 
at the screening visit (see inclusion criterion #13). A pregnancy test (urine or serum test per 
institutional guideline) 72 hours before randomization is required. Within 72 hours before 
randomization, if a positive urine pregnancy test result is confirmed using a serum test in a 
female patient of child bearing potential, then the patient should not be randomized into the 
study. Repeat pregnancy tests (urine or serum test per institutional guideline) are performed 
72 hours before treatment administration of each cycle and at EOT. 
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 laboratory variables to be measured are presented in Table 12 (clinical chemistry), 
Table 13 (hematology), and Table 14 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies (as per local regulations). Hepatitis C 
polymerase chain reaction (PCR) test may also be done if HCV antibody test is positive (see 
exclusion criterion #9).

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Table 12
Clinical Chemistry
Albumin
Magnesium
ALP a
Potassium
ALTa
Sodium
ASTa
Total bilirubin a
Bicarbonate (where available)
Total protein
Calcium
Blood urea nitrogen or Urea, depending on local practice.
Chloride 
Lactate dehydrogenase
Creatinine b
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase.
a
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. 
If total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into 
direct and indirect bilirubin.
b
Creatinine clearance will be calculated by the site using Cockcroft-Gault (using actual body weight).
Table 13
Hematology
Hemoglobin
Platelet count
White blood cell count
Differential white blood cell count a
Hematocrit
Red blood cell count
Coagulation b
a
Differential white blood cell count: neutrophils, lymphocytes, monocytes, eosinophils, basophils. These can 
be recorded as absolute counts or as percentages; absolute counts will be calculated by the site.
b
For coagulation parameters: prothrombin time (PT) or international normalized ratio (INR), and partial 
thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) are to be assessed at baseline 
and as clinically indicated.
Table 14
Urinalysis
Protein
Microscopy assessment (if indicated)
Blood
Specific gravity
Note: Urinalysis should be performed at baseline (screening) and as clinically indicated during the treatment 
period.
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high-power field for 
red and white blood cells. 
Cases where a patient shows elevation in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥ 2 × ULN will need 
to be reported as SAEs. Refer to Appendix E for further instruction on cases of increases in 
liver biochemistry and evaluation of Hy’s Law.
All patients should have hematology and clinical chemistry tests performed at screening, 
Cycle 1, Day 1 (before infusion), Day 8 and Day 15 of Cycle 1, and before infusion on Day 1 

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of all subsequent cycles until EOT. After permanent treatment discontinuation, follow-up 
hematology and clinical chemistry assessments are performed at 40 days (+7 days) after last 
dose of study treatment (see Section 1.3). Coagulation tests and urinalysis should be 
performed at screening and as clinically indicated during treatment period (see Section 1.3).
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 patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from study treatment must 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.
8.2.6
Pulmonary Assessments
Pulse oximetry (SpO2) should be obtained at the timepoints specified in the SoAs 
(Section 1.3). SpO2 should be evaluated by Investigator or the delegate physician prior to the 
administration of study treatment and at the end of infusion (as applicable per SoA) at each 
visit.
Pulmonary function tests should include basic spirometry at a minimum with optional 
additional components as mentioned in Table 15.
Table 15
Spirometry Components
Required spirometry components
Optional spirometry components
FVC (L)
PEF
FVC % predicted
DLCO – see exception in the below text where 
DLCO is mandatory
FEV1 (L)
FEV6
FEV1 % predicted
TLC
FEV1/FVC %
RV
DLCO = diffusion capacity of the lungs for carbon monoxide; FEV = forced expiratory volume; FVC = forced 
vital capacity; PEF = peak expiratory flow; FEV1 = FEV-1 second; FEV6 = FEV-6 seconds; L = liters; 
RV = residual volume; TLC = total lung capacity
Diffusion capacity of the lungs for carbon monoxide (DLCO) will be performed (if feasible), 
but for patients with prior severe and/or clinically significant pulmonary disorders, DLCO is a 
requirement. In event of suspected ILD/pneumonitis, refer to Section 8.2.10.1 for additional 
pulmonary assessments.
HRCT of the chest will be performed as per the SoA at screening, and if ILD/pneumonitis is 

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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, HRCT should be performed 
first.(Section 1.3).
8.2.7
Echocardiograms/Multiple Gated Acquisition Scans
LVEF will be measured by either echocardiogram (ECHO) or multiple gated acquisition 
(MUGA) scan. ECHO/MUGA scans will be performed at screening and before infusion on 
Day 1 of Cycle 5 and every 4 cycles (±7 days) thereafter until the EOT (see Table 5). All 
ECHOs/MUGAs will be evaluated by the Investigator or delegated physician for monitoring 
cardiac function. The modality of the cardiac function assessments must be consistent within a 
patient (i.e., if ECHO is used for the screening assessment, then ECHO should also be used 
for subsequent scans if required). The patients should also be examined using the same 
machine and operator whenever possible. Patients should have high-quality, standardized 
2-dimensional with Doppler echocardiographic examinations performed by an experienced 
sonographer. LVEF determinations will be made quantitatively based on bi-plane 
measurements of end-diastolic and end-systolic left ventricular volumes.
Collect blood samples for troponin (preferably high-sensitivity troponin-T) at screening and as 
needed based on patient reported cardiac signs or symptoms suggesting congestive heart 
failure, myocardial infarction, or other causes of cardiac myocyte necrosis. If at any time a 
patient reports signs or symptoms suggesting congestive heart failure, myocardial infarction, 
or other causes of myocyte necrosis, a sample should be collected for troponin testing and an 
ECG will be performed in triplicate. If ECG is abnormal, follow institutional guidelines. For 
more details on TMGs for varying troponin levels, refer to Appendix H.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.
8.2.8
ECOG Performance Status
ECOG will be assessed at the times specified in the assessment schedules (see 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 (e.g., 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

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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.
8.2.9
Ophthalmologic Assessments
Ophthalmologic assessments including visual acuity testing, slit lamp examination, and 
fundoscopy will be performed at screening and as clinically indicated.
8.2.10
Other Safety Assessments
8.2.10.1
Pneumonitis (ILD) Investigation
If new or worsening pulmonary symptoms (e.g., dyspnea, cough or fever) or radiological 
abnormality suggestive of ILD/pneumonitis is observed, treatment with study drug should be 
interrupted and a full investigation is required as described in detail in the TMGs for T-DXd
(Appendix H). Evaluations should include:
!
High resolution CT of the chest 
!
Pulmonologist consultation (infectious disease consultation if clinically indicated)
!
Pulmonary function tests (including FVC and CO diffusing capacity) and pulse oximetry 
(SpO2) 
!
Arterial blood gases if clinically indicated
!
Bronchoscopy and bronchoalveolar lavage as clinically indicated and feasible 
!
COVID-19 test
!
CBC, blood culture, differential WBC, CRP
!
One blood sample collection for PK as soon as ILD/pneumonitis is suspected, if feasible
!
Additional blood samples for plasma and serum exploratory biomarker analysis as soon 
as ILD/pneumonitis is suspected, if feasible
!
Other tests could be considered, as needed.
The results of the full diagnostic workup (including high-resolution computed tomography 
[HRCT], blood and sputum culture, SARS-CoV-2 [COVID-19] test, 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 

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confirmatory HRCT scans where other causes of respiratory symptoms have been excluded, a 
diagnosis of pneumonitis (ILD) 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 pneumonitis. The results of the assessment will be collected.
!
Physical examination
∀
Signs and symptoms (cough, shortness of breath, and pyrexia, etc.) including 
auscultation for lung field will be assessed.
!
Other items
∀
When pneumonitis (ILD) is suspected during study treatment, the following markers 
should be measured where possible:
(i)
ILD markers (KL-6, SP-D) and β-D-glucan
(ii) Tumor markers: particular tumor markers that are related to disease progression 
(iii) Additional clinical chemistry: C-reactive protein, lactate dehydrogenase
8.3
Adverse Events and Serious Adverse Events
The 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 patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE, see Section 8.3.2.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.1
Time Period and Frequency for Collecting AE and SAE 
Information
For patients who sign the pre-screening ICF, only SAEs directly related to tissue screening 
procedure (i.e., if a patient undergoes a tumor biopsy) will be reported during pre-screening 
period. All SAEs will be recorded from the time of signing of the main ICF.
AEs and SAEs will be collected from the time of the patient signing the ICF until the 

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follow-up period is completed (40 [+7] days after the last dose of study treatment). 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 treatment, then it should be reported as an AE or SAE as 
applicable.
All SAEs will be recorded and reported to AstraZeneca or its designee within 24 hours. The 
Investigator will submit any updated SAE data to AstraZeneca within 24 hours of it being 
available.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
treatment that occurs after the end of the clinical study in a patient treated by him or her, the 
Investigator shall, without undue delay, report the SAE to AstraZeneca.
The following types of events should be reported by the Investigator in eCRF electronic data 
capture (EDC) AE page(s) in the clinical study database within 24 hours of becoming aware 
for the purposes of reporting in the global safety database:
!
SAEs
!
All potential ILD/pneumonitis cases should be reported within 24 hours; including both 
serious and non-serious potential ILD/pneumonitis cases.
!
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law criteria 
defined as an elevated (ALT or AST) ≥ 3 × ULN and an elevated TBL ≥2 × ULN that 
may occur either at different timepoints or simultaneously during the study.
!
Overdose
!
Medication error
!
Pregnancy
8.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All SAEs, non-serious AEs, and AESIs (as defined in 
Appendix B) will be followed until resolution, stabilization, the event is otherwise explained, 
or the patient is lost to follow-up.
Any AE that is unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated 
(this may be beyond the 40 days after the last dose of study treatment), but without further 
recording in the eCRF. AstraZeneca retains the right to request additional information for any 

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patient 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
!
Maximum CTCAE Grade reported
!
Changes in CTCAE Grade (report only the maximum CTCAE grade for a calendar day)
!
Whether the AE is serious or not
!
Investigator causality rating against the Investigational Product(s) (yes or no)
!
Action taken with regard to study treatments
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date the AE met criteria for SAE
!
Date the Investigator became aware of SAE
!
Seriousness criteria
!
Date of hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment to other medication
!
Description of the SAE
The grading scales found in the revised NCI CTCAE v5.0 will be utilized for all events with 
an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE v5.0 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.3 Causality Collection
The Investigator should assess causal relationship between study treatment and each AE with 
respect to each study treatment (T-DXd, capecitabine, paclitaxel and nab-paclitaxel), and 
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 

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the event may have been caused by the study treatment?’
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 Clinical 
Study Protocol (CSP).
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the patient 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 and vital signs will be summarized in the 
Clinical Study Report (CSR). 
Deterioration as compared to baseline in protocol-mandated laboratory values, vital signs and 
ECGs should therefore only be reported as AEs if they fulfil any of the SAE criteria, or are the 
reason for discontinuation of treatment with the investigational product or are considered to be 
clinically relevant as judged by the Investigator (which may include but are not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study treatment, e.g., dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (e.g., anemia vs low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
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.

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8.3.6 Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3 × ULN together with total bilirubin ≥2 × ULN will need 
to be reported as SAEs. Refer to Appendix E for further instruction on cases of increases in
liver biochemistry and evaluation of Hy’s Law.
8.3.7 Disease Progression
Disease progression can be considered a worsening of a patient’s condition attributable to the 
disease for which the investigational product 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, which are 
unequivocally due to disease progression, should not be reported as an AE during the study.
8.3.8 Disease Under Study
Symptoms of disease under study (DUS) are those which might be expected to occur as a 
direct result of breast cancer. Events which are unequivocally due to disease under study 
should not be reported as an AE during the study unless they meet SAE criteria or lead to 
discontinuation of study treatment.
8.3.9
New Cancers
The development of a new cancer should be regarded as an SAE. New primary cancers are 
those that are not the primary reason for the administration of the study treatment and have 
been identified after the patient’s inclusion in this study.
8.3.10
Deaths
All deaths that occur during the study treatment period, or within the protocol-defined 
follow-up period after the administration of the last dose of study drug, must be reported as 
follows:
!
Death clearly resulting from disease progression should be reported to the Study 
Monitor/Physician at the next monitoring visit and 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 progression of the DUS, the AE causing the 
death must be reported to the Study Monitor/Physician 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 main and contributory causes of death.
!
Deaths with an unknown cause should always be reported as an SAE. It should also be 
documented in the Statement of Death page in the eCRF. A postmortem may be helpful in 

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the assessment of the cause of death, and if performed, a copy of the postmortem results 
should be forwarded to AstraZeneca Patient Safety or its representative within the usual 
timeframes.
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow-up period and the
event is considered to be due to a late-onset toxicity to study drug, then it should also be 
reported as an SAE.
8.3.11
Adverse Events of Special Interest
An AESI is an AE of scientific and medical interest specific to understanding of the study 
treatment and may require close monitoring. An AESI may be serious or non-serious. The 
rapid reporting of AESIs allows ongoing surveillance of these events in order to characterize 
and understand them in association with the use of a study treatment.
AESIs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the Investigator for severity, relationship 
to the study treatment, possible etiologies, and whether the event meets criteria for an SAE 
and therefore requires immediate notification to AstraZeneca. If an AESI evolves into a 
condition that meets the regulatory definition of “serious,” it will be reported on the SAE 
Report Form. 
Based on the available pre-clinical and clinical data, review of the cumulative literature, 
reported toxicities for the same class of agents and biological plausibility, ILD/pneumonitis 
and LVEF decrease are considered to be AESIs. 
Interstitial Lung Disease/Pneumonitis 
ILD/pneumonitis is considered an important identified risk based on a comprehensive 
cumulative review of potential ILD/pneumonitis cases reviewed by the independent ILD 
Adjudication 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 IB for a summary of preliminary 
clinical study data. 
!
High resolution CT of the chest and pulmonary function will be measured at baseline. If 
the AE is suspected to be ILD/pneumonitis during the study, treatment with study drug 
should be interrupted pending further evaluations. Evaluations for ILD/pneumonitis 
should include high resolution CT, SARS-CoV-2 (COVID-19) test, pulmonologist 
consultation, pulmonary function tests and pulse oximetry (SpO2), arterial blood gases if 
clinically indicated, bronchoscopy and bronchoalveolar lavage as clinically indicated and 

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feasible and one blood sample collection for PK as soon as ILD/pneumonitis is suspected, 
if feasible. 
Refer to Appendix H for guidelines on management of drug-induced ILD.
LVEF Decrease
LVEF decrease in association with T-DXd is considered to be an important potential risk 
based on the available pre-clinical data, literature and available safety information for drugs of 
similar class. Refer to the current IB for a summary of preliminary clinical trial data.
!
LVEF 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 will be measured at screening and as needed based on patient reported cardiac 
symptoms.
!
At screening, ECGs will be obtained in triplicate (3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. The full set of triplicates should be 
completed within 5 minutes). Subsequent ECGs will be performed in triplicate only if 
abnormalities are noted. 12 lead ECGs will be performed, and standard ECG parameters 
will be measured, including RR, PR, QTcF intervals, and QRS duration. All ECGs must 
be evaluated by Investigator or delegated physician for the presence of abnormalities. 
Whether or not measurement is performed, date performed, results, and findings for each 
parameter is to be recorded in the eCRF
8.3.12
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, 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 one day i.e., 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 one 
calendar day i.e., immediately but no later than 24 hours of when he or she becomes aware 

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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 followed by completion of a 
paper SAE form. 
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.
The reference documents for definition of expectedness/listedness are the current IB for 
T-DXd and the Summaries of Product Characteristics (SmPC) for the investigator’s choice of 
chemotherapy (Latest effective SmPC for Paclitaxel, Hospira UK Limited; Latest effective 
SmPC for Xeloda, Roche Products Limited; Latest effective SmPC for Abraxane, Celgene 
Limited).
8.3.13
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except:
!
If the pregnancy is discovered before the patient has received any study treatment
If a pregnancy is reported during the course of study, the Investigator should inform 
AstraZeneca within 24 hours of learning of the pregnancy and the study treatment should be 
discontinued immediately. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.
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 8.3.12) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.

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8.3.13.1
Paternal Exposure 
Male patients should refrain from fathering a child or donating sperm during the study 
treatment and during the washout period (4 months after the last dose of T-DXd, 6 months 
after the last dose of paclitaxel or nab-paclitaxel, and 3 months after the last dose of 
capecitabine) after the last dose of study treatment. Preservation of sperm should be 
considered prior to randomization in this study. 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 patient’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 until 4 months or as per 
local prescribing information (marketed products) after the last dose and as indicated by 
previous studies (pre-clinical and clinical) should be followed up and documented in the 
Pregnancy Report Form. Consent from the partner must be obtained before the Pregnancy 
Report Form is completed.
When a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the Investigator must obtain the consent of the patient’s partner. Therefore, the local study 
team should adopt the generic ICF template in line with local procedures and submit it to the 
relevant ECs/IRBs prior to use.
Patients who are permanently discontinued from further receipt of study treatment, regardless 
of the reason will enter follow-up (see the SoAs [Section 1.3]).
8.3.14
Management of Study Treatment-related Toxicities
The following general guidance should be followed for management of toxicities:
!
Treat each of the toxicities with maximum supportive care (including withholding the 
agent suspected of causing the toxicity if required).
!
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the randomized study treatment along with appropriate 
continuing supportive care. If medically appropriate, dose modifications are permitted 
(See Section 6.6).
!
All dose modifications should be documented with clear reasoning and documentation of 
the approach taken.
All toxicities will be graded according to NCI CTCAE v5.0.

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8.3.14.1
Specific Toxicity Management and Dose Modification Information for T-DXd
All dose modifications (interruption, reduction and/or discontinuation) should be based on the 
worst preceding toxicity (CTCAE v5.0). Specific criteria for interruption, re-initiation, dose 
reduction and/or discontinuation of T-DXd are listed in TMGs for T-DXd (see Appendix H), 
which is applicable only to TEAEs that are assessed as related to use of T-DXd by the 
Investigator(s). A TEAE is defined as an AE that occurs, having been absent before the first 
dose of study drug, or has worsened in severity or seriousness after initiating the study drug 
until the 40-day (+7 days) safety follow-up visit.
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 I for additional information on dose modification for suspected or 
confirmed COVID-19 infection for patients treated with T-DXd. 
ILD/Pneumonitis Management Guidance:
Refer to Appendix H for the management of DI-ILD.
ILD/pneumonitis should be ruled out if a patient 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, follow the management guidance outlined in 
the in the dose modification section of the study protocol (Section 6.6). 
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. Evaluations should include high resolution CT, pulmonologist 
consultation, pulmonary function tests, SARS-CoV-2 [COVID-19] test, and SpO2, arterial 
blood gases if clinically indicated, bronchoscopy and bronchoalveolar lavage as clinically 
indicated and feasible and one blood sample collection for PK as soon as ILD/pneumonitis is 
suspected, if feasible. Other tests could be considered, as needed. As soon as ILD/pneumonitis 
is suspected, corticosteroid treatment should be started promptly as per clinical treatment 
guidelines.
If the AE is confirmed to be ILD/pneumonitis, follow the TMGs for management of drug-
induced ILD (DI-ILD)/pneumonitis (Appendix H). All events of ILD/pneumonitis regardless 
of severity or seriousness will be followed until resolution including after study treatment 
discontinuation.
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 (e.g., smoking, radiation, COPD and other 

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chronic lung conditions), diagnostic evaluation, treatment and outcome of the event.
LVEF Decrease Management Guidance:
LVEF 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 will be measured at screening and as needed based on patient reported cardiac 
signs or symptoms suggesting congestive heart failure, myocardial infarction, or other 
causes of cardiac myocyte necrosis. If at any time a patient reports signs or symptoms 
suggesting congestive heart failure, myocardial infarction, or other causes of myocyte 
necrosis, a sample should be collected for troponin testing and an ECG will be performed 
in triplicate. If ECG is abnormal, follow institutional guidelines. 
!
ECGs will be performed, and standard ECG parameters will be measured, including RR, 
PR, QTcF 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 
treatment at Cycle 1 Day 1, Cycle 4 Day 1 and every 4th cycle thereafter. Whether or not 
measurement is performed, date performed, results, and findings for each parameter is to 
be recorded in the eCRF.
Dose Reduction Levels for T-DXd
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 16). 
More than 2 dose reductions are not allowed, and the patient will be discontinued from the 
study treatment if further toxicity meeting the requirement for dose reduction occurs.
Table 16
Dose Reduction Levels for T-DXd
Starting Dose
Dose Level -1
Dose Level -2
5.4 mg/kg
4.4 mg/kg 
3.2 mg/kg 
Dose Interruption and Modification/Toxicity Management Guidelines:
!
Every effort should be made to limit T-DXd delay, however in circumstances of AE 
management or medical intervention, T-DXd can be held up to 18 weeks (126 days) from 
the last T-DXd dose. During this time scheduled CT/MRI scans should continue as per 
protocol, and patients should fulfil all of the following criteria: 
∀
T-DXd 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 scan must be done within 6 weeks prior to restarting the 
study drug.

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∀
T-DXd is restarted within the guidance of the TMGs for T-DXd.
∀
No prohibited concomitant medications have been administered since the last dose of 
T-DXd.
Treatment cycles for a patient 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 discontinuation of T-DXd
according to the patient’s condition.
Refer to Appendix H for more detailed guidance on toxicity management. 
8.3.14.2
Toxicity Management and Dose Modification Information for Investigator’s 
Choice of Chemotherapy
Investigators should follow local standard clinical practice regarding toxicity management for 
the selected investigator’s choice chemotherapy. Refer to the local prescribing information for 
paclitaxel, nab-paclitaxel and capecitabine. If a patient is assessed as requiring a dose delay of 
longer than 28 days, resumption of treatment must be discussed with the AstraZeneca Study 
Physician.
8.4
Medication Error, Drug Abuse, and Drug Misuse
8.4.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, i.e., immediately but no later than 24 hours of when they become aware 
of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (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 event of medication error, drug abuse, or misuse (see Section 8.3.12) 
and within 30 days for all other events.
8.4.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
patient or has the potential to cause harm to the patient.
The full definition and examples of medication error can be found in Appendix B 4.

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8.4.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
8.4.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B 4.
8.5
Overdose
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 patient. 
!
Overdose is always serious. By definition, an overdose is medically important, which 
meets the seriousness criterion of important medical event. An overdose can occur 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. Use of T-DXd (20% more than the intended 
w/v dose), capecitabine, paclitaxel, and nab-paclitaxel (according to labels) in doses that 
are in excess of those specified in the protocol is considered to be an overdose. There is 
currently no specific treatment in the event of overdose of the study treatments used in the 
study, and possible symptoms of overdose are not established. Refer to the local 
prescribing information for treatment in cases of an overdose related to paclitaxel, 
capecitabine and nab-paclitaxel. The Investigator will use clinical judgement to treat any 
overdose. Investigators should be advised that any patient who receives a higher dose 
than that intended should be monitored closely, managed with appropriate supportive 
care, and followed up expectantly.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the overdose CRF module.
!
An overdose without associated symptoms is only reported on the overdose CRF module 
and not the AE module.

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If an overdose on an IMP or AstraZeneca NIMP occurs in the course of the study, the 
Investigator or other site personnel inform the 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 8.3.12) and within 30 days
for all other overdoses.
8.6
Human Biological Samples
Instructions for the collection and handling of biological samples are provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on handling of human biological 
samples see Appendix C. 
Outside of China, PK samples will be disposed of 6 months after issuance of the Bioanalytical 
Report, unless consented for future analyses. 
∀
Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
Remaining anti-drug antibody (ADA) sample aliquots will be retained at AstraZeneca or its 
designee for a maximum of 5 years following issuance of the CSR. Additional use includes 
but is not limited to further characterization of any ADAs, 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.
In China, PK samples will be disposed within 6 months after issuance of the Bioanalytical 
Report and ADA samples will be disposed of within 1 year after issuance of the CSR. 
PK/ADA samples collected in China will be stored and disposed of according to local laws 
and regulations. AstraZeneca, as a Foreign Entity, will not biobank in China, in line with HGR 
regulations.
8.6.1
Pharmacokinetics 
PK for T-DXd will be assessed as a secondary objective for this study.
Blood samples for determination of T-DXd, total anti-HER2 antibody and MAAA-1181a 
concentrations in serum will be obtained as according to the SoAs (see Section 1.3) and will 
be analyzed by a designated third party on behalf of AstraZeneca.  

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Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual. 
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.6.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be collected pre-infusion on Day 1 
Cycle 1, Day 1 Cycle 2, and Day 1 Cycle 4, then on D1 of every 4 cycles, as according to the 
SoAs (see Section 1.3). 
Samples will be measured for the presence of ADAs and also potentially for 
ADA-neutralizing antibodies for T-DXd using validated assays. Tiered analysis will be 
performed to include screening, confirmatory, and titer assay components, and positive 
negative cut points previously statistically determined from drug-naïve validation samples will 
be employed.
Full details of the methods used will be described in a separate report. ADA samples may also 
be further tested for characterization of the ADA response and/or other exploratory safety 
biomarkers. 
See Laboratory Manual for further details on requirements including sample collection, and 
shipping.
8.7
Human Biological Sample Biomarkers
Samples and generated data may be used to support diagnostic development.
8.7.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to participate in the study the patient consents to participate in the mandatory 
research components of the study. Samples for biomarker research are required and will be 
collected from all patients in this study as specified in the SoA (see Section 1.3). 
The following mandatory samples will be collected from all patients including screen failures 
wherever possible. 
!
MANDATORY: A mandatory FFPE tumor sample obtained at the time of metastatic 
disease or later (most recent pre-randomization tumor sample) must be provided. The 
tumor sample(s) submitted should be of sufficient quantity to allow for assessment of 
HER2 status (12 slides) and for other exploratory biomarker analyses (8 slides; see 
below): 

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∀
Tumor tissue block is preferred. If a tissue block is unavailable, 20 freshly-cut 
unstained serial tumor slides from the most recently collected pre-randomization 
tumor sample from the time of metastatic disease or later is required. Samples with 
limited tumor content, fine needle aspirate specimens and specimens from metastatic 
bone lesions that require decalcification are not acceptable (see Lab manual for 
further details). If enough tumor tissue is not available from a single lesion, then the 
following options may be acceptable: 
o
An aggregate of 20 slides from a newly acquired biopsy and a previously 
acquired sample from the time of metastatic disease or later can be provided (at 
least 12 slides must be available from one of the lesions). 
o
An aggregate of 20 slides from multiple previously acquired samples from 
metastatic disease or later can be provided (at least 12 slides must be available 
from a single lesion).
o
If only one of the samples contains more than 12 slides, that sample will be used 
for central HER2 testing. If both submitted samples contain more than 12 slides, 
then the most recently collected pre-randomization tumor sample will be used for 
central HER2 testing.
If fewer than 20 slides are available, patients may be eligible following discussion with the 
AstraZeneca Study Physician.
∀
HER2 IHC analysis will be performed at a central reference laboratory testing 
service using an IHC assay, investigational for the HER2 IHC 2+, IHC1+ and 
IHC >0 <1+ cut-offs. Testing will be carried out in a laboratory operating to GCP 
and with pathology staff fully trained by the diagnostic manufacturer to score 
reproducibly at the HER2 IHC cut-offs under development (IHC >0 <1+ and 
IHC1+). 
∀
Tumor lesions used for fresh biopsies should not be the same lesions used as 
RECIST 1.1 TLs, unless there are no other lesions suitable for biopsy. For patients 
with a single TL, if screening biopsy is collected prior to screening imaging for 
baseline tumor assessment, allow time for healing (e.g., 1-2 weeks) before imaging 
scans are acquired; and, if imaging occurs prior to biopsy, in order to ensure that 
lesion size is unaffected by biopsy, biopsy sampling should be no larger than core 
needle size.
See Laboratory Manual for further details on requirements including sample collection, and 
shipping. 
Baseline measures will be correlated with outcomes. Note that samples will be obtained from 
patients randomized to each treatment arm. Comparisons will be made between baseline 

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measures to determine if biomarkers (or combination of markers) are prognostic or predictive 
of outcomes associated with treatment. The following assessments will be performed with the 
samples collected, where applicable.
!
Tumor samples will be tested for HER2 expression by IHC at 2+, 1+ and >0 <1+ cut-offs 
to evaluate their association with the observed clinical responses PFS, OS, ORR to 
T-DXd and investigator’s choice of chemotherapy. 
!
Tumor samples centrally confirmed to be HER2 IHC 2+ will be confirmed to be 
HER2 ISH negative using an approved HER2 ISH assay per manufacturers requirements
!
Exploration of IHC and other assay technologies to determine tumoral HER2 expression, 
and IHC analysis, and expression of, but not limited to, associated family members.
!
Exploration of protein expression (IHC and proteomic analysis including, but not limited 
to erythroblastic oncogene B (ERBB2), related family members and topoisomerase I 
[TOPO-1] expression).
Note: According to Human Genetic Resources (HGR) policy, tumor samples collected in 
China will not be used for additional exploratory biomarker studies, beyond the check of 
HER2 status. Please refer to China laboratory manual for sample requirements specific to 
China. Tumor samples collected for central HER2 testing in China will be destroyed or 
repatriated within 1 year of issuance of the CSR.
!
MANDATORY: Blood sample for the isolation of plasma to enable the assessment, 
analysis and interpretation of circulating tumor DNA (ctDNA) will be collected from all 
patients at screening, on Day 1 of C1 to C7, then every 6 weeks (q6w ± 1 week until 
Week 48, and q9w ± 1 week post Week 48 until progression of disease in alignment with 
RECIST 1.1 assessments) and at disease progression (see Section 1.3). The buffy coat 
layer obtained during the plasma isolation process of the baseline sample may be retained 
and analyzed for germline mutations according to local regulations.
∀
ctDNA samples will be analyzed for predictive biomarkers of response to treatment 
and may be used to develop and validate future in vitro diagnostic (IVD) tests to 
identify patients most likely to respond to the treatment. The sample is requested 
prior to treatment in order to maximize the probability of detecting ctDNA where the 
tumor burden is relatively high.
∀
ctDNA samples taken during treatment and a final sample taken at disease 
progression will be used for additional exploratory research which may include but is 
not limited to interrogation of changes in genetic alterations as well as the dynamics 
of the biomarkers on treatment and potential mechanisms of resistance to treatment.
Note: These samples will not be collected in China.

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!
MANDATORY: Blood samples for gene expression analysis will be collected from all 
patients as described in SoAs (Section 1.3) to characterize molecular alterations 
pre-treatment and predict patients who may respond to treatment based on their molecular 
profiles. 
Note: These samples will not be collected in China.
!
MANDATORY: Blood samples for peripheral blood mononuclear cell (PBMC) analysis 
will be collected from the patients as described in SoAs (see Section 1.3) to assess a range 
of oncology and immunological biomarkers that may correlate with drug response. These 
biomarkers may include but are not limited to soluble biomarkers, T-cell receptor 
repertoire analysis and analysis of gene expression biomarkers associated with 
immunomodulatory effects.
Note: These samples will not be collected in China.
!
MANDATORY: Blood samples to perform exploratory safety or clinical benefit analyses 
to identify candidate markers which may correlate with likelihood of clinical 
benefit/tolerability will be collected from patients as described in the SoAs (see 
Section 1.3). These analyses may include but are not limited to the detection of the 
presence of viruses including but not limited to the SARS-CoV-2 virus and the 
characterization of the safety profile for patients with antibodies to the SARS-CoV-2 
virus treated with T-DXd or chemotherapy compared to the safety profile of patients 
without evidence of immune response (antibodies) treated with T-DXd or chemotherapy. 
∀
Blood samples for serum isolation will be collected from the patients assigned to the 
investigator’s choice chemotherapy arm, per the SoA; blood samples for serum 
isolation from patients assigned to the T-DXd arm will be taken from already 
collected samples (see Section 8.7.3).
8.7.2
Collection of Optional Biomarker Samples
Collection of optional samples for biomarker research is also part of this study as specified in 
the SoA (Section 1.3) and is subject to agreement to optional consent. These samples will not 
be collected in China. Collection of the following samples are optional:
!
Optional tumor biopsies will be collected at time of disease progression, if consented for, 
and should be obtained at any point post-progression. These samples will be used to 
explore mechanisms of resistance to T-DXd and standard of care therapies. Biopsies on 
progression may be particularly valuable when there is a marked phenotypic change in a 
particular lesion, and Investigators are encouraged to contact AstraZeneca in these cases. 
The provision of tumor tissue is encouraged only if clinically appropriate and not 
considered detrimental to participant care.
!
Paired biopsies should be collected (1) at screening or before infusion on Day 1 of Cycle 
1 and (2) during the treatment period on Day 1 of Cycle 2 ([any day between Cycle 2, 

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Week 1, Day 2 and Cycle 2, Week 3 is allowed] recommended >4 hours post-dose) as 
described in SoAs (Section 1.3).
∀
The samples will be used for exploration of protein and RNA expression pre- and 
on-treatment (Immunohistochemistry and proteomic analysis including, but not 
limited to ERBB2, related family members and TOPO-1 expression). 
See Laboratory Manual for further details on requirements including sample collection and 
shipping.
Procedures for withdrawal of consent for optional samples, labelling/shipping and chain of 
custody, refer to Appendix C.
8.7.3
Other Study Related Biomarker Research
Already collected samples may be analyzed on different biomarkers thought to play a role in 
efficacy outcomes including, but not limited to serum analytes, or tissue biomarkers and/or 
specific candidate genes/genome-wide analysis for RNA to evaluate their association with 
observed clinical responses to study treatments as well as analyzing whether the presence of 
antibodies to SARS-CoV-2 will provide any noted differences with the safety profile of 
patients treated with T-DXd or chemotherapy. The presence of viruses such as the 
SARS-CoV-2 virus may also be investigated.
A range of oncology and immunological biomarkers might also be assessed that may correlate 
with drug response. These biomarkers may include but are not limited to soluble biomarkers, 
T-cell receptor repertoire analysis and analysis of gene expression biomarkers associated with 
immunomodulatory effects.
Biomarker analyses will not be performed for Chinese patients, with the exception of the 
SARS-CoV-2-related safety profile analysis.
For storage, re-use and destruction of biomarker samples see Section 8.6. 
Management of Biomarker Data
The biomarker data will be exploratory in nature and will have unknown clinical significance. 
AstraZeneca will not provide biomarker research results to patients, their family members, 
any insurance company, an employer, Study Investigator, general physician, or any other third 
party, unless required to do so by law. The patient’s samples will not be used for any purpose 
other than those described in the CSP.
Individual patients will not be identified in any report or publication resulting from this work. 
The data and results of this research may be reviewed with collaborators and published, but 
neither the patient’s name nor any other personal identifiers will appear in any publication or 

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report.
8.8
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA (Section 1.3) and is subject to agreement in the ICF addendum. 
Participation is optional. Patients who do not wish to participate in the genetic research may 
still participate in the study. 
A blood sample will be obtained from the patients on Day 1 (first infusion day) prior to 
treatment administration (at or after randomization). If for any reason the sample is not drawn 
on Day 1, it may be taken at any visit until the last study visit. Only 1 sample should be 
collected per patient. 
Note: This sample will not be collected in China.
See Appendix D for information regarding genetic research. Details on processes for 
collection and shipment, storage and destruction of these samples can be found in the 
Laboratory Manual.
8.9
Medical Resource Utilization
The impact of treatment and disease on healthcare resource use will be captured in this study 
on an event-driven basis. The Hospital Admission (HOSPAD) module in eCRF will be used to 
collect information on key health care resource use that a patient receives that is not part of the 
study. The data may be used to support health technology assessments and payer related 
submissions.
At each scheduled visit, the site should review clinical notes for any non-study related hospital 
admissions and visits that have occurred. Where any visits have occurred, the site should 
complete the HOSPAD. This review should be done at every scheduled clinic visit up to and 
including the post-study treatment discontinuation follow-up visit. If a patient discontinues 
study treatment for reasons other than RECIST 1.1 progression, the HOSPAD form should 
continue to be administered until progression has been confirmed. Study mandated visits 
should not be included in the HOSPAD.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The null hypothesis for the primary and key secondary efficacy endpoints (PFS and OS) is 
that there is no difference in PFS/OS distribution between T-DXd and the investigator’s choice 
chemotherapy. The intention of the study is to demonstrate the superiority of T-DXd over the 
investigator’s choice chemotherapy, in the HER2-low population and the ITT population.

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9.1.1
Multiple Testing Procedure
PFS in the HER2-low population and ITT population will be tested once, when PFS reaches 
approximately 65% maturity (456 events) in the HER2-low population. This is estimated to 
occur 29 months after the first patient is randomized (4 months after randomization is 
completed) assuming a non-uniform accrual of patients with a duration of 25 months. At this 
time, it is expected that at least 553 events (65% maturity) will have been observed in the ITT 
population.
OS in the HER2-low population and ITT population will be tested at two interim and one final 
analysis as described below:
!
The first interim OS analysis will be performed at the time of the final PFS analysis. It is 
expected that 216 OS events (31% maturity or 41% information fraction) will have been 
observed in the HER2-low population and 263 OS events will have been observed in the 
ITT population.  
!
The second interim OS analysis will occur when approximately 392 OS events have been 
observed in the HER2-low population (56% maturity or 75% information fraction). This 
is anticipated to occur approximately 44 months after the first patient is randomized. It is 
expected that 477 OS events have been observed in the ITT population at this time. 
!
The final OS analysis will be performed when approximately 521 OS events have been 
observed in the HER2-low population (74% maturity), which is expected to occur 
approximately 63 months after the first patient is randomized. At this time, it is estimated 
that 632 OS events will have been observed in the ITT population.
To strongly control the family wise error rate at 5% in terms of the primary and key secondary 
endpoints, a multiple testing procedure (MTP) with the following gatekeeping strategy will be 
employed (Figure 1):
Step 1: Test PFS in the HER2-low population at a 5% alpha level. If significance is achieved, 
go to Step 2.
Step 2: Test PFS in the ITT population at a 1.5% alpha level and OS in the HER2-low 
population at the 3.5% alpha level. If PFS in the ITT population is significant, the 1.5% alpha 
will be recycled to OS in the HER2-low population. Similarly, if OS in the HER2-low 
population is significant at either the interim or final analysis, the 3.5% alpha will be recycled 
to PFS in the ITT population (i.e. PFS in the ITT population at the PFS analysis DCO will be 
tested at 5% alpha). If both PFS in the ITT population and OS in the HER2-low population are 
significant, go to Step 3.
Step 3: Test OS in the ITT population at a 5% alpha level.

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The 3.5% initial alpha allocated to OS in the HER2-low population will be distributed 
between the two interim and final analyses using the Lan DeMets spending function that 
approximates the O’Brien Fleming alpha-spending approach (Lan and DeMets 1983). Under 
this procedure, the adjusted significance levels at the interim and final analyses are determined 
by the information fraction available at the time of analysis (i.e., exact number events 
observed), giving greater weight to analyses performed at the end of the study than those 
performed earlier. 
If PFS in the ITT population is significant at 1.5% alpha (Step 2 above) such that this alpha is 
reallocated to OS in the HER2-low population, the adjusted significance levels at each of the 
analysis time points for OS in the HER2-low population will be updated per the Group 
sequential Holm variable procedure (Ye et al 2013). The Lan DeMets spending function that 
approximates the O'Brien-Fleming alpha-spending approach will be used to derive the 
updated significance levels. The same significance levels will be used for the interim OS 
analyses in the HER2-low population and ITT population. The significance level at the final 
OS analysis will be derived separately for each population and will be based on the actual 
number of events at the interim and final analysis, and the alpha already spent at the interim 
analyses for the HER2-low and ITT population, respectively.
An interim futility analysis will be performed after the first 70 patients in the 
HER2 IHC >0 <1+ population have been randomized and have had at least 24 weeks of 
follow-up from the point of randomization or withdrawn from the study. The IDMC will make 
a recommendation on whether or not to stop recruitment in the HER2 IHC >0 <1+ population 
based on the results of the interim futility analysis (Section 9.5.1). If it is decided to limit 
further recruitment only to the HER2-low population, tests on the ITT population will not be 
performed.
9.2
Sample Size Determination
The study will randomize approximately 850 patients (700 HER2 IHC 2+/ISH- and IHC 1+ 
[HER2-low] patients and 150 HER2 IHC >0 <1+ patients). The HER2-low (IHC 2+/ISH- and 
IHC 1+) strata will be closed once a total of 700 patients have been randomized in these strata. 
At this time, a decision will be made by AstraZeneca on whether recruitment into the 
HER2 IHC >0 <1+ population will be stopped if the 150-patient target has not been met.
Approximately 1417 patients will be screened with an approximate screen failure rate of 40% 
to achieve randomization of approximately 850 patients to the study treatment.
The study provides adequate power to show a statistically significant between-treatment 
difference in PFS in the HER2-low population. Based on a 2-sided significance level of 5%, 
a total of 456 PFS events (65% maturity) will provide at least 95% power to detect a hazard 
ratio of 0.55 (increase in median PFS from 5.5 to 10 months) in the HER2-low population, 

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assuming an exponential distribution for both treatment groups.
If PFS in the HER2-low population is significant, the study also provides sufficient power to 
demonstrate a statistically significant difference in OS in the HER2-low population. Based on 
a 2-sided alpha of 3.5% and taking into account 2 interim OS analyses, a total of 521 OS 
events will be required to achieve 80% power to detect a hazard ratio of 0.77 (increase in 
median OS from 20.5 to 26.6 months) in the HER2-low population, assuming an exponential 
distribution for both treatment groups. Assuming 74% maturity at the time of the final OS 
analysis, approximately 700 patients will need to be randomized in the HER2-low subgroup. 
In addition to the 700 patients in the HER2-low population, approximately 150 patients with 
HER2 IHC >0 <1+ expression will be randomized, which will total up to approximately 
850 patients randomized in the study.
9.3
Populations for Analyses
Table 17 defines the populations upon which the analyses are based.
Table 17
Populations for Analyses
Population/Analysis set
Description
Full analysis set (FAS) (ITT)
The ITT population, also termed as FAS, will include all randomized 
patients. Treatment arms will be compared on the basis of randomized study 
treatment, regardless of the study treatment actually received. Patients who 
were randomized but did not subsequently go on to receive study treatment 
are included in the analysis in the treatment arm to which they were 
randomized.
HER2-low
The HER2-low population comprises the subset of patients included in the 
ITT population with HER2 IHC 2+/ISH- and IHC 1+ as determined per the 
IRT data for HER2 IHC expression.  
HER2 IHC >0 <1+
The HER2 IHC >0 <1+ population comprises the subset of patients included 
in the ITT population with HER2 IHC >0 <1+ as determined by central 
laboratory testing and who have had at least 24 weeks of follow-up at the 
time of the interim futility DCO (i.e. randomized ≥ 24 weeks prior to 
interim futility DCO).
Safety (SAF)
All patients who received at least 1 dose of study treatment. Safety data will 
be summarized according to the treatment received. Erroneously treated 
patients (e.g., those randomized to treatment A but actually given treatment 
B) will be summarized according to the treatment they actually received. 
HER2-low SAF
The HER2-low SAF comprises the subset of patients included in the SAF 
with HER2 IHC 2+/ISH- and IHC 1+ as determined per the IRT data for the 
HER2 IHC expression.
PK
The PK analysis set will include all patients who receive at least 1 dose of 
T-DXd per the protocol for whom any postdose data are available.

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Table 17
Populations for Analyses
Population/Analysis set
Description
ADA
All patients who receive at least 1 dose of T-DXd per the protocol, have 
non-missing baseline ADA and at least 1 non-missing post-baseline ADA 
results. All major ADA analyses will be based on the ADA evaluable set.
ADA = anti-drug antibody; DCO = data cutoff; FAS = full analysis set; HER2 = human epidermal growth 
factor receptor 2; IHC = immunohistochemistry; ISH = in situ hybridization; ITT = intent-to-treat; 
PK = pharmacokinetic; SAF = safety analysis set; T-DXd trastuzumab deruxtecan.
9.4
Statistical Analyses
The statistical analysis plan (SAP) will be finalized before the first patient is randomized and 
it will include a more technical and detailed description of the statistical analyses described in 
this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints (Table 18).  Additional 
analyses to be performed at the time of the PFS and OS analyses for the HER2 IHC >0<1+ 
population will be specified in the SAP.
9.4.1
General Considerations
Table 18
Summary of Outcome Variables and Analysis Populations
Outcome variable
Populations
Efficacy data
PFS
HER2-low, HER2 IHC >0 <1+ a, and ITT
OS
HER2-low and ITT
ORR 
HER2-low, HER2 IHC >0 <1+ a and ITT
DoR 
HER2-low, HER2 IHC >0 <1+ a and ITT
DoR will be based on the subset of patients in the 
HER2-low/ITT who achieved objective tumor 
response
DCR at 24 weeks
HER2 IHC >0 <1+ a
PFS2, TFST, TSST
HER2-low and ITT
PROs
HER2-low and ITT
Study population/Demography data
Demography characteristics
HER2-low and ITT
Baseline and disease characteristics
HER2-low and ITT
Important deviations
HER2-low and ITT
Medical/surgical history
HER2-low and ITT
Previous anti-cancer therapy
HER2-low and ITT
Concomitant medications/procedures
HER2-low and ITT
Subsequent anti-cancer therapy
HER2-low and ITT

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Table 18
Summary of Outcome Variables and Analysis Populations
Outcome variable
Populations
PK data
PK data
PK analysis set
Immunogenicity data
Immunogenicity data
Listings will be based on SAF
Summaries will be based on ADA evaluable set
Safety data
Exposure
HER2-low SAF and SAF 
AEs
HER2-low SAF and SAF
Laboratory measurements
HER2-low SAF and SAF 
Vital signs
HER2-low SAF and SAF 
ECGs
HER2-low SAF and SAF 
ADA = anti-drug antibody; AEs = adverse events; DCR = disease control rate; DoR = duration of response; 
ECG = electrocardiogram; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; 
ITT = intent-to-treat population; KM = Kaplan Meier; ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival; PFS2 = time from randomization to second progression or death; 
PK = pharmacokinetic; PROs = patient reported outcomes; SAF = safety analysis set; TFST = time to first
subsequent treatment or death; TSST = time to second subsequent treatment or death
a
An interim futility analysis will be performed in the HER2 IHC >0 <1+ subgroup to compare ORR 
between T-DXd and the investigator’s choice of chemotherapy. As supportive summaries, DoR, PFS KM 
plot and DCR at 24 weeks by treatment arm will also be provided for the HER2 IHC >0 <1+ subgroup.
Depending on the extent of any impact, summaries of data relating to patients diagnosed with 
COVID-19, and impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued IP, and other protocol deviations) may be generated. More detail will be provided 
in the SAP.
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint (PFS by BICR in the HER2-low Population)
The primary endpoint of the study is PFS by BICR according to RECIST 1.1 in the HER2-low 
population.
PFS is defined as the time from the date of randomization until the date of disease 
progression, as defined by RECIST 1.1, or death (by any cause in the absence of progression) 
regardless of whether the patient withdraws from randomized therapy or receives another 
anticancer therapy prior to progression. Patients who have not had disease progression or 
death at the time of analysis will be censored at the time of the latest date of assessment from 
their last evaluable RECIST 1.1 assessment. However, if the patient has disease progression or 
dies immediately after two or more consecutive missed visits, the patient will be censored at 

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the time of the latest evaluable RECIST 1.1 assessment prior to the two missed visits. If the 
patients have no evaluable visits or do not have baseline data, they will be censored at Day 1 
unless they die within two visits of baseline (12 weeks plus 1 week allowing for a late 
assessment within the visit window).
PFS distribution will be compared between T-DXd and investigator’s choice chemotherapy 
using a stratified log-rank test adjusting for prior CDK4/6 inhibitor use (yes vs no), HER2 
IHC expression (IHC 1+ vs IHC 2+/ISH-), and prior taxane use in the non-metastatic setting 
(yes vs no). The stratification variables in the statistical modelling will be based on the values 
entered in IRT. If there are insufficient events per stratum, the strata will be pooled following a 
pooling strategy that will be prespecified in the SAP. The hazard ratio and its CI will be 
estimated from a stratified Cox Proportional Hazards model with strata being the same as the 
stratification variables from IRT.
Kaplan-Meier plots of PFS will be presented by treatment arm. 
Sensitivity analyses for PFS will be described in the SAP.
9.4.2.2
Secondary Endpoints
PFS by Investigator Assessment in the HER2-low Population
PFS by Investigator assessment according to RECIST 1.1 in the HER2-low population will be 
analyzed as described for the primary endpoint (Section 9.4.2.1).
PFS by BICR in the ITT Population
PFS by BICR according to RECIST 1.1 in the ITT Population will be analyzed as described 
for the primary endpoint (Section 9.4.2.1), except the stratification factors will include prior 
CDK4/6 inhibitor use (yes vs no), HER2 IHC expression (IHC >0 <1+, IHC 1+ or 
IHC 2+/ISH-), and prior taxane use in the non-metastatic setting (yes vs no).
As a sensitivity analysis, PFS by Investigator assessments according to RECIST 1.1 will be 
analyzed in the ITT population using the same methodology as described above.
Overall Survival
OS is defined as the time from the date of randomization until death due to any cause 
regardless of whether the patient withdraws from randomized therapy or receives another 
anticancer therapy. Any patient not known to have died at the time of analysis will be censored 
based on the last recorded date on which the patient was known to be alive.
Analysis of OS will be performed to compare T-DXd vs investigator’s choice chemotherapy in 

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HER2-low and ITT analysis sets using the same methodology as for PFS.
Objective Response Rate
ORR is defined as the percentage of patients with at least one visit response of complete or 
partial response (using RECIST 1.1) and will be based on all randomized patients. Data 
obtained up until progression, or last evaluable assessment in the absence of progression, will 
be included in the assessment of ORR. However, patients who receive subsequent anticancer 
therapy (note that for this analysis radiotherapy is not considered a subsequent anticancer 
therapy) after discontinuing study treatment without progression and then respond will not be 
included as responders in the ORR.
At the time of the formal PFS and OS analyses, the ORR (by BICR according to RECIST 1.1) 
will be compared between T-DXd and investigator’s choice chemotherapy using logistic 
regression model adjusting for the same stratification factors as the primary endpoint as 
covariates in the model. This analysis will be performed in the HER2-low and ITT analysis 
sets. The ORR using Investigator assessments according to RECIST 1.1 will be analyzed 
using the same methodology as supportive analyses.
As a sensitivity analysis, confirmed ORR, defined as the percentage of patients with a 
confirmed response of CR or PR (by BICR and by Investigator assessments according to 
RECIST 1.1) will be analyzed using the same methodology as described above. Furthermore, 
ORR and confirmed ORR will also be calculated and summarized based upon the subgroup of 
patients with measurable disease at baseline per BICR and Investigator assessment.
At the interim futility analysis, confirmed ORR (by Investigator assessments according to 
RECIST 1.1) will be summarized by treatment arm using the HER2 IHC >0 <1+ analysis set. 
Details are described in Section 9.5.
Summaries will be produced that present the number and percentage of patients with a tumor 
response (complete response [CR]/partial response [PR]) for HER2-low and ITT analysis sets. 
Overall visit response data will be listed for all patients (i.e., the ITT). Best overall response 
(BOR) will be summarized by n (%) for each category (CR, PR, stable disease [SD], 
progressive disease [PD], and not evaluable [NE]) for each treatment arm in HER2-low and 
ITT analysis sets. No formal statistical analyses are planned for BOR.
Duration of Response
For patients who achieve complete or partial response per RECIST 1.1, DoR is defined as the 
time from the date of first documented response until date of documented progression (using 
RECIST 1.1) or death in the absence of disease progression. The end of response should 
coincide with the date of progression or death from any cause used for the PFS endpoint. If a 

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patient does not progress following a response, then their DoR will use the PFS censoring 
time.
Descriptive data will be provided for the DoR by BICR and by Investigator assessment 
according to RECIST 1.1 in responding patients, including the associated Kaplan-Meier 
curves (without any formal comparison of treatment arms or p-value attached). These 
summaries will be presented in the HER2-low and ITT analysis set. 
Disease Control Rate (DCR) at 24 weeks 
DCR at 24 weeks is defined as the percentage of patients who have a BOR of CR or PR or 
who have SD (without subsequent cancer therapy) for at least 23 weeks after randomization 
(to allow for an early assessment within the assessment window). DCR at 24 weeks will only
be reported at the interim futility analysis using the HER2 IHC >0 <1+ analysis set. Similar to 
ORR, DCR at 24 weeks will be summarized by treatment arm.
PFS2
PFS2 is defined as time from randomization 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 and may involve any of the following: 
objective radiological imaging, symptomatic progression, or death. Patients alive and for 
whom a second disease progression has not been observed should be censored at the earliest 
of: date of study termination, date last known alive, DCO or, if a patient has not had a first 
subsequent therapy; the date last known not to have received a first subsequent therapy (TFST 
censoring date).
Analysis of PFS2 will be performed to compare T-DXd vs investigator’s choice chemotherapy
in HER2-low and ITT analysis sets using the same methodology as for PFS.
TFST
TFST is defined as time from randomization to the start date of the first subsequent 
anti-cancer therapy after discontinuation of randomized treatment or death due to any cause. 
Patients alive and not known to have had a first subsequent anti-cancer treatment will be 
censored at the earliest of: date of study termination, date last known alive, DCO or, the last 
date that the patient was known not to have received a first subsequent anti-cancer treatment.
Analysis of TFST will be performed to compare T-DXd vs investigator’s choice chemotherapy
in HER2-low and ITT analysis sets using the same methodology as for PFS.

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TSST
TSST is defined as time from randomization to the start date of the second subsequent 
anti-cancer therapy after discontinuation of randomized treatment or death due to any cause. 
Patients alive and not known to have had a second subsequent anti-cancer treatment will be 
censored at the earliest of: date of study termination, date last known alive, DCO or, the last 
date that the patient was known not to have received a second subsequent anti-cancer 
treatment.
Analysis of TSST will be performed to compare T-DXd vs investigator’s choice chemotherapy
in HER2-low and ITT analysis sets using the same methodology as for PFS.
9.4.3
Safety
Safety summaries will be provided using the safety analysis set (SAF) and the HER2-low 
SAF. Safety data will be presented using descriptive statistics unless otherwise specified.
Baseline
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of study treatment. Details are described in the SAP.
Adverse Events
Adverse events will be coded using the most recent version of MedDRA that will be released 
for execution at AstraZeneca. 
Any TEAE occurring until 47 days after the last dose of the study treatment and prior to the 
start of a new anticancer treatment will be included in the AE summaries. Any other AEs will 
be flagged in the data listings, but not included in the summaries.
An overview of TEAEs will be provided for each treatment group: the number and percentage 
of participants with any TEAE, TEAEs with outcome of death, serious TEAEs, and TEAEs 
leading to discontinuation of study treatment, as well as TEAEs leading to study treatment 
dose interruption, and TEAEs leading to study treatment dose reduction.
TEAEs will be presented for each treatment group by system organ class (SOC) and/or 
preferred term covering number and percentage of patients reporting at least one event and 
number of events where appropriate. 
Separate TEAE tables will be provided taking into consideration the relationship of TEAE to 
study treatment as assessed by the Investigator, the CTCAE Grade, seriousness, death and 
events leading to discontinuation of study treatment as well as other action taken related to 

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study treatment, AESIs and other significant TEAEs (if applicable).
An additional table will be presented for the number and percentage of patients with most 
common TEAEs. Most common TEAEs will be defined in the SAP.
Key patient information will be presented for patients with TEAEs with outcome of death, 
serious TEAEs, and TEAEs leading to discontinuation of study treatment.
An AE listing will cover details for each individual AE.
AEs occurring prior to start of study treatment, TEAEs and post-treatment AEs will be 
presented separately.
Full details of AE analyses will be provided in the SAP.
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover number of patients (n), mean, standard deviation, median, 
Minimum (Min.) and Maximum (Max).  
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. Summary statistics for 
continuous variables cover number of patients (n), mean, standard deviation, median, Min. 
and Max. Frequency tables and shift tables cover number and percentage of patients in the 
respective category. 
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
hematology parameters will be presented for observed values and change from baseline. 
Elevation in liver parameters for assessment of Hy’s Law will be done and reported 
appropriately if potential cases have been identified during the course of the study. 
A shift table for urinalysis will be presented with baseline assessment against the maximum on 
treatment category if a sufficient number of urinalysis assessments are recorded. 
Supportive laboratory listings will cover observed values and changes from baseline for each 
individual patient as well as abnormalities. 

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Details of laboratory analyses will be provided in the SAP.
9.4.4
Other Analyses 
9.4.4.1
Patient-reported Outcomes
The main PRO endpoints identified in the secondary objectives are symptoms, functioning 
and HRQoL of the EORTC QLQ-C30 and EORTC QLQ-BR45. PROs are not part of the main 
MTP and will be analyzed as supportive endpoints. Further details of the analyses will be 
described in the SAP.
9.4.4.2
Healthcare Resource Utilization
An exploratory health economic analysis of hospital episodes including inpatient admissions, 
intensive care unit admissions, and length of stay in hospital to examine the impact of disease 
and treatment on resource use to primarily support the economic evaluation of T-DXd vs 
investigator’s choice chemotherapy will be outlined in the payer analysis plan. This would 
include providing descriptive statistics as appropriate, including means, median, and ranges.
9.4.4.3
Pharmacokinetic Data
PK concentration data for T-DXd, total anti-HER2 antibody, and MAAA-1181a will be listed 
for each sampling time for each patient and each dosing day, and a summary will be provided 
for all evaluable patients. Descriptive statistics may be calculated.
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modeling approach.
9.4.4.4
Immunogenicity Data
Immunogenicity results will be listed by patient, and a summary will be provided by the 
number and percentage of patients who develop ADA for T-DXd. The immunogenicity titer 
and neutralizing ADA data will be listed for samples confirmed positive for the presence of 
T-DXd antibodies.
The effect of immunogenicity as well as the effect of its neutralizing properties on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow. A detailed plan 
will be written by the AstraZeneca Clinical Pharmacology group or designee.

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9.5
Interim Analyses 
9.5.1
Interim Futility Analysis
An interim futility analysis will be carried out after 70 patients have been randomized in the 
HER2 IHC >0 <1+ subgroup (approximately 35 per treatment group) and have had at least 24 
weeks of follow-up from the point of randomization or withdrawn from the study. This is 
expected to occur approximately 20 months after the first patient is randomized. A non-
binding stopping boundary will be applied to guide the decision of whether to limit 
recruitment to the HER2-low subgroup only. Confirmed ORR by Investigator assessments 
according to RECIST 1.1 in the HER2 IHC >0 <1+ analysis set will be used in the interim 
futility analysis. If the observed ORR difference (T-DXd vs investigator's choice 
chemotherapy) in the HER2 IHC >0 <1+ analysis set is ≤ -7%, the recommendation will be to 
stop enrollment in the HER2 IHC >0 <1+ subgroup. The stopping boundary was selected such 
that the probability of crossing the futility boundary is at most 10% if the true ORR difference 
(T-DXd vs investigator's choice chemotherapy) is at least 8%, assuming a 30% ORR in the 
chemotherapy arm. Furthermore, the probability of crossing the futility boundary is 7% if the 
true ORR difference is 10%, and 61%, if the true ORR difference is -10%, assuming a 30% 
ORR in the chemotherapy arm. 
As supportive summaries, ORR, DoR, DCR at 24 weeks and PFS KM plot per Investigator 
assessment will also be provided using the HER2 IHC >0 <1+ analysis set. Further details will 
be included in the SAP.
The IDMC will make a recommendation on whether or not to stop recruitment in the 
HER2 IHC >0 <1+ population based on the results of the futility analysis. If recruitment in 
this subgroup is permanently stopped, patients already dosed may be allowed to continue 
treatment based on a case-by-case assessment at the discretion of the Investigator, and if the 
Investigator deems that a patient continues to derive clinical benefit from treatment.
9.5.2
Interim Efficacy Analysis
OS in the HER2-low population and ITT population will be tested at two interim analyses as 
described in Section 9.1.
The SAP will describe the planned interim analyses in greater detail.
9.6
Data Monitoring Committees
9.6.1
IDMC Committee
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. An IDMC comprised of 
independent experts will be convened and will meet approximately 6 months after the study 

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has started or after the first 60 patients have been randomized, whichever occurs first. The 
IDMC will review unblinded 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 and at each meeting make recommendations to continue, amend, or stop 
the study based on safety findings. 
In addition, the IDMC will be asked to review efficacy data at pre-specified timepoints (e.g., 
interim futility analysis for HER2 IHC >0 <1+ subgroup). For further details on the futility 
analysis, see Section 9.5. Full details of the IDMC procedures, processes, and interim analyses 
can be found in the IDMC Charter.
9.6.2
ILD Adjudication Committee
An ILD Adjudication Committee will review all cases of potential ILD/pneumonitis. To 
ensure adequate evaluation, relevant additional data from within the clinical database and 
other sources, including imaging data, may be provided to the adjudication committee to fully 
characterize medical history (e.g., smoking, radiation and pulmonary history), diagnostic 
evaluation, treatment and outcome of the event. Further details can be found in the ILD 
Adjudication Charter.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the protocol and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines
∀
Applicable ICH GCP Guidelines
∀
Applicable laws and regulations
!
The protocol, protocol amendments, ICF, IB, and other relevant documents (e.g., 
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 patients.
!
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.

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!
The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the Investigator to AstraZeneca of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study treatment under clinical investigation are met.
!
AstraZeneca 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. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.
!
For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and AstraZeneca policy and forwarded to investigators as 
necessary.
∀
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
!
An investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the IB or other documents and will notify the IRB/IEC, 
if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
!
Prompt notification by the investigator to the Sponsor of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
∀
A “serious breach” means a breach likely to affect to a significant degree the safety 
and rights of a subject or the reliability and robustness of the data generated in the 
clinical study.
!
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.
!
In certain regions/countries, the Sponsor has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
∀
The Sponsor will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, the Sponsor is required to enter 

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details of serious breaches into the EMA CTIS. It is important to note that redacted 
versions of serious breach reports will be available to the public via CTIS.
!
The investigator should have a process in place to ensure that:
∀
The site staff or service providers delegated by the Investigator/institution are able to 
identify the occurrence of a (potential) serious breach
∀
A (potential) serious breach is promptly reported to the Sponsor or delegated party, 
through the contacts (e-mail address or telephone number) provided by the Sponsor.
A 2
Financial Disclosure
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course 
of the study and for 1 year after completion of the study.
A 3
Informed Consent Process
!
An optional pre-screen ICF may 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 
patient or his/her legally authorized representative and answer all questions regarding the 
study.
!
Patients 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. Patients 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 (CFR) 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) 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 patient 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.
!
Patients 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 patient or the patient’s legally authorized 
representative.
Patients who are rescreened are required to sign a new ICF.
If a patient declines to participate in any voluntary exploratory genetic research component of 

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the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
If a patient’s partner becomes pregnant during or within washout period (4 months after the 
last dose of T-DXd, 6 months after the last dose of paclitaxel or nab-paclitaxel, and 3 months 
after the last dose of capecitabine), the partner is asked to sign the "Adult Study Informed 
Consent Form for Pregnant Partners of Study Patients" and provide information about the 
pregnancy accordingly.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each patient the objectives of the exploratory research. Patients will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Patients who decline to participate 
in this optional research will indicate this in the ICF. If a patient withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented. If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
A 4
Data Protection
The ICF will incorporate wording that complies with relevant data protection and privacy 
legislation. In some cases, such wording will be in a separate accompanying document. 
AstraZeneca will not provide individual genotype results to patients (with the exception of 
results from the optional biopsy at disease progression; these results will be provided back to 
the patient), their family members, their general physician, any insurance company, any 
employer, or any other third party, unless required to do so by law; however, AstraZeneca may 
share data and biosamples with research partners.
Precautions are taken to preserve confidentiality and prevent genetic data from being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and might also have access to his or her genetic data. Also, regulatory authorities may 
require access to the relevant files. Even so, the patient’s medical information and the genetic 
files would remain physically separate.
!
Patients will be assigned an unique identifier by AstraZeneca. Any patient records or 
datasets that are transferred to AstraZeneca will contain the identifier only; patient names 
or any information which would make the patient identifiable will not be transferred.

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!
The patient must be informed that his/her personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the patient in the IC. 
!
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going 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://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted.
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant.
A 7
Data Quality Assurance
!
All patient data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (e.g., laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by electronically
signing the eCRF.
!
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These predefined parameters 
will be monitored during the study, and important deviations from the QTLs and remedial 
actions taken will be summarised in the CSR.
!
Monitoring details describing strategy, including definition of study-critical data items 
and processes (e.g., risk-based initiatives in operations and quality such as Risk 

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Management and Mitigation Strategies and Analytical Risk-based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are included in the internal 
sponsor documents like Integrated Quality Risk Management plan (IQRMP) and 
Monitoring Plan.
!
AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Medical Oversight Plan.
!
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.
!
AstraZeneca assumes accountability for actions delegated to other individuals (e.g., 
CROs).
!
Study monitors will perform ongoing source data verification as per the Monitoring 
Plan(s) 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 
patients are being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for a minimum of 25 years after study archiving or as 
required by local regulations, according to the AstraZeneca Global Retention and 
Disposal (GRAD) Schedule. No records may be destroyed during the retention period 
without the written approval of AstraZeneca. No records may be transferred to another 
location or party without written notification to AstraZeneca.
A 8
Source Documents
!
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
!
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
!
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies).
!
A digital copy of all imaging scans should be stored as source documents.

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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 
patients.
AstraZeneca designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of AstraZeneca. 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 AstraZeneca 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, AstraZeneca's procedures, or GCP guidelines
!
Inadequate recruitment of patients by the Investigator
!
Discontinuation of further study treatment development
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CRO used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the patient and should assure appropriate patient 
therapy and/or follow-up.
Patients 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 AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments.
!
AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of multicenter studies only in their entirety and not as individual site 
data. In this case, a coordinating Investigator will be designated by mutual agreement.

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!
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 in a patient or clinical study 
patient administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(e.g., an abnormal laboratory finding), symptom (e.g., nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
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 treatment has been administered.
B 2
Definitions of Serious Adverse Event
A SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-up), 
that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient 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 patient or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events (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 judgement on an individual 
event basis should be applied to clarify that the malignant tumor event should be assessed and 
reported as a Non-Serious AE. For example, if the tumor is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumor, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumors, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.

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The above instruction applies only when the malignant tumor event in question is a new 
malignant tumor (i.e., it is not the tumor for which entry into the study is a criterion and that is 
being treated by the investigational product 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 (e.g., 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 patient is 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 patient’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., 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 patient 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 judgement 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 patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement 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 (e.g., 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:
!
mild (awareness of sign or symptom, but easily tolerated)
!
moderate (discomfort sufficient to cause interference with normal activities)
!
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
The grading scales found in the revised NCI CTCAE v5.0 will be utilized for all events with 
an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate and severe events into 
CTCAE grades should be used. A copy of the CTCAE v5.0 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
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 patient actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?
!
Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?
!
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
!
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.

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In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, and Drug Misuse 
B 4.1
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 drug 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 patient.
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; e.g., medication prepared incorrectly, even if it was not actually given 
to the patient
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration

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!
Drug not taken as indicated; e.g., tablet dissolved in water when it should be taken as a 
solid tablet 
!
Drug not stored as instructed; e.g., kept in the fridge when it should be at room 
temperature 
!
Wrong patient received the medication (excluding IRT errors)
!
Wrong drug administered to participant (excluding IRT errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IRT - including those that lead to one of the above 
listed events that would otherwise have been a medication error 
!
Participant accidentally missed drug dose(s); e.g., forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
B 4.2
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a patient or if the drug abuse involves a person not enrolled in 
the study (such as a relative of the patient).
Examples of drug abuse include but are not limited to:
!
The drug is used with the intent of getting a perceived reward (by the patient or a person 
not enrolled in the study).
!
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high.
B 4.3
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 

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for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a patient or if the drug misuse regards a person not enrolled in the study 
(such as a relative of the patient).
Examples of drug misuse include but are not limited to:
!
The drug is used with the intention to cause an effect in another person
!
The drug is sold to other people for recreational purposes
!
The drug is used to facilitate assault in another person
!
The drug is deliberately administered by the wrong route
!
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole
!
Only half the dose is taken because the patient feels that he/she is feeling better when not 
taking the whole dose
!
Someone who is not enrolled in the study intentionally takes the drug.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each center keeps full traceability of collected biological samples from the 
patients while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca team 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 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent.If a patient withdraws consent to the 
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.
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 patients’ withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.
!
Ensures that relevant human biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of as appropriate, and the action documented.
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.

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AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented, and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (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 e.g., 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 e.g., 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 patient 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
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease. Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated. Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis 
from consenting patients.
!
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. 
!
This optional genetic research may consist of the analysis of the structure of the patient´s 
DNA, i.e., the entire genome. 
!
The results of genetic analyses may be reported in a separate study summary.
!
AstraZeneca will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
!
The samples will be retained while research on T-DXd continues but no longer than 
15 years or other period as per local requirements.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
All patients will be asked to participate in this genetic research. Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit. The patient will 
not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the CSP and provide informed consent for the Genomics Initiative 
sampling and analyses.

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Exclusion Criteria
!
Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:
∀
Previous allogeneic bone marrow transplant
∀
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of Consent for Genetic Research:
!
Patients may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
section 7.2 of the main CSP.
Collection of Samples for Genetic Research
!
An optional blood sample will be obtained from the patients on Day 1 (first infusion day) 
prior to study treatment administration (at or after randomization). If for any reason the 
sample is not drawn on Day 1, it may be taken at any visit until the last study visit. Only 
1 sample should be collected per patient. Although DNA is stable, early sample collection 
is preferred to avoid introducing bias through excluding patients who may withdraw due 
to an AE. 
Coding and Storage of DNA Samples
!
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 
15 years from the date of last patient last visit, after which they will be destroyed. DNA is 
a finite resource that is used up during analyses. Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
!
An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA).
!
The link between the patient enrollment/randomization code and the second number will 
be maintained and stored in a secure environment, with restricted access at AstraZeneca 
or designated organizations. The link will be used to identify the relevant DNA samples 

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for analysis, facilitate correlation of genotypic results with clinical data, allow regulatory 
audit, and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
!
The principles for ethical and regulatory requirements for the study, including its 
genetics research component, are outlined in Appendix A.
Informed Consent
!
The genetic component of this study is optional, and the patient may participate in other 
components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the patient must sign and date both the 
consent form for the main study and the addendum for the Genomics Initiative component 
of the study. Copies of both signed and dated consent forms must be given to the patient 
and the original filed at the study center. The Principal Investigator(s) is responsible for 
ensuring that consent is given freely, and that the patient understands that they may freely 
withdrawal from the genetic aspect of the study at any time.
Patient Data Protection
!
AstraZeneca will not provide individual genotype results to patients, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.
!
Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the patient. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a patient. For 
example, in the case of a medical emergency, an AstraZeneca Study Physician or an 
Investigator might know a patient’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the patient’s 
medical information and the genetic files would remain physically separate.
Data Management
!
Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
!
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organizations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 

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purposes. Researchers may see summary results, but they will not be able to see 
individual patient data or any personal identifiers. 
!
Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.

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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 Potential Hy’s Law (PHL) cases and Hy’s Law (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 patient 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 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 Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the study treatment. 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3×Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2×ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)
AST or ALT ≥ 3×ULN together with TBL ≥ 2×ULN, where no other reason, other than the 
study treatment, can be found to explain the combination of increases, e.g., elevated ALP 
indicating cholestasis, viral hepatitis, another drug. 

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For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., 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 patient 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 patient 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 patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient 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 patient does meet PHL criteria the Investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study 
treatment (see Section E 6)
!
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 

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Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.
!
For patients that met PHL criteria prior to starting study treatment, the Investigator is not 
required to submit a PHL SAE unless there is a significant change (see note below) in the 
patient’s condition
!
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up (including any further laboratory testing) and 
the continuous review of data
!
Subsequent to this contact the Investigator will:
∀
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Complete follow-up SAE Form as required.
∀
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. 
∀
Complete the relevant Liver eCRF Modules as information becomes available 
Note: ‘A significant change’ in the patient’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) 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 treatment, 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 patient 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 

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

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At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition# compared with the 
last visit where PHL criteria were met#
!
If there is no significant change no action is required
!
If there is a significant change, notify the AstraZeneca representative, who will inform the 
central study team, then follow the subsequent process described in Section E 4.2
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
!
Was the alternative cause for the previous occurrence of PHL criteria being met found to 
be the disease under study e.g., chronic or progressing malignant disease, severe infection 
or liver disease or did the patient meet PHL criteria prior to starting study treatment and at 
their first on-study treatment visit as described in Appendix E 6.
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE
If Yes: Determine if there has been a significant change in the patient’s condition# compared 
with when PHL criteria were previously met
!
If there is no significant change no action is required
!
If there is a significant change, follow the process described in Section E 4.2 for reporting 
PHL as an SAE
# A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any 
of the individual liver biochemistry parameters (ALT, AST or total bilirubin) 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.

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E 8
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory (Table 19). When local 
laboratories are used, this list may be modified according to clinical judgement. Any test result 
must be recorded.
Table 19
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
HBV DNA a
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
CD-transferrin b
Autoimmune hepatitis
ANA
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
ASMA
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
ANA = antinuclear antibody; ASMA = anti-smooth muscle antibody; CD = carbohydrate deficient; 
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = gamma glutamyl 
transferase; HAV = hepatitis A virus; HBc = hepatitis B core antibody; HBsAg = surface antigen of the hepatitis 
B virus; HBV = hepatitis B virus; HCV = hepatitis C virus; HEV = hepatitis E virus; HSV = herpes simplex 
virus; INR = international normalized ratio; IgG = immunoglobulin G; IgM = immunoglobulin M; LDH = lactate 
dehydrogenase; LKM = liver/kidney microsomal; RNA = ribonucleic acid; 
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly

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E 9
References
Aithal et al, 2011
Aithal et al, 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation

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Appendix F
ASCO/CAP Guidelines on HER2 Testing in Breast Cancer
This protocol will determine human epidermal growth factor receptor 2 (HER2) status using 
guidelines from the American Society of Clinical Oncology (per ASCO/CAP 2018 
guidelines). Per the guidelines, patients are HER2-negative if they have 
immunohistochemistry (IHC) 0/1+ or are fluorescent in situ hybridization (FISH) negative 
(Table 20).

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Table 20
Summary of ASCO/CAP Guideline Recommendations 2018
Procedure
Recommendations
Optimal algorithm for HER2 testing HER2 is positive if IHC 3+.
HER2 IHC 2+ is equivocal (the revised definition of IHC 2+ 
[equivocal] is invasive breast cancer with “weak to moderate
complete membrane staining observed in > 10% of tumor 
cells”) and triggers ISH testing.
Diagnostic criteria by ISH is defined by HER2 copy number 
(signals/cell) and, for dual probe assay, by HER2/CEP17 ratio: 
For dual probe assay, HER2-positive is defined as:
!
(Group 1) OR (Group 2 AND concurrent IHC 3+) OR (Group 3 
AND concurrent IHC 2+ or 3+) OR (Group 4 AND concurrent IHC
3+)
Where Groups 1-4 are defined:
!
Group 1: ratio ≥ 2.0 and ≥ 4.0 signals/cell
!
Group 2: ratio ≥ 2.0 and < 4.0 signals/cell
!
Group 3: ratio < 2.0 and ≥ 6.0 signals/cell
!
Group 4: ratio < 2.0 and ≥ 4.0 to < 6.0 signals/cell
!
Group 5: ratio < 2.0 and < 4.0 signals/cell
For tumors in groups 2-4 by dual probe assay, definitive diagnosis will 
be made based on additional work-up as detailed in ASCO/CAP 
guidelines 2018.
For single probe assay, HER2-positive is defined as:
!
(HER2 copy number ≥ 6.0 signals/cell) OR (HER2 copy number ≥
4.0 and < 6.0 signals/cell AND concurrent IHC 3+) OR (HER2 
copy number ≥ 4.0 and < 6.0 signals/cell AND concurrent dual 
probe Group 1).
!
All other tumors will be defined as HER2- as defined by 
ASCO/CAP 2018.
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

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Procedure
Recommendations
ISH rejection criteria
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 two 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
IHC rejection criteria
Fixation for fewer than 6 hours or longer than 48 hours is not 
recommended
Test is rejected and repeated or tested by FISH if:
!
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

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Procedure
Recommendations
Optimal tissue
handling requirements
!
Time from tissue acquisition to fixation should be as short as 
possible; samples for HER2 testing are fixed in 10% neutral 
buffered formalin for 6-72 hours. Samples should be sliced at 5-
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
!
Any exception to this process must be included in report
Optimal internal
validation procedure
!
Validation of test must be done before test is offered
!
Initial test validation requires 25-100 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 
two 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
Optimal laboratory accreditation
!
Onsite 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
ASCO/CAP American Society of Clinical Oncology/College of American Pathologists; CEP17, chromosome
17 centromere; FISH, fluorescent in situ hybridization; HER2, human epidermal growth factor receptor 2; IHC,
immunohistochemistry; ISH in situ hybridization; QA, quality assurance.
Excerpt from: (Wolff et al 2018)

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The following tables provide additional information from the ASCO/CAP Guidelines for what 
needs to be reported for IHC and FISH (Table 21 and Table 22). 
Table 21
Reporting Elements for IHC 
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.
Table 22
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)

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Table 22
Reporting Elements for FISH (Local HER2 Test)
Patient identification information
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 (Response Evaluation Criteria in 
Solid Tumors)
Introduction
This appendix details the implementation of RECIST 1.1 guidelines. 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, 
Non-Target Lesions (NTLs), and New Lesions (NLs) is provided in Table 23.
Table 23
Summary of Imaging Modalities for Tumor Assessment
Target Lesions 
Non-Target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
FDG-PET/CT
CT = computed tomography; FDG-PET/CT = 18F-Fluoro-deoxyglucose positron emission tomography/CT; 
MRI = magnetic resonance imaging.
CT and MRI 
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 (i.e., for measurement of TLs, assessment of NTLs, and identification of NLs). 
It is essential that the same correct imaging modality, image acquisition parameters 
(e.g., anatomic coverage, imaging sequences, etc.), imaging facility, tumor assessor 
(e.g., radiologist), and method of tumor assessment (e.g., RECIST 1.1) are used consistently 
for each patient 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; Section 1.3), 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 (e.g., to investigate clinical signs/symptoms of 
progression) and the patient 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 (e.g., heart, major 

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blood vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and 
temporal resolutions; however, there are many image acquisition variables involved in MRI, 
which greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumor evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic Coverage: Optimal anatomic coverage for most solid tumors is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual patients. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a new lesion 
representing disease progression, 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 timepoints are specified 
in the SoA (Section 1.3). 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 patients 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 patient 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 patient. 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
All patients 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 (q6w ±1 week from the date of randomization for 48 weeks, and then q9w ±1 week, 
starting at Week 48 thereafter until RECIST 1.1 disease progression per investigator 
assessment) are mandatory for all patients who were enrolled with baseline stable brain 
metastases, while patients without brain metastases do not need additional brain scans for 
subsequent tumor assessments, unless clinically indicated. Scans following investigator 
determined RECIST 1.1 progression should include brain scans for patients who are enrolled 
with baseline stable brain metastases or if 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, such as CT, be used to confirm the presence of NLs.

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Plain X-ray1
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
Isotopic Bone Scan 
All patients in this study will receive bone (scintigraphy) scans at screening/baseline. Bone 
lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or X-ray at 
baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray). 
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 
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.  
FDG-PET/CT
18F-Fluoro-deoxyglucose positron emission tomography/computed tomography/CT 
(FDG-PET/CT) scans may be used as a method for identifying new lesions for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive 18F-Fluoro-deoxyglucose uptake 2 not present on baseline or prior FDG-PET scan or 
in a location corresponding to a NL on a companion CT/MRI collected close in time to the 
FDG-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 FDG-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 FDG-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 
                                               
1 In this study, a patient with non-measurable, bone-only disease assessed by X-ray at screening must have lytic 
or mixed lytic bone lesions; i.e., bone-only patients with exclusively sclerotic (blastic) bone lesions in the 
absence of measurable disease are not eligible.
2 A positive FDG-PET scan lesion should be reported only when an uptake (e.g., SUV) greater than twice that of 
the surrounding tissue or liver is observed.

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contrast) to a dedicated diagnostic CT scan, then the CT portion of the PET/CT can be used 
for RECIST 1.1 tumor assessments. Caution that this is not recommended because the PET 
portion of the CT introduces additional (PET) data that may bias an Investigator if it is not 
routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumors as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumor size. Tumors identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
Other Tumor Assessments
Clinical Examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
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 (e.g., 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 complete response (all other disease disappears/reverts 
to normal) would be changed to PR if an effusion remains present radiologically.
Measurability of Tumor Lesions at Baseline
RECIST 1.1 Measurable Lesions at Baseline:
A tumor lesion that can be accurately measured at baseline as ≥10 mm in the longest diameter 
for non-nodal lesions or ≥15 mm in short axis3 diameter for lymph node lesions with IV 
contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. 
                                               
3
The short axis is defined as the longest in-plane axis perpendicular to the long axis.

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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 baseline4)
!
Previously irradiated lesions5
!
Brain metastasis [All patients in this study will receive an intravenous (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 patients who were
enrolled with baseline stable brain metastases, while patients without brain metastases do 
not need additional brain scans for subsequent tumor assessments, unless clinically 
indicated.]
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 6.
                                               
4
Lymph nodes with <10-mm short axis diameter are considered non-pathological and should not be 
recorded or followed as NTLs.
5
Localized post-radiation changes that affect lesion size may occur. Therefore, lesions that have been 
previously irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of 
the NTL assessment.
6 In this study, a patient with non-measurable, bone-only disease assessed by X-ray at screening must have lytic 
or mixed lytic bone lesions; i.e., bone-only patients with exclusively sclerotic (blastic) bone lesions in the 
absence of measurable disease are not eligible.

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!
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 patient, these should be selected over cystic 
lesions as TLs.
RECIST 1.1 TL Selection at Baseline:
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (e.g., adrenal 
glands), a segmented organ (e.g., liver), or a multilobed organ (e.g., 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 whole (integer) millimeters and calculated values should be rounded to whole 
numbers. 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 
maximal short axis diameter of the coalesced mass should be recorded. Non-nodal lesions 
that coalesce should similarly be assessed by the longest axis diameter.
!
Tumor lesions selected for fresh screening biopsy should not be selected as TLs, unless 
imaging occurred at least approximately 2 weeks after biopsy, allowing time for healing.
!
If the CT/MRI slice thickness used is >5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

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!
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 New 
Lesion.
RECIST 1.1 NTL Selection at Baseline:
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of Tumor Response and Progression
RECIST 1.1 TL Assessment at Follow-up
This section defines the criteria used to determine objective tumor visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be rounded to and recorded in whole millimeters. The sum of the diameters for all TLs at each 
follow-up visit will be compared to the baseline sum of diameters (for response or stable 
disease) 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 maximal short axis diameter is recorded.
!
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 an unscheduled, non-protocol intervention, the following apply:
∀
Target Lesion Intervention may include radiotherapy, embolization, excisional 
biopsy, surgery, etc. that is not a part of study treatment and might adversely affect 
the size of that Target lesion

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∀
If an Intervention on a Target Lesion is ticked in the case report form, the diameter of 
the lesion is still recorded (0 mm if no longer present) and is included in the sum of 
diameters. 
∀
If a Target Lesion Intervention is ticked, the Intervention must be reported for all 
subsequent assessments of that Target lesion. 
∀
If a Target Lesion has an Intervention, the only Overall Visit Responses allowed to 
be recorded by the Investigator are NE or PD, with PD if the sum of diameters 
exceeds a 20% increase and at least a 5 mm absolute increase in the visit sum of 
diameters compared to the previous minimum (nadir) sum of diameters.
∀
No visit with a recorded Target Lesion Intervention can be used as the minimum 
(nadir) sum of diameters. 
Table 24
RECIST 1.1 Evaluation of Target Lesions
Complete response (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.
Partial response (PR)
At least a 30% decrease in the sum of the diameters of TL, taking as 
reference the baseline sum of diameters.
Stable disease (SD)
Neither sufficient decrease in the sum of diameters to qualify for PR nor 
sufficient increase to qualify for PD.
Progression of disease (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.
Not evaluable (NE)
Only relevant if any of the TLs at follow-up were not assessed or not 
evaluable (e.g., missing anatomy) or had a lesion intervention at this 
visit. Note: If the sum of diameters meets the progressive disease 
criteria, progressive disease overrides not evaluable as a TL response.
Not applicable (NA)
Only relevant if no TLs present at baseline.
CR = complete response; NE = not evaluable; PD = progression of disease; PR = partial response; RECIST 
1.1 = Response Evaluation Criteria In Solid Tumors, version 1.1; 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 

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change in non-target disease in the face of SD or PR of target disease will therefore be 
extremely rare (Table 25).
Table 25
RECIST 1.1 Evaluation of Non-target Lesions
Complete response (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.
Progression (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.
Not evaluable (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 patients 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 (NA)
Only relevant if no NTLs present at baseline
CR = complete response; NA = not applicable; NE = not evaluable; NTL = non-target lesion; 
PD = progression of disease; RECIST 1.1 = Response Evaluation Criteria In Solid Tumors, version 1.1; 
TL = target lesion
RECIST 1.1 New Lesion (NL) Identification at Follow-up
Details, including the imaging modality, the date of scan, and the location of any new lesion 
(NL) will also be recorded in the case report form. The presence of 1 or more NLs is assessed 
as progression. The finding of a NL should be unequivocal, i.e., 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 disease progression.
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 26.

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Table 26
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) a
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
CR = complete response; NA = not applicable (only relevant if there were no target lesions at baseline or 
non-target lesions at baseline), NE = not evaluable; PD = progressive disease; PR = partial response; RECIST 
1.1 = Response Evaluation Criteria In Solid Tumors, version 1.1; SD = stable disease; TL = target lesion.
a
Non-CR/Non-PD for Overall Response if only NTLs (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.
The following overall visit responses are possible depending on the extent of tumor disease at 
baseline:
!
For patients with TLs (at baseline): CR, PR, SD, PD, or NE
!
For patients 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 QC, storage, and for BICR. Guidelines for image 
acquisition, de-identification, storage of digital copies at the investigative site (as source 
documents), and transfer to the imaging CRO will be provided in a separate document. 
Electronic image transfer from the sites to the iCRO is strongly encouraged. A BICR of 
images will be performed at the discretion of AstraZeneca. Results of these independent 
reviews will not be communicated to Investigators, and results of Investigator RECIST 1.1 
assessments will not be shared with the central reviewers. The management of patients will be 
based in part upon the results of the RECIST 1.1 assessment conducted by the Investigator. 
Further details of the BICR will be documented in the independent review charter (IRC).

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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
Toxicity Management Guidelines for T-DXd
Each of the toxicities should be treated with maximum supportive care (including withholding 
the agent suspected of causing the toxicity if required).
If the symptoms promptly resolve with supportive care, consideration should be given to 
continuing the same dose of the assigned study drug along with appropriate continuing 
supportive care. If medically appropriate, dose modifications are permitted for T-DXd. In 
addition, guidelines for T-DXd dose modifications are provided in Section 6.6. In the event of 
toxicity that cannot be managed by following the toxicity management guidelines for T-DXd, 
consider stopping treatment with T-DXd.
All dose modifications should be documented with clear reasoning and documentation of the 
approach taken. 
All dose modifications (interruption, reduction, and/or discontinuation) should be based on the 
worst preceding toxicity. Specific criteria for interruption, re-initiation, dose reduction, and/or 
discontinuation of T-DXd are listed in Table 27, which is applicable only to TEAEs that are 
assessed as related to use of T-DXd by the Investigator. For non-drug related TEAEs, follow 
standard clinical practice. Appropriate clinical experts should be consulted as deemed 
necessary.
If AE causality is possibly, probably, or definitely related to T-DXd, the most conservative 
toxicity guidance should be adopted. Discussion with AstraZeneca’s Study Physician is 
recommended in such cases.
Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
No toxicity
Maintain dose and schedule
Infusion-related reaction
Grade 1 (Mild transient reaction; 
infusion interruption not indicated; 
intervention not indicated)
If infusion related reaction (such as fever and chills, with and without 
nausea/vomiting, pain, headache, dizziness, dyspnea, and/or 
hypotension) is observed during administration, the infusion rate should 
be reduced by 50%, and patients should be closely monitored. 
If no other reactions appear, the subsequent infusion rate could be 
resumed at the initial planned rate. 

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Grade 2 (Therapy or infusion 
interruption indicated but responds 
promptly to symptomatic treatment 
(e.g., antihistamines, nonsteroidal 
anti-inflammatory drugs (NSAIDs), 
narcotics, and/or IV fluids); 
prophylactic medications indicated 
for ≤24 hrs)
Administration of T-DXd should be interrupted a and symptomatic 
treatment started (e.g., antihistamines, NSAIDs, narcotics, and/or IV 
fluids).
If the event resolves or improves to Grade 1, infusion can be restarted 
at a 50% reduced infusion rate.
Subsequent administrations should be conducted at the reduced rate.
Grade 3 or 4 (Prolonged or 
life-threatening consequences; 
urgent intervention indicated)
Administration of T-DXd should be discontinued immediately and 
permanently.
Urgent intervention indicated. Antihistamines, steroids, epinephrine,
bronchodilators, vasopressors, intravenous fluid therapy, oxygen 
inhalation, etc., should be administered.
Hematologic toxicity (if supportive therapy fails [as clinically indicated and according to local practice], 
consider additional TMG as below). For any Grade 4 hematological toxicity with significant clinical 
symptoms that does not resolve with treatment within 4 weeks, resuming the investigational medicinal product 
may be possible if the toxicity resolved, in consultation with the study physician.
Neutrophil count decreased and/or white blood cell count decreased
Grade 3 
Delay dose a until resolved to ≤ Grade 2, then maintain dose
Grade 4
Delay dose a until resolved to ≤ Grade 2, then reduce dose 1 level
Febrile neutropenia (absolute 
neutrophil count < 1 × 109/L, fever 
> 38.3°C, or a sustained 
temperature of ≥ 38 °C for more 
than 1 hour)
Delay dose a until resolved, then reduce dose 1 level
Lymphocyte count decreased b
Grade 1 to Grade 3 lymphopenia
No dose modification
Grade 4 (< 0.2 × 109/L)
Delay dose a until resolved to ≤ Grade 2:
If resolved in ≤ 14 days from day of onset, then maintain dose
If resolved in > 14 days from day of onset, then reduce dose 1 level
Anemia
Grade 3 (Hemoglobin < 8.0 g/dL); 
transfusion indicated
Delay dose a until resolved to ≤ Grade 2, then maintain dose
Grade 4 Life threatening 
consequences; urgent intervention 
indicated
Delay dose a until resolved to ≤ Grade 2, then reduce dose 1 level

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Platelet count decreased
Grade 3 (platelets < 50 to 25 × 
109/L)
Delay dose a until resolved to ≤ Grade 1:
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
Grade 4 (platelets < 25 × 109/L)
Delay dose a until resolved to ≤ Grade 1, then reduce dose 1 level
Cardiac toxicity
Symptomatic CHF
Discontinue patient from study treatment
Decrease in LVEF 10% to 20% 
(absolute value), but LVEF > 45%
Continue treatment with T-DXd
LVEF 40% to ≤ 45% and decrease 
is < 10% (absolute value) from 
baseline
Continue treatment with T-DXd
Repeat LVEF assessment within 3 weeks
LVEF 40% to ≤ 45% and decrease 
is 10% to 20% (absolute value) 
from baseline
Interrupt a T-DXd dosing
Repeat LVEF assessment within 3 weeks.
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue patient from study treatment
If LVEF recovers to within 10% from baseline, resume study drug 
treatment
LVEF < 40% or > 20% (absolute 
value) drop from baseline
Interrupt a T-DXd dosing.
Repeat LVEF assessment within 3 weeks.
If LVEF < 40% or > 20% drop from baseline is confirmed, discontinue 
patient from study treatment
If LVEF has recovered to > 40% and decrease is < 20% from baseline, 
follow appropriate guidance above
Electrocardiogram QTcF prolonged
Grade 3 (Average QTcF > 500 ms 
or > 60 ms change from baseline) 
Delay dose a until resolved to ≤ Grade 1 (corrected QTcF≤ 480 ms), 
then determine if another medication the patient was taking may be 
responsible and can be adjusted or if there are any changes in serum 
electrolytes that can be corrected. If attributed to T-DXd, reduce dose 
1 level
Grade 4 (Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia)
Discontinue patient from study treatment

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Pulmonary Toxicity
Any evidence of ILD/pneumonitis should be promptly investigated:
If a patient develops radiographic changes potentially consistent with 
ILD/pneumonitis or develops an acute onset of new or worsening 
pulmonary or other related signs/symptoms such as dyspnea (resting or 
exertional), cough, fever, unexplained fatigue or decrease in oxygen 
saturation, rule out ILD/pneumonitis.
Evaluations should include:
!
High resolution CT 
!
Pulmonologist consultation (infectious disease consultation as 
clinically indicated)
!
COVID-19 test
!
Blood culture and complete blood count, differential WBC 
count, CRP. 
!
Consider bronchoscopy and bronchoalveolar lavage if 
clinically indicated and feasible
!
Pulmonary function tests (including forced vital capacity 
(FVC) and carbon monoxide (CO) diffusing capacity) and 
pulse oximetry (SpO2)
!
Arterial blood gases if clinically indicated 
!
One blood sample collection for PK analysis as soon as 
ILD/pneumonitis is suspected, if feasible
!
Additional blood samples for plasma and serum exploratory 
biomarker analysis as soon as ILD/pneumonitis is suspected, if 
feasible
Other tests could be considered, as needed. 
Appropriate management for ILD/pneumonitis should be instituted 
promptly as per management guideline below when ILD is suspected.
If the AE is confirmed to have an etiology other than treatment-related 
ILD/pneumonitis, follow the management guidance outlined in the 
“Other Non-Laboratory Adverse Events” dose modifications.
If another etiology for the AE cannot be identified and it could be 
related to T-DXd, then follow the ILD/pneumonitis management 
guidance as outlined below.
Consideration should be given to the possibility of an alternate etiology 
occurring concurrently with DI-ILD.
Whenever corticosteroids have been administered, the dose should be 
tapered gradually over at least 4 weeks even if an alternate etiology is 
confirmed.
All events of ILD/pneumonitis regardless of severity or seriousness 
should be followed until resolution.

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Grade 1
Management:
Monitor and closely follow-up in 2 to 7 days for onset of clinical 
symptoms and pulse oximetry, then weekly as indicated
Consider follow-up imaging in 1-2 weeks (or as clinically indicated)
Consider starting systemic steroids (e.g. at least 0.5 mg/kg/day 
prednisone/prednisolone or equivalent) until improvement, followed by 
gradual taper over at least 4 weeks
If worsening of diagnostic observations despite initiation of 
corticosteroids, then follow Grade 2 guidelines *
Dose modification:
The administration of T-DXd must be interrupted. T-DXd can be 
restarted only if the event is fully resolved to Grade 0:
If resolved in ≤ 28 days from day of onset, maintain dose
If resolved in > 28 days from day of onset, reduce dose 1 level 
Management of Grade 1 ILD/Pneumonitis: If the event Grade 1 
ILD/pneumonitis occurs beyond cycle Day 22 and has not resolved 
within 18 weeks (126 days) from the last infusion, the drug should be 
discontinued.
* If a patient is asymptomatic, then the patient should still be 
considered as Grade 1 even if steroid treatment is given.
Grade 2
Dose Modification:
Permanently discontinue patient from study treatment.
Management:
Promptly start and treat with systemic steroids (e.g., at least 
1 mg/kg/day prednisone/prednisolone or equivalent) for at least 14 days 
followed by a gradual taper over at least 4 weeks
Monitor symptoms closely
Re-image as clinically indicated
If worsening or no improvement in clinical or diagnostic observations 
in 3-5 days, 
Consider increasing dose of steroids (e.g., 2 mg/kg/day 
prednisone/prednisolone or equivalent) and switching treatment 
administration to intravenous (e.g., methylprednisolone)
Re-consider additional work-up for alternative etiologies as described 
above
Escalate care as clinically indicated

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Grade 3 or 4
Dose modification:
Permanently discontinue patient from study treatment.
Management:
Hospitalization required
Promptly initiate empiric high-dose methylprednisolone IV treatment 
(e.g., 500-1000 mg/day for 3 days), followed by at least 1.0 mg/kg/day 
of prednisone/prednisolone (or equivalent) for at least 14 days followed 
by gradual taper over at least 4 weeks
Re-image as clinically indicated
If still no improvement within 3 to 5 days, 
Re-consider additional work-up for alternative etiologies as described 
above
Consider other immunosuppressants and/or treat per local practice 
Ocular
Grade 3
Delay dose a until resolved to ≤ Grade 1:
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
Grade 4
Discontinue patient from study treatment
Blood creatinine increased
Grade 3 (> 3.0 to 6.0 × ULN)
Delay dose a until resolved to ≤ Grade 2 or baseline, then reduce dose 1 
level
Grade 4 (> 6.0 × ULN)
Discontinue patient from study treatment
Hepatic toxicity
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous blood 
bilirubin increased
AST/ALT ≥ 3.0 x ULN with 
simultaneous total bilirubin > 
2.0 × ULN
Delay study medication a until drug-induced liver injury can be ruled 
out. 
If drug-induced liver injury is ruled out, the patient should be treated 
accordingly, and resumption of study drug may occur after discussion 
between the Investigator and Sponsor. 
If drug-induced liver injury cannot be ruled out from diagnostic 
workup, permanently discontinue study treatment.
Monitor AST/ALT and total bilirubin twice weekly until resolution or 
return to baseline.

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
Grade 2 (> 3.0 to 5.0 × ULN if 
baseline was normal; > 3.0 to 
5.0 × baseline if baseline was 
abnormal)
No action for Grade 2 AST/ALT 
Grade 3 (> 5.0 to 20.0 × ULN if 
baseline was normal; > 5.0 to 
20.0 × baseline if baseline was 
abnormal)
In patients without liver metastases 
and patients with liver metastases 
and baseline level ≤ 3 × ULN
Repeat testing within 3 days. Delay dosea until resolved to ≤ Grade 1 if 
baseline ≤ 3 x ULN, otherwise delay dose until resolved to ≤ baseline, 
then:
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
Grade 3: (> 8.0 to 20.0 × ULN if 
baseline was normal; > 8.0 to 
20.0 × baseline if baseline was 
abnormal)
In patients with liver metastases, if 
the baseline level was > 3 × ULN
Repeat testing within 3 days. Delay dosea until resolved to ≤ baseline 
level:
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
Grade 4 (> 20 × ULN if baseline 
was normal; > 20.0 × baseline if 
baseline was abnormal)
Discontinue patient from study treatment
Blood bilirubin increased
Grade 2 (> 1.5 to 3.0 × ULN if 
baseline was normal; > 1.5 to 
3.0 × baseline if baseline was 
abnormal)
If no documented Gilbert’s syndrome or liver metastases at baseline, 
delay dose a until resolved to ≤ Grade 1:
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
If documented Gilbert’s syndrome or liver metastases at baseline, 
continue study treatment
Grade 3 (> 3.0 to 10.0 × ULN if 
baseline was normal; > 3.0 to 
10.0 × baseline if baseline was 
abnormal)
If no documented Gilbert’s syndrome or liver metastases at baseline, 
repeat testing within 3 days. Delay dose a until resolved to ≤ Grade 1:
If resolved in ≤ 7 days from day of onset, then reduce dose 1 level
If resolved in > 7 days from day of onset, then discontinue T-DXd
If documented Gilbert’s syndrome or liver metastases at baseline, 
repeat testing within 3 days. Delay dose a until resolved to < Grade 2:
If resolved in ≤ 7 days from day of onset, then reduce dose 1 level
If resolved in > 7 days from day of onset, then discontinue T-DXd
Grade 4 (> 10.0 × ULN if baseline 
was normal; > 10.0 × baseline if 
baseline was abnormal)
Discontinue patient from study treatment

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Table 27
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 
Grade (unless otherwise 
specified)
Management guidelines for T-DXd
Blood alkaline phosphatase increased
Grade 3 (> 5.0 to 20.0 × ULN if 
baseline was normal; > 5.0 to 
20.0 × baseline if baseline was 
abnormal)
Or Grade 4 (> 20.0 × ULN if 
baseline was normal; > 20.0 × 
baseline if baseline was abnormal)
No modification unless determined by the Investigator to be clinically 
significant or life-threatening.
Gastrointestinal
Nausea
Grade 3 
Delay dose a until resolved to ≤ Grade 1: 
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
Diarrhea/Colitis
Grade 3
Delay dose a until resolved to ≤ Grade 1:
If resolved in ≤ 3 days from day of onset, then maintain dose
If resolved in > 3 days from day of onset, then reduce dose 1 level
Grade 4
Discontinue patient from study treatment
Other laboratory adverse events
Grade 3
Delay dose a until resolved to ≤ Grade 1 or baseline level: 
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level
Grade 4
Discontinue patient from study treatment
Other non-laboratory adverse events
Grade 3
Delay dose a until resolved to ≤ Grade 1 or baseline: 
If resolved in ≤ 7 days from day of onset, then maintain dose
If resolved in > 7 days from day of onset, then reduce dose 1 level 
Grade 4
Discontinue patient from study treatment
AE = adverse event; ALT = alanine transaminase; AMI = acute myocardial infarction; AST = aspartate 
transaminase; CHF = congestive heart failure; CT = computer tomography; CTCAE = common terminology 
criteria for adverse events; ECG = electrocardiogram; ILD = interstitial lung disease; IV = intravenous; 
LVEF = left ventricular ejection fraction; NSAIDS = non-steroidal anti-inflammatory drugs; 
PK = pharmacokinetics; SpO2 = pulse oximetry; TMGs = toxicity management guidelines; ULN = upper 
limit normal
a See Section 6.6 Dose Modifications
b There will be no dose modifications for Grade 1 to Grade 3 lymphopenia
Note: All dose modifications should be based on the worst preceding toxicity 

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Appendix I
Instructions Related to COVID-19
I 1
Concomitant Medication and T-DXd Dose Modification Relevant 
to COVID-19
Prior and concomitant medications
Treatment for COVID-19 is evolving, and the Investigator should consult the product label for 
any treatments considered.
Dose modification criteria
In addition to Section 6.6, the following text is relevant for patients with COVID-19:
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. If a 
subject presents to the clinic with symptoms suggestive of COVID-19, infection should be 
confirmed via NAAT (nucleic acid amplification test such as RT-PCR) or rapid antigen 
testing. SARS-CoV-2 antigen testing can be used to confirm infection, but not to rule it out.
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 and report COVID-19-related AEs.
Dose modification criteria for suspected or confirmed COVID-19
If asymptomatic or symptomatic COVID-19 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, manage 
COVID-19 per local guidance until recovery from COVID-19 (no respiratory 
signs/symptoms of COVID 19, and completely or nearly resolved chest CT findings 
which are equivalent to CT Severity Score of 1 or 2 (CT Severity Score of 1 = Subtle 
Ground Glass Opacities and very few findings; CT Severity Score of 2 = Several 
Ground Glass Opacities and/or subtle reticulation)*.
* Luger AK, et al. Chest CT of lung injury 1 year after COVID-19 Pneumonia: The 
CovILD study. Radiology 2022;304(2):462-70.

After recovery, then follow below dose modifications:

If grade 1, resume T-DXd at the same dose 

If grade 2

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o
Maintain same dose if chest CT findings are completely 
resolved.
o
Reduce dose 1 level if chest CT findings are nearly resolved 
(equivalent to CT Severity Score of 1 or 2). 

If grade 3 
o
Reduce dose 1 level if chest CT findings are completely 
resolved.
o
Otherwise, discontinue study treatment if chest CT findings 
are not completely resolved. 

If grade 4, discontinue study treatment.
Closely monitor signs/symptoms after restarting T-DXd, initially with a weekly phone call or 
site visit for 6 weeks.
!
If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline. 
I 2
Benefit/Risk Considerations for COVID-19
The emergence of coronavirus 2019-nCoV (COVID-19) infection presents a potential safety 
risk for patients, therefore, several risk mitigation factors have been implemented in this 
study. Notably, the eligibility criteria exclude patients with COVID-19 infections (see 
Section 5.2).
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 patients 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 patients 
enrolled in this study outweigh the potential risks.

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Appendix J
European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire C30 and BR45

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Appendix K
Country-specific Protocol Information
K 1
Sweden

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K 2
Germany

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Appendix L
Abbreviations
Abbreviation or special 
term
Explanation
ADA
anti-drug antibody
ADC
antibody drug conjugate
AE
adverse event
AESI
adverse event of special interest
AI
aromatase inhibitor
ALP
alkaline phosphatase
ALT
alanine transaminase
Anti-HBc
hepatitis B core antibody 
AST
aspartate transaminase
ASCO/CAP
American Society of Clinical Oncology/College of American Pathologists
AZ
AstraZeneca
BfS
Federal Office for Radiation Protection in Germany
BICR
blinded independent central review
BOR
best overall response
CBC
complete blood count
CDK
cyclin-dependent kinase
CDK4/6i
cyclin-dependent kinase 4/6 inhibitor
CHF
congestive heart failure
CI
confidence interval
CO
carbon monoxide
COPD
chronic obstructive pulmonary disorder
COVID-19
corona virus disease 2019
CR
complete response
iCRO
imaging Contract Research Organization
CRP
C-reactive protein
CSP
Clinical Study Protocol
CSR
Clinical study report
CT
computer tomography
ctDNA
circulating tumor DNA
CTIS
Clinical Trial Information System
CTR
Clinical Trials Regulation
DAR
drug-to-antibody ratio
DCO
data cut off

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Abbreviation or special 
term
Explanation
DI-ILD
drug-induced ILD
DLCO
diffusing capacity of the lungs for carbon monoxide
DCO
data Cut Off
DNA
deoxyribonucleic acid 
DoR
duration of response
DUS
disease under study
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECHO
echocardiogram
eCRF
electronic Case Report Form
EMA
European Medicines Agency
EOT
end of treatment
EORTC QLQ
European Organisation for the Research and Treatment of Cancer Quality of Life 
Questionnaire
EQ-5D-5L
European Quality of Life 5-Domain 5-Level Scale
ER
estrogen receptor
ET
endocrine therapy
EU
European Union
FAS
Full Analysis Set
FFPE
Formalin-fixed and Paraffin-embedded
FISH
fluorescent in situ hybridization
FVC
forced vital capacity
GCP
Good Clinical Practice
HBsAg
surface antigen of the hepatitis B virus
HBV
hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HFS
hand and foot syndrome
HIV
human immunodeficiency virus
HOSPAD
hospital admission
HR
hormone receptor
HRCT
high-resolution computed tomography
HRQoL
health-related quality of life

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Abbreviation or special 
term
Explanation
IB
Investigator’s Brochure
IDMC
Independent Data Monitoring Committee
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
ILD
interstitial lung disease
INR
international normalized ratio
IMP
investigational medicinal product
IRB
Institutional Review Board
IRT
interactive response technology
ISH
in situ hybridization
ITT
intent-to-treat population
IV
intravenous(ly)
IVD
in vitro diagnostic
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mTOR
mammalian target of rapamycin
MUGA
Multiple gated acquisition scans
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NIMP
non-investigational medicinal product
NLs
new lesions
NSCLC
non-small cell lung cancer
NYHA
New York heart association
ORR
objective response rate
PBMC
peripheral blood mononuclear cell
OS
overall survival
PD
progressive disease
PFS
progression-free survival
PFS2
time from randomization to second progression or death

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Abbreviation or special 
term
Explanation
PFT
pulmonary function test
PGI-BR
Patient Global Impression – Benefit/Risk
PGIC
Patient Global Impression–Change
PGIS
Patient Global Impression–Severity
PGI-TT
Patient Global Impression–Treatment Tolerability
PgR
progesterone receptor
PK
pharmacokinetic 
PI3-K
phosphoinositide 3-kinase
PR
partial response
PRO
patient-reported outcome
PRO-CTCAE
Patient-reported outcomes version of the Common Terminology Criteria for 
Adverse Events
PT
prothrombin time
q3w
every 3 weeks
q9w
every 9 weeks
RECIST 1.1
Response Evaluation Criteria In Solid Tumors version 1.1
RNA
ribonucleic acid
RT-PCR
reverse transcriptase polymerase chain reaction
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SAS
Safety Analysis Set
SD
stable disease
SmPC
Summary of Product Characteristics
SoA
Schedule of Assessments
SOC
system organ class
SpO2
pulse oximetry
TBL
total bilirubin
T-DM1
Ado-trastuzumab emtansine
TEAE
treatment-emergent adverse event
TFST
time to first subsequent treatment or death
TLs
target lesions
TMG
toxicity management guidelines
TSST
time to second subsequent treatment or death
ULN
upper limit of normal

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Abbreviation or special 
term
Explanation
US
United States
US FDA
US Food and Drug Administration
WBC
white blood cell

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Document Title:
D9670C00001 Clinical Study Protocol version 5
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