A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled Study of DS-8201a (Trastuzumab Deruxtecan), an Anti-HER2 Antibody Drug Conjugate (ADC), Versus Ado Trastuzumab Emtansine (T-DM1) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With Trastuzumab and Taxane
Phase: PHASE3
Conditions: Breast Cancer
Sponsor: Daiichi Sankyo

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CLINICAL STUDY PROTOCOL 
A PHASE 3, MULTICENTER, RANDOMIZED, 
OPEN-LABEL, ACTIVE-CONTROLLED STUDY OF 
TRASTUZUMAB DERUXTECAN (DS-8201A), AN 
ANTI-HER2-ANTIBODY DRUG CONJUGATE, VERSUS 
ADO-TRASTUZUMAB EMTANSINE (T-DM1) FOR 
HER2-POSITIVE, UNRESECTABLE AND/OR 
METASTATIC BREAST CANCER SUBJECTS 
PREVIOUSLY TREATED WITH TRASTUZUMAB AND 
TAXANE  (DESTINY-Breast03) 
 
DS8201-A-U302 
 
IND/EudraCT NUMBERS 127553/2018-000222-61 
 
VERSION 6.0, 25 SEP 2020 
Daiichi Sankyo Inc. 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo Inc. The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement. Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo Inc.  

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CRITICAL STUDY CONTACT LIST 
 
Sponsor (United States) 
Daiichi Sankyo Inc. 
211 Mt Airy Rd 
Basking Ridge, NJ 07920 
USA 
 

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DOCUMENT HISTORY 
Version Number 
Version Date 
5.0 
23 April 2020 
4.0 
26 April 2019 
3.0 
08 Mar 2019 
2.0 
20 June 2018 
1.0 
23 March 2018 
 

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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 6.0 (dated 25 Sep 2020) vs. 
protocol Version 5.0 (dated 23 Apr 2020) for actual changes in text.  The summary of changes 
below is a top-line summary of major changes in the current DS8201-A-U302 clinical study 
protocol (Version 6.0) by section. 
Amendment Rationale: 
DS8201-A-U302 was recently amended in April 2020 to Version 5.0, which incorporated 
coronavirus disease 2019 (COVID-19) management updates.  This amendment is primarily 
driven by the addition of biomarker analyses to evaluate the impact of the global pandemic 
caused by COVID-19 at the subject-level and study-level and a change in the stopping rules for 
the progression-free survival (PFS) interim analysis.  The exploratory endpoints were also 
revised to include evaluation of progression-free survival on the next line of therapy (PFS2) and 
withdrawal of consent language was clarified.  Other changes are noted in the table below. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/Ethics Committee (EC) of the European Parliament and the Council of the 
European Union. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in the Summary of Changes. 
Minor edits, such as an update to language that does not alter original meaning, an update to 
version numbering, formatting, a change in font color, a correction to a typographical error, the 
use of abbreviations, moving verbiage within a section or table, a change in style or numbering, 
or a change in case, are not noted in the table below. 
 
Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis 
 
 
 
Destiny number was added 
 
The exploratory objective was 
updated 
 
The following exploratory 
endpoint was added: 
• Progression on the next line of 
treatment (PFS2) based on 
investigator assessment 
 
The efficacy boundary for the 
interim analysis was updated 
To provide clarification 
 
To provide clarification 
 
 
To explore emerging PFS data 
 
 
 
 
To include a change in the 
stopping rules 

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2.1.4. Exploratory Objectives 
 
2.3.4. 
Exploratory Efficacy  
             Endpoints 
These subsections were updated 
To explore emerging PFS data 
5.9. Study Drug Discontinuation 
and Discontinuation from the 
Study 
The heading and subheadings of 
this section were updated 
To provide clarification 
6.2. Screening 
6.4.1.2. Day 1; Before Infusion 
(All Cycles, Unless Otherwise 
Noted) 
6.5. End of Treatment 
COVID-19 serology testing was 
added 
To align with the latest safety 
information 
6.4. Treatment Period 
6.5. End of Treatment 
6.6. Follow-up 
10.1.1. European Organization 
for Research and Treatment of 
Cancer Quality of Life 
Questionnaires C30 and BR45 
Timing of completion of specific  
Health Economics and 
Outcomes Research (HEOR) 
outcomes questionnaires was 
specified  
To provide clarification 
7.1.4. Exploratory Efficacy 
Endpoints 
PFS and PFS2 analyses were 
added  
To explore emerging PFS data 
8.1. Pharmacokinetic 
Assessments 
 
 
Table 17.2   Schedule of Events 
Conditions for collecting PK 
samples from subjects treated 
with Chloroquine or 
Hydroxychloroquine were added  
 
To monitor potential drug-drug 
interactions between 
investigational/study drug 
treatment and COVID-19 
specific treatment 
11.1. 
General Statistical 
Considerations 
This section was updated 
To provide further clarification 
Table 11.1.    Efficacy Stopping 
Boundaries for PFS/overall 
survival (OS) Interim and Final 
Analyses 
This table was updated  
To reflect the changes to the 
efficacy stopping boundaries 
for PFS interim analysis 
Table 11.2.   Probability of Study 
Outcomes Under Various True 
Hazard Ratios 
This table was updated 
To reflect the changes to the 
efficacy stopping boundaries 
for PFS interim analysis 
11.4.1.1.   Primary Efficacy 
Analyses 
The description of the interim 
analysis was updated  
To include a change in the 
stopping rules 
11.4.1.3.2. Analyses of 
Exploratory Efficacy Endpoints 
The analysis of PFS2 data was 
described  
To explore emerging PFS data 

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11.4.3.1. 
Pharmacokinetic 
Analyses 
This section was updated  
To provide further clarification 
11.4.4.7. 
Immunogenicity 
(Anti-Drug Antibody) Analyses 
This section was updated 
To provide further clarification 
11.5.   Interim Analyses 
This section was updated  
To include a change in the 
stopping rules 
11.6.   Sample Size 
Determination 
This section was updated  
To include a change in the 
stopping rules 
16.    References 
This section was updated 
To include references for the 
new stopping rule 
Table 17.1.  
Schedule of Events 
The table and footnotes were 
updated 
To provide clarification 
To align with the latest safety 
information 
17.8. 
Instructions Related to 
Coronavirus Disease 2019 
(COVID-19) 
This section was updated 
To align with the latest 
management guidelines for 
COVID-19 

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PROTOCOL SYNOPSIS 
EudraCT: 
2018-000222-61 
IND Number: 
127553 
NCT Number 
NCT03529110 
Protocol Number: 
DS8201-A-U302 
Investigational 
Product: 
Trastuzumab deruxtecan (DS-8201a; also known as fam-trastuzumab 
deruxtecan) 
Active Ingredients: 
Trastuzumab deruxtecan consists of an antibody component, MAAL-9001, 
covalently conjugated via a maleimide tetrapeptide linker, to a drug 
component MAAA-1181a 
Study Title: 
A Phase 3, multicenter, randomized, open-label, active-controlled study of 
trastuzumab deruxtecan (DS-8201a), an anti-HER2-antibody drug 
conjugate, versus ado-trastuzumab emtansine (T-DM1) for HER2-positive, 
unresectable and/or metastatic breast cancer subjects previously treated 
with trastuzumab and taxane  (DESTINY-Breast03) 
Study Phase: 
Phase 3 
Indication Under 
Investigation: 
Unresectable/metastatic breast cancer with human epidermal growth factor 
receptor 2 (HER2)-positive expression 
Study Objectives: 
Primary Objective: 
 To compare the progression-free survival (PFS) benefit of 
trastuzumab deruxtecan to T-DM1for HER2-positive, unresectable 
and/or metastatic breast cancer subjects previously treated with 
trastuzumab and taxane. 
Key Secondary Objective: 
 To compare overall survival (OS) benefit of trastuzumab deruxtecan 
to T-DM1.  
Other Secondary Objectives: 
 To evaluate efficacy of trastuzumab deruxtecan compared to T-DM1 
on: 
 Confirmed objective response rate (ORR); 
 Duration of response (DoR). 
 To further determine pharmacokinetics (PK) of trastuzumab 
deruxtecan. 
 To further evaluate safety of trastuzumab deruxtecan compared to 
T-DM1. 
 To evaluate Health Economics and Outcomes Research (HEOR) 
endpoints for trastuzumab deruxtecan compared to T-DM1. 

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Exploratory Objectives: 
 To evaluate efficacy of trastuzumab deruxtecan compared to T-DM1 
by clinical benefit rate (CBR) and progression-free survival on the 
next line of therapy (PFS2). 
 To evaluate potential biomarkers of response/resistance (eg, serum 
HER2-extracellular domain [HER2ECD]). 
 To evaluate exposure-response relationships for efficacy and safety 
endpoints. 
Study Design: 
This is a randomized, 2-arm, Phase 3, open-label, multicenter study to 
compare the safety and efficacy of trastuzumab deruxtecan versus T-DM1 
in HER2-positive, unresectable and/or metastatic breast cancer subjects 
previously treated with trastuzumab and taxane. Approximately 500 
subjects will be randomized 1:1 to trastuzumab deruxtecan versus T-DM1. 
Randomization will be stratified by: 
 Hormone receptor status (positive, negative) 
 Prior treatment with pertuzumab (yes, no) 
 History of visceral disease (yes, no) 
 Study Design Schema of DS8201-A-U302 
 
There will be follow-up visits after permanent discontinuation of study 
treatment to obtain information about subsequent treatment(s) and survival 
status. 
Study Duration: 
Enrollment is planned to occur over approximately 22 mo. 
The end of the study hypothesis-testing period is the date when 
approximately 250 OS events have been observed. The total anticipated 
duration of the study is approximately 51 mo. 
For each subject there will be a 40-Day (+ 7 d) Follow-up after the last 
study treatment administration or before starting new anticancer treatment, 
whichever comes first, followed by Long-term/Survival Follow-up every 
3 mo (± 14 d) from the date of 40-Day (+ 7 d) Follow-up, until death, 
withdrawal of consent, loss to follow-up, or study closure, whichever 
occurs first.  
Study Sites and 
Location: 
Approximately 175 sites including but not limited to: North America, 
Asia, and Europe. 

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Subject Eligibility 
Criteria: 
Key Inclusion Criteria: 
 Adults ≥18 y old. (Please follow local regulatory requirements if the 
legal age of consent for study participation is >18 y old.) 
 Pathologically documented breast cancer that: 
 is unresectable or metastatic 
 has confirmed HER2-positive expression as determined according 
to American Society of Clinical Oncology – College of American 
Pathologists guidelines evaluated at a central laboratory. 
 was previously treated with trastuzumab and taxane in the 
advanced/metastatic setting or progressed within 6 mo after 
neoadjuvant or adjuvant treatment involving a regimen including 
trastuzumab and taxane. 
 Documented radiologic progression (during or after most recent 
treatment or within 6 mo after completing adjuvant therapy). 
 Subjects must be HER2-positive as confirmed by central laboratory 
assessment of most recent tumor tissue sample available. If archived 
tissue is not available, a fresh biopsy is required. 
Female subjects of reproductive/childbearing potential must agree 
to use a highly effective form of contraception or avoid 
intercourse during and upon completion of the study and for at 
least 7 mo after the last dose of trastuzumab deruxtecan and 7 mo 
after the last dose of T-DM1. Male subjects must agree to inform 
all potential female partners that they are participating in a clinical 
trial of a drug that may cause birth defects. Male subjects must 
also agree to either avoid intercourse or that they and/or any 
female partners of reproductive/childbearing potential will use a 
highly effective form of contraception during and upon 
completion of the study and for at least 4.5 mo after the last dose 
of trastuzumab deruxtecan or 4 mo after the last dose of T-DM1. 
 Adequate renal function, defined as: 
 Creatinine clearance ≥ 30 mL/min, as calculated using the 
Cockcroft-Gault equation 
 Adequate hepatic function, defined as: 
 Total bilirubin ≤ 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 metastases 
at baseline, and 
 Aspartate aminotransferase (AST)/alanine aminotransferase 
(ALT) ≤ 3 × ULN. 

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Key Exclusion Criteria: 
 Prior treatment with an anti-HER2 antibody drug conjugate (ADC) 
(such as T-DM1) in the metastatic setting. Prior treatment in the 
adjuvant/neoadjuvant setting would be allowed if progression of 
disease did not occur within 12 mo of end of adjuvant therapy. 
 Uncontrolled or significant cardiovascular disease, including any of 
the following: 
 History of myocardial infarction within 6 mo before 
randomization  
 History of symptomatic congestive heart failure (New York Heart 
Association Class II to IV) 
 Troponin levels consistent with myocardial infarction as defined 
according to the manufacturer within 28 d prior to randomization 
 Corrected QT interval prolongation to > 470 ms (females) or 
> 450 ms (male) based on average of Screening triplicate 12-lead 
electrocardiogram (ECG)  
 Left ventricular ejection fraction (LVEF) < 50% within 28 d prior 
to randomization 
 Has a history of (noninfectious) interstitial lung disease 
(ILD)/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be 
ruled out by imaging at Screening. 
 Spinal cord compression or clinically active central nervous system 
(CNS) metastases, defined as untreated or symptomatic, or requiring 
therapy with corticosteroids or 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 wk must have elapsed between the end of whole brain 
radiotherapy and study enrollment. 
 Prior participation in a study involving an ADC produced by Daiichi 
Sankyo. 
Dosage Form,  
Dose and Route  
of Administration: 
Trastuzumab deruxtecan for injection 100 mg: A trastuzumab deruxtecan 
lyophilized powder containing 100 mg of trastuzumab deruxtecan in a 
glass vial. The starting dose of trastuzumab deruxtecan will be 5.4 mg/kg.  
T-DM1 for injection lyophilized powder in single-use vials. The starting 
dose of T-DM1 will be 3.6 mg/kg. 

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The drug for intravenous (IV) infusion is prepared by dilution of the 
required volume of the drug product calculated based on the subject’s 
body weight to a 100 mL or 250 mL infusion bag, by the study site 
pharmacist. The study treatment will be administered as an IV infusion 
every 3 wk, initially for approximately 90 min, then, if there is no infusion 
related reaction, for a minimum of 30 min thereafter.  
Study Endpoints: 
Primary Efficacy Endpoint: 
 Progression-free survival (PFS) as determined by blinded independent 
central review (BICR). 
Key Secondary Efficacy Endpoint: 
 OS 
Other Secondary Efficacy Endpoints: 
 ORR based on BICR and investigator assessment (confirmation of 
complete response [CR]/partial response [PR] is required) 
 DoR based on BICR  
 PFS based on investigator assessment 
Exploratory Efficacy Endpoints: 
 Time to response based on BICR  
 Best percent change in the sum of the diameter of measurable tumors 
based on BICR  
 CBR based on BICR 
 PFS2 based on investigator assessment  
Health Economic and Outcomes Research Endpoints:  
 European Organization for Research and Treatment of Cancer 
(EORTC) quality of life questionnaire (QLQ) 
 C30 
 BR45 
 EuroQol-5 dimensions-5 levels of severity (EQ-5D-5L) 
 Hospitalization-related endpoints  
Pharmacokinetic Endpoints:  
 Serum concentrations of trastuzumab deruxtecan, total anti-HER2 
antibody, and MAAA-1181a 
Biomarker Endpoints: 
 Serum biomarkers (eg, HER2 extracellular domain [HER2ECD])  
 Other potential biomarkers (eg, cell free deoxyribonucleic acid, RNA 
profiling) 
Safety Endpoints: 
 Serious adverse events (SAEs)  

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 Treatment-emergent adverse events (TEAEs), graded according to the 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events version 5.0 
 Adverse events of special interest (AESIs) 
 TEAEs associated with discontinuation of study treatment 
 Physical examination findings (including Eastern Cooperative 
Oncology Group performance status [ECOG PS])  
 Vital sign measurements 
 Standard clinical laboratory parameters  
 ECG parameters  
 Echocardiogram (Echo)/multigated acquisition scan (MUGA) 
findings  
 Anti-drug antibodies (ADA)  
Planned Sample Size: The target sample size will be approximately 500 subjects, randomized in 
a 1:1 ratio into 2 treatment groups (trastuzumab deruxtecan versus 
T-DM1). 
Statistical Analyses: Efficacy Analyses 
The primary efficacy endpoint is PFS based on BICR. An interim and a 
final analysis for PFS is planned in this trial. The interim analysis will be 
performed when approximately 234 BICR-assessed PFS events (70% 
information fraction) have been observed. If the trial is not statistically 
significant at this interim analysis, the final PFS analysis will be 
performed after observing 335 BICR-assessed PFS events. 
The primary efficacy analyses will be performed for the Full Analysis Set 
that consists of all randomized subjects. Following intent-to-treat 
principles, patients will be analyzed according to the treatment and the 
strata they were randomized to during the randomization process by 
Interactive Web/Voice Response System (IXRS).  
The survival distribution of PFS will be estimated by Kaplan-Meier 
method for each treatment group and results will be presented graphically. 
The median PFS times and 2-sided 95% confidence intervals (CIs) for the 
medians will be provided using Brookmeyer and Crowley method for each 
treatment group.  
The primary efficacy analysis will be the comparison of the survival 
distribution of PFS between the 2 treatment groups, using a stratified log-
rank test stratified by the randomization stratification factors as recorded 
by IXRS, at an overall 2-sided significance level of 0.05.  The treatment 
effect hazard ratio (HR) and its 95% CIs will be estimated, using stratified 
Cox proportional hazards regression model stratified by the randomization 
stratification factors as recorded by the IXRS. 
An interim analysis for superiority is planned after at least 234 of the 335 
targeted PFS events (70% information fraction) have been documented. 

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The primary intent of the interim analysis is to demonstrate superiority of 
the primary efficacy endpoint of PFS only and a formal futility evaluation 
is not planned. A group sequential design, utilizing a Haybittle-Peto 
efficacy boundary36, 37 will be used to control the type I error rate for the 
primary efficacy analysis.  
The key secondary efficacy endpoint, OS, will be compared between the 2 
treatment groups using stratified log-rank test stratified by the 
randomization stratification factors as recorded by IXRS, at 2-sided 
significance level of 0.05, provided superiority in PFS is demonstrated at 
either interim or final analysis. A hierarchical testing procedure will be 
adopted in this study and the OS analyses will be performed only if the 
primary efficacy endpoint PFS is statistically significant. Up to three 
analyses for OS could be performed: 
 First interim analysis at the time of the interim analysis for PFS 
(provided PFS is significant), at which point a total of 96 OS 
events (38.4% information fraction) are expected.  
 If the OS interim analysis is not significant, a second interim 
analysis for OS is planned at the time of the final analysis for PFS 
when approximately 153 OS events (61.2% information fraction) 
are expected.   
 If the second OS analysis is not significant, a final analysis for OS 
after approximately 250 OS events have been observed (expected 
51 months from date of first subject to be randomized).  
OS will be analyzed in the same manner as the primary analysis for PFS. 
To maintain type I error rate, in addition to the hierarchical testing 
strategy, a Lan-DeMets alpha spending function with O’Brien-Fleming 
boundary, independent of the PFS analysis will be utilized.  
Other secondary efficacy endpoints are ORR (the proportion of subjects 
who achieved a best overall response of CR or PR) based on BICR and 
investigator assessment, DoR based on BICR, and PFS based on 
investigator assessment.  
Cochran-Mantel-Haenszel tests stratified by the randomization 
stratification factors as recorded by IXRS will be used to compare ORR 
between the treatment groups. The estimate of ORR and its 2-sided 95% 
CIs will be provided using Clopper-Pearson method. 
Duration of response (based on BICR) will be summarized with median 
event time and its 2-sided 95% CIs using Brookmeyer and Crowley 
method for each treatment group.  
The survival distribution of PFS based on investigator assessment will be 
estimated using the Kaplan-Meier method and will be presented 
graphically by treatment group. The median PFS and its two-sided 95% CI 
using Brookmeyer and Crowley method will be provided for each 
treatment group.  PFS rates at fixed time points (e.g., 3, 6, 9, 12 months) 

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and the two-sided 95% CIs will be provided for each treatment group. The 
treatment effect hazard ratio and its two-sided 95% CI will be estimated 
using stratified Cox proportional hazards regression model with the same 
stratification factors as the randomization stratification factors taken from 
IXRS. The survival distribution of PFS based on investigator assessment 
between the two treatment groups will be compared at a two-sided 
significance level of 0.05, using a stratified log-rank test stratified by the 
randomization stratification factors as recorded by IXRS, at the time when 
primary analysis of PFS per BICR is statistically significant. 
Health Economic and Outcomes Research Analyses  
A detailed analysis plan of quality of life (QoL) endpoints, including 
control of type I error regarding QoL analyses, will be provided in the 
Statistical Analysis Plan (SAP).  
Descriptive analyses of the HEOR endpoints based on the following 
patient reported outcome (PRO) questionnaires will be analyzed by 
treatment arm and compared using appropriate statistical methods. For the 
European Organization for Research and Treatment of Cancer quality of 
life questionnaires (EORTC QLQ)-C30 and EORTC QLQ-BR45: changes 
from baseline over time on the global QoL scale, the functioning scales, 
symptom scales, and single-item scales of the QLQ-C30 and in each of the 
subscales of EORTC QLQ-BR45. For the EQ-5D-5L visual analogue 
scale, all 5 dimensions and associated utility scores; and for 
hospitalization-related endpoints: time to hospitalization as well as reason, 
discharge diagnosis, intensive care unit stay, and length of stay will be 
reported. 
Time to definitive deterioration on the ‘breast symptoms’ and ‘arm 
symptoms’ subscales of the EORTCQLQ-BR45, and the pain symptom 
subscale of the EORTC QLQ-C30 will also be assessed. Time to definitive 
deterioration will be compared between the 2 treatment groups using a 
stratified log-rank test stratified by the randomization stratification factors 
as recorded by IXRS, at a two-sided significance level of 0.05. The 
survival distributions will be estimated by Kaplan-Meier method and 
results will be presented graphically. The median time to definitive 
deterioration and the proportion of patients without definitive deterioration 
at specific time points will be reported as well as the 2-sided 95% CIs for 
the medians. A stratified Cox regression model will be used to estimate the 
HR of time to definitive deterioration, along with 95% CI. 
Pharmacokinetic Analyses  
Descriptive statistics will be provided for all serum concentration data 
(trastuzumab deruxtecan, total anti-HER2 antibody, and MAAA-1181a) at 
each time point. 
The population PK (pop-PK) analysis to evaluate the effect of intrinsic and 
extrinsic factors of trastuzumab deruxtecan, and if appropriate, total anti-
HER2 antibody, and MAAA-1181a will be characterized including 

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available PK data. After establishment of the pop-PK model, a 
pop-PK/pharmacodynamic model may be developed to evaluate the 
relationship between exposure and efficacy and toxicity. The results of the 
nonlinear mixed effects pop-PK and pop-PK/pharmacodynamic models 
may be reported separately from the clinical study report. 
Biomarker Analyses  
Archived tissue will be requested for re-analysis of HER2 status by 
immunohistochemistry and/or in situ hybridization as well as for 
exploratory biomarkers analyses. Biomarkers will be summarized by 
treatment group using descriptive statistics. 
Safety Analyses 
Safety endpoints will include SAEs, TEAEs, AESIs, discontinuations due 
to AEs, physical examination findings (including ECOG PS), vital sign 
measurements, standard clinical laboratory parameters, ECG parameters, 
Echo/MUGA findings, and ADAs. TEAEs will be graded according to the 
National Cancer Institute-Common Terminology Criteria for Adverse 
Events version 5.0. Safety analyses in general will be descriptive and will 
be presented in tabular format with the appropriate summary statistics. 

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TABLE OF CONTENTS 
DOCUMENT HISTORY.................................................................................................................3 
INVESTIGATOR AGREEMENT...................................................................................................4 
SUMMARY OF CHANGES ...........................................................................................................5 
PROTOCOL SYNOPSIS ................................................................................................................8 
LIST OF ABBREVIATIONS ........................................................................................................27 
1. 
INTRODUCTION ...........................................................................................................31 
1.1. 
Background ......................................................................................................................31 
1.1.1. 
Investigational Product ....................................................................................................31 
1.1.1.1. Name ................................................................................................................................31 
1.1.1.2. Description ......................................................................................................................31 
1.1.1.3. Intended Use Under Investigation ...................................................................................32 
1.1.1.4. Comparator (T-DM1) ......................................................................................................32 
1.1.1.5. Nonclinical Studies of Trastuzumab Deruxtecan ............................................................32 
1.1.1.6. Clinical Experience .........................................................................................................32 
1.1.1.7. Summary of Clinical Pharmacokinetics ..........................................................................33 
1.2. 
Study Rationale ...............................................................................................................35 
1.3. 
Risks and Benefits for Study Subjects .............................................................................36 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................................................38 
2.1. 
Study Objectives ..............................................................................................................38 
2.1.1. 
Primary Objective ............................................................................................................38 
2.1.2. 
Key Secondary Objective ................................................................................................38 
2.1.3. 
Other Secondary Objectives ............................................................................................38 
2.1.4. 
Exploratory Objectives ....................................................................................................38 
2.2. 
Study Hypothesis .............................................................................................................38 
2.3. 
Study Endpoints ...............................................................................................................38 
2.3.1. 
Primary Efficacy Endpoint ..............................................................................................39 
2.3.2. 
Key Secondary Efficacy Endpoint ..................................................................................39 
2.3.3. 
Other Secondary Efficacy Endpoints ..............................................................................39 
2.3.4. 
Exploratory Efficacy Endpoints ......................................................................................39 
2.3.5. 
Health Economic and Outcomes Research Endpoints ....................................................39 
2.3.6. 
Pharmacokinetic/Biomarker Endpoints ...........................................................................39 

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2.3.6.1. Pharmacokinetic Endpoints .............................................................................................39 
2.3.6.2. Biomarker Endpoints .......................................................................................................40 
2.3.7. 
Safety Endpoints ..............................................................................................................40 
3. 
STUDY DESIGN ............................................................................................................41 
3.1. 
Overall Design .................................................................................................................41 
3.1.1. 
Duration of the Study ......................................................................................................41 
3.1.2. 
Duration of Subject Participation ....................................................................................42 
3.1.3. 
Definition of the End of the Study ..................................................................................42 
3.2. 
Discussion of Study Design .............................................................................................42 
4. 
STUDY POPULATION ..................................................................................................43 
4.1. 
Inclusion Criteria .............................................................................................................43 
4.2. 
Exclusion Criteria ............................................................................................................45 
5. 
STUDY TREATMENTS ................................................................................................48 
5.1. 
Assigning Subjects to Treatments and Blinding .............................................................48 
5.1.1. 
Treatment Groups ............................................................................................................48 
5.1.2. 
Method of Treatment Allocation .....................................................................................48 
5.1.3. 
Blinding ...........................................................................................................................48 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................48 
5.2. 
Trastuzumab Deruxtecan .................................................................................................48 
5.2.1. 
Description ......................................................................................................................48 
5.2.2. 
Labeling and Packaging ..................................................................................................49 
5.2.3. 
Preparation .......................................................................................................................49 
5.2.4. 
Storage .............................................................................................................................49 
5.3. 
Control Treatment (T-DM1) ............................................................................................49 
5.3.1. 
Description ......................................................................................................................49 
5.3.2. 
Labeling and Packaging ..................................................................................................49 
5.3.3. 
Preparation .......................................................................................................................49 
5.3.4. 
Storage .............................................................................................................................49 
5.4. 
Administration of either Trastuzumab Deruxtecan or T-DM1 ........................................50 
5.5. 
Drug Accountability ........................................................................................................50 
5.6. 
Dose Interruptions and Reductions .................................................................................51 
5.6.1. 
Dose Reduction and Interruption Guidelines ..................................................................51 

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5.6.1.1. Dose Modifications .........................................................................................................52 
5.7. 
Method of Assessing Treatment Compliance ..................................................................61 
5.8. 
Concomitant Medications (Drugs and Therapies) ...........................................................61 
Prohibited Medications and Treatments ........................................................................................62 
5.9. 
Study Drug Discontinuation and Discontinuation from the Study ..................................62 
5.9.1. 
Discontinuation of Study Drug ........................................................................................62 
Procedures for Discontinuation from Study Drug .........................................................................63 
Modified Follow-up Options .........................................................................................................64 
5.9.2. 
Withdrawal Procedures ...................................................................................................64 
5.9.3. 
Subject Replacement .......................................................................................................65 
5.9.4. 
Subject Re-screening Procedures ....................................................................................65 
6. 
STUDY PROCEDURES .................................................................................................66 
6.1. 
Tissue Screening ..............................................................................................................66 
6.2. 
Screening .........................................................................................................................66 
6.3. 
Randomization .................................................................................................................68 
6.4. 
Treatment Period .............................................................................................................68 
6.4.1. 
Cycle 1 to 4 and Subsequent Cycles ................................................................................68 
6.4.1.1. Between -3 Days Through Immediately Before Infusion (All Cycles) ...........................68 
6.4.1.2. Day 1; Before Infusion (All Cycles, Unless Otherwise Noted) ......................................69 
6.4.1.3. Day 1: Dosing and End of Infusion (All Cycles, Unless Otherwise Noted) ...................70 
6.4.1.4. Day 8 (± 1 d) and Day 15 (± 1 d) (Cycle 1 Only) ...........................................................71 
6.4.2. 
Every 2 Cycles after Cycle 3 ...........................................................................................71 
6.4.3. 
Every 4 Cycles (± 7 d) after Cycle 1 ...............................................................................71 
6.4.4. 
Every 6 Weeks (± 7 d) .....................................................................................................71 
6.5. 
End of Treatment .............................................................................................................72 
6.6. 
Follow-up ........................................................................................................................73 
6.6.1. 
40-Day (+ 7 d) Follow-up................................................................................................73 
6.6.2. 
Long-term/Survival Follow-up Visits .............................................................................74 
7. 
EFFICACY ASSESSMENTS .........................................................................................75 
7.1. 
Assessments for Efficacy Endpoints ...............................................................................75 
7.1.1. 
Primary Efficacy Endpoint ..............................................................................................75 
7.1.2. 
Key Secondary Efficacy Endpoint ..................................................................................75 

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7.1.3. 
Secondary Efficacy Endpoints ........................................................................................75 
7.1.4. 
Exploratory Efficacy Endpoints ......................................................................................76 
7.2. 
Appropriateness of Selected Efficacy Assessments ........................................................76 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ...........................78 
8.1. 
Pharmacokinetic Assessments .........................................................................................78 
8.2. 
Pharmacodynamic Assessment .......................................................................................78 
8.3. 
Biomarker Assessments ...................................................................................................78 
8.3.1. 
Tumor Sampling ..............................................................................................................79 
8.3.2. 
Blood Sampling ...............................................................................................................79 
8.3.3. 
Additional Biomarker Assessments ................................................................................79 
8.3.4. 
Disclosure of the Results of Additional Biomarker Assessments ...................................79 
8.4. 
Immunogenicity ...............................................................................................................79 
8.5. 
Pharmacogenetic Analysis ...............................................................................................79 
8.5.1. 
Genomic or Genetic Banking and Analysis ....................................................................79 
8.5.1.1. Disclosure of the Results of Genomic or Genetic Analysis ............................................80 
8.5.1.2. Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis ...........................................................................................................................80 
9. 
SAFETY EVALUATION AND REPORTING ..............................................................81 
9.1. 
Assessment of Safety Endpoints .....................................................................................81 
9.2. 
Adverse Event Collection and Reporting ........................................................................81 
9.3. 
Adverse Events of Special Interest ..................................................................................82 
9.3.1. 
Interstitial Lung Disease/Pneumonitis .............................................................................82 
9.3.1.1. Clinical Summary ............................................................................................................82 
9.3.1.2. Management Guidance ....................................................................................................82 
9.3.1.3. Interstitial Lung Disease Adjudication Committee .........................................................83 
9.3.2. 
Left Ventricular Ejection Fraction Decrease ...................................................................83 
9.3.2.1. Clinical Summary ............................................................................................................83 
9.3.2.2. Management Guidance ....................................................................................................83 
9.4. 
Adverse Event .................................................................................................................83 
9.4.1. 
Definition of Adverse Event ............................................................................................83 
9.4.2. 
Serious Adverse Event ....................................................................................................84 
9.4.3. 
Severity Assessment ........................................................................................................84 
9.4.4. 
Causality Assessment ......................................................................................................85 

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9.4.5. 
Action Taken Regarding Study treatments ......................................................................85 
9.4.6. 
Other Action Taken for Event .........................................................................................86 
9.4.7. 
Adverse Event Outcome ..................................................................................................86 
9.5. 
Adverse Events Reporting–Procedure for Investigators .................................................86 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee .................................................................................................88 
9.7. 
Exposure In Utero During Clinical Studies .....................................................................88 
9.8. 
Clinical Laboratory Evaluations ......................................................................................89 
9.9. 
Vital Signs .......................................................................................................................89 
9.10. 
Electrocardiograms ..........................................................................................................90 
9.11. 
Physical Examinations .....................................................................................................90 
9.12. 
Other Examinations .........................................................................................................90 
9.12.1. Cardiac Assessments .......................................................................................................90 
9.12.2. Pulmonary Assessments ..................................................................................................90 
10. 
OTHER ASSESSMENTS ...............................................................................................91 
10.1. 
Patient Reported Outcomes .............................................................................................91 
10.1.1. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaires C30 and BR45 ........................................................................................91 
10.1.2. EuroQoL Five Dimensions Five Levels (EQ-5D-5L) Patient Reported Outcome 
Questionnaire ...................................................................................................................92 
10.2. 
Health-related QoL Endpoints .........................................................................................92 
10.2.1. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Endpoints .................................................................................................92 
10.2.2. EuroQoL Five Dimensions Five Levels Endpoints .........................................................93 
10.3. 
Pharmacoeconomic Assessments ....................................................................................93 
10.3.1. Hospitalization-Related Endpoint ...................................................................................93 
11. 
STATISTICAL METHODS ...........................................................................................94 
11.1. 
General Statistical Considerations ...................................................................................94 
11.2. 
Analysis Sets ...................................................................................................................94 
11.2.1. Full Analysis Set ..............................................................................................................94 
11.2.2. Safety Analysis Set ..........................................................................................................94 
11.2.3. Per-protocol Analysis Set ................................................................................................95 
11.2.4. Pharmacokinetic Analysis Set .........................................................................................95 

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11.3. 
Study Population Data .....................................................................................................95 
11.4. 
Statistical Analysis ..........................................................................................................95 
11.4.1. Efficacy Analyses ............................................................................................................95 
11.4.1.1. Primary Efficacy Analyses ..............................................................................................95 
11.4.1.2. Secondary Efficacy Analyses ..........................................................................................96 
11.4.1.3. Exploratory Efficacy Analyses ........................................................................................97 
11.4.2. Analyses of Health Economic and Outcomes Research Endpoints ................................98 
11.4.2.1. EuroQoL Five Dimensions Five Levels ..........................................................................98 
11.4.2.2. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 and BR45 ..........................................................................................99 
11.4.2.3. Hospitalization-Related Endpoints ..................................................................................99 
11.4.3. Pharmacokinetic/Pharmacodynamic/Biomarker Analyses..............................................99 
11.4.3.1. Pharmacokinetic Analyses ...............................................................................................99 
11.4.3.2. Pharmacodynamic Analyses ..........................................................................................100 
11.4.3.3. Biomarker Analyses ......................................................................................................100 
11.4.4. Safety Analyses .............................................................................................................100 
11.4.4.1. Adverse Event Analyses ................................................................................................100 
11.4.4.2. Clinical Laboratory Evaluation Analyses ......................................................................100 
11.4.4.3. Vital Sign Analyses .......................................................................................................101 
11.4.4.4. Electrocardiogram Analyses ..........................................................................................101 
11.4.4.5. Physical Examination Analyses ....................................................................................101 
11.4.4.6. Concomitant Medication Analyses ................................................................................101 
11.4.4.7. Immunogenicity (Anti-Drug Antibody) Analyses .........................................................101 
11.4.4.8. Other Safety Analyses ...................................................................................................101 
11.5. 
Interim Analyses ............................................................................................................101 
11.6. 
Sample Size Determination ...........................................................................................103 
11.7. 
Statistical Analysis Process ...........................................................................................105 
12. 
DATA INTEGRITY AND QUALITY ASSURANCE ................................................106 
12.1. 
Monitoring and Inspections ...........................................................................................106 
12.2. 
Data Collection ..............................................................................................................106 
12.3. 
Data Management ..........................................................................................................107 
12.4. 
Study Documentation and Storage ................................................................................107 
12.5. 
Record Keeping .............................................................................................................108 

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13. 
FINANCING AND INSURANCE ................................................................................109 
13.1. 
Finances .........................................................................................................................109 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................109 
14. 
PUBLICATION POLICY .............................................................................................110 
15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................111 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance ........................................111 
15.2. 
Subject Confidentiality ..................................................................................................111 
15.3. 
Informed Consent ..........................................................................................................111 
15.4. 
Regulatory Compliance .................................................................................................112 
15.5. 
Protocol Deviations .......................................................................................................112 
15.6. 
Supply of New Information Affecting the Conduct of the Study .................................113 
15.7. 
Protocol Amendments ...................................................................................................113 
15.8. 
Study Termination .........................................................................................................114 
15.9. 
Data Monitoring Committee ..........................................................................................114 
15.10. 
Address List ...................................................................................................................114 
16. 
REFERENCES ..............................................................................................................115 
17. 
APPENDICES ...............................................................................................................118 
17.1. 
Schedule of Events ........................................................................................................118 
17.2. 
Cockcroft-Gault Equation .............................................................................................125 
17.3. 
Eastern Cooperative Oncology Group Performance Status ..........................................126 
17.4. 
Modified Response Evaluation Criteria in Solid Tumors, Version 1.1 .........................126 
17.4.1. Measurability of Tumor at Baseline ..............................................................................126 
17.4.1.1. Definitions .....................................................................................................................126 
17.4.1.2. Specifications by Methods of Measurements ................................................................127 
17.4.2. Tumor Response Evaluation ..........................................................................................128 
17.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease ..................................128 
17.4.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ..................................128 
17.4.2.3. Response Criteria ...........................................................................................................129 
17.4.2.4. Evaluation of Best Overall Response ............................................................................131 
17.4.2.5. Frequency of Tumor Re-evaluation ...............................................................................133 
17.5. 
New York Heart Association Functional Classification ...............................................134 
17.6. 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 and BR45 ........................................................................................135 

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17.6.1. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (version 3.0) ....................................................................................135 
17.6.2. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire BR45 ......................................................................................................137 
17.7. 
EuroQoL Five Dimensions Five Levels ........................................................................140 
17.8. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) ..................................143 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered ...............................143 
COVID-19 Assessment(s) ...........................................................................................................144 
 

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LIST OF TABLES 
Table 1.1: Mean Pharmacokinetic Parameters of Trastuzumab Deruxtecan (± Standard 
Deviation) ...................................................................................................................34 
Table 1.2: Mean Pharmacokinetic Parameters of Total Antibody (±Standard Deviation) ..........34 
Table 1.3: Mean Pharmacokinetic Parameters of MAAA-1181a (±Standard Deviation) ...........35 
Table 5.1: Dose Reduction Levels of Trastuzumab Deruxtecan .................................................51 
Table 5.2: Dose Reduction Levels of T-DM1 .............................................................................51 
Table 5.3: Dose Modification for Trastuzumab Deruxtecan .......................................................52 
Table 8.1: Blood Sampling for Pharmacokinetic Analysis ..........................................................78 
Table 11.1: Efficacy Stopping Boundaries for PFS/OS Interim and Final Analyses ..................103 
Table 11.2: Probability of Study Outcomes Under Various True Hazard Ratios ........................104 
Table 17.1: Schedule of Events – Tissue Screening and Screening Period .................................119 
Table 17.2: Schedule of Events – Treatment and Follow-up Period ...........................................121 
Table 17.3: Eastern Cooperative Oncology Group Performance Status Scale ............................126 
Table 17.4: Overall Response: Subjects with Target (+/–Non-target) Disease ...........................132 
Table 17.5: New York Heart Association Functional Classification ...........................................134 
 

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LIST OF FIGURES 
Figure 3.1: Study Design Schema .................................................................................................41 
 

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LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee 
ADA 
anti-drug antibody(ies) 
ADC  
antibody drug conjugate  
ADCC 
antibody-dependent cellular cytotoxic 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC0-21d 
area under the concentration-time curve from time 0 to 21 days 
AUC∞ 
area under the concentration-time curve from 0 extrapolated to infinity 
BI 
before infusion  
BICR 
blinded independent central review 
CBR 
clinical benefit rate 
cfDNA 
cell free deoxyribonucleic acid 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum plasma/serum concentration 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DAE 
discontinuation due to adverse event 
DCR 
disease control rate 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DoR 
duration of response  

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ABBREVIATION 
DEFINITION 
EC 
Ethics Committee 
ECD 
extracellular domain 
ECG 
electrocardiogram 
Echo 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EIU 
exposure in utero  
EOI 
end of infusion 
EORTC QLQ 
European Organization for Research and Treatment of Cancer quality of life 
questionnaire(s) 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQol-5 dimensions-5 levels of severity 
FAS 
Full Analysis Set 
GCP 
Good Clinical Practice  
HCV 
hepatitis C virus 
HEOR 
health economics and outcomes research  
HER2 
human epidermal growth factor receptor 2 
HER2ECD 
HER2 extracellular domain 
HIV 
human immunodeficiency virus 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation  
ICU 
intensive care unit 
ILD 
interstitial lung disease 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
IXRS 
Interactive Web/Voice Response System 
LVEF 
left ventricular ejection fraction 
Lyo-DP 
lyophilized powder 

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ABBREVIATION 
DEFINITION 
mAb 
monoclonal antibody 
mBC 
metastatic breast cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MUGA 
multigated acquisition (scan) 
NAB 
Neutralizing anti-drug antibody 
NCI 
National Cancer Institute 
NSAIDs 
nonsteroidal anti-inflammatory drugs 
OATP 
organic anion transporting polypeptide 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PD 
progressive disease 
PFS 
progression-free survival 
PFS2 
Progression-free survival on the next line of therapy 
PK 
pharmacokinetic 
pop-PK 
population pharmacokinetic 
PPS 
Per-protocol Analysis Set 
PR 
partial response 
PRO 
patient reported outcome 
PT 
preferred term 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
QT intervals corrected for heart rate by Fridericia’s formula 
RT-PCR 
real-time polymerase chain reaction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAVER 
Serious Adverse Event Report 
SD 
stable disease 
SID 
subject identification 

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ABBREVIATION 
DEFINITION 
SMQ 
Standardised MedDRA Query 
SOC 
system organ class 
SOP 
Standard Operating Procedure 
SpO2 
peripheral oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
t½  
terminal elimination half-life 
T-DM1 
ado-trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum plasma/serum concentration (Cmax) 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analogue scale 
Vss 
volume of distribution at steady state 

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1. 
INTRODUCTION 
1.1. 
Background 
Breast cancer remains the most common cancer and the second leading cause of cancer mortality 
in women both in the United States (US) and globally. In 2015, there were 2.4 million new 
cancer cases leading to 523,000 deaths worldwide. Breast cancer was also the leading cause of 
morbidity in women, resulting in an estimated burden of 15.1 million disability-adjusted life 
years.1  
In approximately 20% of breast cancer cases, overexpression of human epidermal growth factor 
receptor 2 (HER2) occurs.2 Compared to HER2-negative breast cancer, these HER2-positive 
breast cancers have historically been associated with more aggressive disease and worse 
outcomes. Although anti-HER2 targeted therapies have improved outcomes, they are not 
curative in the metastatic setting. Based on results of the CLEOPATRA study, current guidelines 
recommend the regimen of trastuzumab/pertuzumab/taxane for first line therapy for 
HER2-positive disease.3 The only anti-HER2 agent specifically approved for second line therapy 
is ado-trastuzumab emtansine (T-DM1). 
T-DM1 obtained approval based on the results of the EMILIA study in which T-DM1 was 
compared with the combination of lapatinib and capecitabine for the treatment of patients who 
had progressed after treatment with the combination of trastuzumab and taxane chemotherapy.4 
It is important to note that this study was conducted prior to the introduction of pertuzumab to 
first line therapy. Although the mechanism remains unclear, there is a suggestion that response 
rates to second line T-DM1 are lower when given after pertuzumab-containing regimens.5  
Trastuzumab deruxtecan is an antibody drug conjugate (ADC) composed of an anti-HER2 
antibody conjugated to a drug-linker carrying a topoisomerase I payload. Trastuzumab 
deruxtecan was studied in the Phase 1 DS8201-A-J101 study in HER2-expressing solid tumors 
and the DS8201-A-U201 study in HER2-positive metastatic breast cancer previously treated 
with T-DM1. Based on the results of these studies, trastuzumab deruxtecan (Enhertu®) obtained 
accelerated approval in the US on 20 December 2019 for the treatment of adults with 
unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior 
anti-HER2-based regimens in the metastatic setting based on the results of Study 
DS8201-A-U201. On 25 March 2020, trastuzumab deruxtecan (Enhertu) on second use, obtained 
approval under the conditional early approval system in Japan for the treatment of patients with 
HER2-positive unresectable or recurrent breast cancer after prior chemotherapy (limit the use to 
patients who are refractory or intolerant to standard treatments). 
1.1.1. 
Investigational Product 
1.1.1.1. 
Name 
Trastuzumab deruxtecan (DS-8201a)  
1.1.1.2. 
Description 
Trastuzumab deruxtecan consists of an antibody component, MAAL-9001, covalently 
conjugated via a maleimide tetrapeptide linker, to a drug component MAAA-1181a. 

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MAAL-9001 is an in-house humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) 
with the same amino acid sequence as trastuzumab. MAAA-1181a, an exatecan derivative, is a 
topoisomerase I inhibitor that is cell membrane permeable and more potent than SN-38 (the 
active metabolite of irinotecan).6,7,8 This ADC achieves a high drug-to-antibody ratio 
(approximately 8) with homogeneous conjugation with MAAA-1181a.9 After binding to HER2 
and internalization, trastuzumab deruxtecan is cleaved by lysosomal enzymes and releases 
MAAA-1181a in the cytoplasm.  
The lyophilized powder (Lyo-DP) form of trastuzumab deruxtecan will be administered in this 
study. 
The trastuzumab deruxtecan Phase 1 clinical study DS8201-A-J101 was initiated with the 
antibody component, MAAL-9001, produced using the Chinese hamster ovary (CHO)-
 cell 
line (FL-DP1). To support new clinical studies, as well as commercial development, transition 
was made to MAAL-9001 production using a CHO
cell line (FL-DP2). Analytic comparison 
of the 2 cell line products has shown comparability across a wide range of variables. Minor 
differences have been observed in glycan profile, charge variants, size variants, FcgRIIIA 
binding, FcRn binding, and antibody-dependent cellular cytotoxic (ADCC) activity. Following 
single intravenous (IV) administration of trastuzumab deruxtecan to cynomolgus monkeys, mean 
maximum plasma/serum concentration (Cmax) of trastuzumab deruxtecan was similar, while the 
area under the concentration-time curve (AUC) was about 22% lower for FL-DP2 material as 
compared to FL-DP1 material. However, in a xenograft study, no difference was seen in 
cytotoxicity between the 2 products.  
1.1.1.3. 
Intended Use Under Investigation 
This study will compare the efficacy and safety of trastuzumab deruxtecan versus T-DM1 in 
subjects with HER2-positive, unresectable and/or metastatic breast cancer (mBC) previously 
treated with trastuzumab and taxane. 
1.1.1.4. 
Comparator (T-DM1) 
T-DM1 is a HER2-targeted antibody and microtubule inhibitor conjugate indicated, as a single 
agent, for the treatment of patients with HER2-positive mBC who previously received 
trastuzumab and a taxane, separately or in combination. T-DM1 is described in the approved 
regulatory documents in each respective country. 
1.1.1.5. 
Nonclinical Studies of Trastuzumab Deruxtecan 
The pharmacology, safety pharmacology, pharmacokinetics (PK), and toxicology of trastuzumab 
deruxtecan have been examined in nonclinical studies. For details of these experiments, please 
see the latest version of the Investigator’s Brochure (IB).10  
1.1.1.6. 
Clinical Experience 
As of 08 Jun 2019, trastuzumab deruxtecan has been evaluated in 12 company-sponsored clinical 
studies (11 monotherapy studies and 1 combination therapy study), with an estimated 
1036 subjects exposed to at least 1 dose of trastuzumab deruxtecan. 10  Three studies are 
complete (have finalized clinical study reports presenting the results for the study primary 
CCI
CCI

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objective), and 9 studies are ongoing. 10For updated results, please refer to the latest version of 
the IB.10 
The trastuzumab deruxtecan study, Protocol DS8201-A-U201, is a 2-part, open-label, 
single-group, multicenter, phase 2 study in adults with pathologically documented 
HER2-positive metastatic breast cancer who had received previous treatment with trastuzumab 
emtansine.  In the first part of the study, 3 different doses of trastuzumab deruxtecan were 
evaluated to establish a recommended dose and in the second part of the study, efficacy and 
safety were evaluated at the recommended dose of 5.4 mg/kg.   
Results as of 01 August 2019 were reported in The New England Journal of Medicine. 11  
Among the 184 subjects who received trastuzumab deruxtecan at the recommended dose of 
5.4 mg/kg, the BICR confirmed response rate was 60.9% (95% CI: 53.4, 68.0); of these subjects, 
6.0% had a complete response, and 54.9% had a partial response. 11  The disease control rate was 
97.3% (95% CI: 93.8, 99.1). 11  The median time to response was 1.6 months (95% CI: 1.4, 2.6) 
and the median duration of response was 14.8 months (95% CI: 13.8, 16.9). 11  The median PFS 
was 16.4 months (95% CI: 12.7, not reached). 11  Estimated OS was 93.9% (95% CI: 89.3, 96.6) 
at 6 months and 86.2% (95% CI: 79.8, 90.7) at 12 months; the median overall survival was not 
reached. 11 
As of 01 August 2019, among 184 subjects who received 5.4 mg/kg trastuzumab deruxtecan, 
99.5% had at least one AE and 57.1% had an AE of grade 3 or higher. 11  The most common 
grade 3 or higher AEs were neutrophil count decreased (20.7%), anemia (8.7%), nausea (7.6%), 
white blood cell count decreased (6.5%), lymphocyte count decreased (6.5%), and fatigue 
(6.0%).11  AEs led to dose interruption in 35.3%, dose reduction in 23.4%, and dose 
discontinuation in 15.2% of subjects.11  A total of 25 deaths were reported, including 7 that 
occurred during treatment as a result of either disease progression (in 3 subjects) or adverse 
events (hemorrhagic shock, general physical health deterioration, pneumonia, and acute organ 
failure in 1 subject each). 11  During survival follow-up (which was defined as 47 days after the 
end of treatment), 18 of the 25 deaths occurred, 2 of which were caused by events associated 
with interstitial lung disease (ILD) that started during treatment; the remaining 16 deaths were 
considered by investigators to be unrelated to trastuzumab deruxtecan. 11 For further details 
related to the efficacy and safety of trastuzumab deruxtecan reported from clinical studies, please 
see the latest version of the IB.10 
1.1.1.7. 
Summary of Clinical Pharmacokinetics 
Pharmacokinetics were evaluated in 24 subjects who received trastuzumab deruxtecan. 
Following a single IV administration, the systemic exposure increased approximately in 
proportion to the dose. The PK parameters at 5.4, 6.4, and 8.0 mg/kg are shown in Table 1.1. The 
Cmax of trastuzumab deruxtecan at 6.4 mg/kg was achieved with a median time to Cmax (Tmax) of 
2.16 hours. The Cmax and AUC from time 0 to 21 d (AUC0-21d) at 6.4 mg/kg were 181 μg/mL and 
901 μg•d/mL, respectively (Table 1.1). The systemic exposure at 6.4 mg/kg in subjects in Cycle 
1 was observed to exceed the systemic efficacious exposure observed during the nonclinical 
pharmacology evaluation. At this dose, the mean terminal elimination half-life (t½) of 
trastuzumab deruxtecan was 7.33 d at 6.4 mg/kg, and the volume of distribution at steady state 
(Vss) was 58.6 mL/kg which is similar to the serum volume. 

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The PK parameters of total antibody were close to that of trastuzumab deruxtecan (Table 1.2). 
The Cmax and AUC for the dosing interval (AUC0-21d) of MAAA-1181a, which were quite low, 
were 6.80 ng/mL and 31.0 ng•d/mL at 6.4 mg/kg, respectively (Table 1.3). The t½ of 
MAAA-1181a was similar to that of trastuzumab deruxtecan. 
Table 1.1: 
Mean Pharmacokinetic Parameters of Trastuzumab Deruxtecan (± Standard 
Deviation) 
Dose 
(mg/kg) 
Cmax 
(g/mL) 
 
Tmax 
(h) 
Median 
(range) 
AUC0-21d 
(μgd/mL) 
 
AUC∞ 
(μgd/mL) 
 
t½ 
(d) 
 
CL 
(mL/d/kg) 
 
Vss 
(mL/kg) 
 
5.4 
(N=6) 
127 ± 17.2 
1.92 
(1.92, 2.16) 
544 ± 165 
590 ± 186 
6.03 ± 0.603 
10.1 ± 3.90 
75.2 ± 24.2 
6.4 
(N=6) 
181 ± 33.1 
2.16 
(1.44, 4.08) 
901 ± 155 
1030 ± 209 
7.33 ± 1.64 
6.41 ± 1.12 
58.6 ± 11.0 
8.0 
(N=3) 
216 ± 52.0 
1.92 
(1.92, 2.16) 
914 ± 235 
1020 ± 279 
6.97 ± 0.357 
8.17 ± 1.93 
69.7 ± 13.1 
AUC = area under the concentration-time curve; AUC0-21d = AUC from the time 0 to 21 d; AUC∞ = AUC from 0 
extrapolated to infinity; CL = clearance; Cmax = maximum plasma/serum concentration; d = day, N = number of 
evaluable subjects; t½ = terminal elimination half-life; Tmax = time to Cmax; Vss = volume of distribution at steady 
state. 
Table 1.2: 
Mean Pharmacokinetic Parameters of Total Antibody (±Standard Deviation) 
Trastuzumab 
Deruxtecan Dose 
(mg/kg) 
Cmax (μg/mL) 
 
Tmax (h) 
Median (range) 
AUC0-21d 
(μgd/mL) 
 
AUC∞ 
(μgd/mL) 
 
t½ (d) 
 
5.4 
(N=6) 
116 ± 13.9 
1.92  
(1.92, 6.96) 
609 ±151 
682 ± 172 
6.78 ± 2.39 
6.4 
(N=6) 
146 ± 18.9 
3.84  
(2.16, 6.96) 
878 ± 97.1 
1050 ± 149 
8.25 ± 2.16 
8.0 
(N=3) 
178 ± 18.5 
2.16  
(1.92, 6.72) 
1090 ± 213 
1270 ± 296 
7.35 ± 0.417 
AUC = area under the concentration-time curve; AUC0-21d = AUC from the time 0 to 21 d; AUC∞ = AUC from 0 
extrapolated to infinity; Cmax = maximum plasma/serum concentration; d = day; N = number of evaluable subjects; 
t½ = terminal elimination half-life; Tmax = time to Cmax. 

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Table 1.3: 
Mean Pharmacokinetic Parameters of MAAA-1181a (±Standard Deviation) 
Trastuzumab 
Deruxtecan Dose 
(mg/kg) 
Cmax (ng/mL) 
Tmax (h) 
median (range) 
AUC0-21 d 
(ngd/mL) 
AUC∞ 
(ngd/mL) 
t½ (d) 
5.4  
(N=6) 
10.8 ± 7.56 
5.28 
(3.84, 23.76) 
40.6 ± 19.8 
43.6 ± 21.2 
6.11 ± 0.811 
6.4  
(N=6) 
6.80 ± 1.72 
6.72 
(4.08, 7.20) 
31.0 ± 5.11 
34.2 ± 5.63 
6.28 ± 1.17 
8.0  
(N=3) 
9.25 ± 3.18 
6.72 
(6.72, 6.96) 
39.4 ± 6.43 
43.4 ± 9.16 
6.36 ± 1.53 
AUC = area under the concentration-time curve; AUC0-21d = AUC from time 0 to 21 d; AUC∞= AUC from 0 
extrapolated to infinity; Cmax = maximum plasma/serum concentration; d = day; N = number of evaluable subjects; 
t½ = terminal elimination half-life; Tmax = time to Cmax. 
1.2. 
Study Rationale 
A member of the HER superfamily, HER2 initiates signal transduction via the PI3K/Akt and 
RAS/MAPK pathways.12,13 In human advanced solid tumors, expression of HER2 protein has 
been reported in various tumor tissues and a variety of cultured tumor cell lines including breast 
cancer,13,14 gastric cancer,15,16 pancreatic cancer,17 lung cancer,18 colorectal cancer,19 and ovarian 
cancer.20 There are also many reports demonstrating an association between expression of HER2 
protein and poor clinical prognosis. In normal human tissue, low expression of HER2 protein has 
been reported on cell membranes of epithelial cells in the gastrointestinal, respiratory, 
reproductive, and urinary tract as well as in the skin, breast, and placenta.21 
The current first line standard of care for HER2-positive mBC, with the addition of pertuzumab 
to trastuzumab and chemotherapy, was established based on results of the CLEOPATRA study. 
Like trastuzumab, pertuzumab is a humanized mAb that binds HER2 at a separate epitope in the 
extracellular domain. In addition to ADCC activity, pertuzumab adds a novel mechanism of 
action by inhibiting dimerization of HER2, a process thought to be important for HER2 
activation. The CLEOPATRA study randomized subjects to receive trastuzumab plus docetaxel 
with or without the addition of pertuzumab as first line therapy for metastatic HER2-positive 
breast cancer. The addition of pertuzumab improved median progression-free survival (PFS) 
from 12.4 to 18.5 mo and median overall survival (OS) from 40.8 to 56.5 mo, leading to a new 
standard of care for patients with mBC who have not received prior anti-HER2 therapy or 
chemotherapy for metastatic disease.5  
In the setting of HER2-positive breast cancer following treatment with a trastuzumab containing 
regimen, the EMILIA study established T-DM1 as the standard for subsequent anti-HER2 
therapy. T-DM1 is an ADC linking the trastuzumab antibody to emtansine, a tubulin inhibitor. In 
the EMILIA study, T-DM1 was compared with the combination of lapatinib and capecitabine for 
the treatment of subjects who had progressed after treatment with a trastuzumab and taxane 
combination. In this study, T-DM1 improved median PFS from 6.4 to 9.6 mo and median OS 
from 25.1 to 30.9 mo.22 It is important to note that this study was conducted prior to the 
introduction of pertuzumab to first line therapy. 

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In contrast to T-DM1, trastuzumab deruxtecan is a HER2-targeting ADC with a high 
drug-to-antibody ratio (7 to 8), and a novel topoisomerase I inhibitor as payload. Trastuzumab 
deruxtecan is expected to inhibit tumor growth on the basis of the following reasons: like 
trastuzumab, it induces ADCC activities and inhibits Akt phosphorylation when it binds to 
HER2; and the MAAA-1181a that is released from trastuzumab deruxtecan after the 
internalization induces apoptosis by inhibiting topoisomerase I. Nonclinical evidence 
demonstrates that the HER2 targeting of trastuzumab deruxtecan is highly specific. In 
nonclinical models, trastuzumab deruxtecan showed a much broader antitumor spectrum than 
T-DM1, including efficacy against T-DM1 resistant and HER2 low-expressing tumors. In vivo 
studies using a tumor-bearing mouse model suggest that administration of trastuzumab 
deruxtecan results in the regression of HER2-positive tumors. 
In the Phase 1 clinical study DS8201-A-J101, preliminary results from HER2-positive breast 
cancer subjects pretreated with T-DM1 showed that almost all subjects experienced tumor 
shrinkage and durable treatment duration. Subjects evaluable for confirmed responses (at least 
2 post-baseline scans, total n=33) showed ORR of 60.6% (20 of 33). The current Kaplan-Meier 
estimate for median PFS reaches 10.4 mo (95% confidence interval [CI]: 32.1, not applicable). 
In the combined Part 1 and Part 2 population of HER2-positive breast cancer subjects who 
received pertuzumab pretreatment (a subset of the T-DM1 treated population), an ORR of 60.0% 
(total of 18 responders out of 30 subjects in Part 1 and Part 2) and a DCR of 96.7% was 
observed. Of 7 subjects with a minimum of 2 post-baseline scans who did not have prior 
pertuzumab therapy, 4 (57.1%) achieved PR when treated with trastuzumab deruxtecan 
suggesting that trastuzumab deruxtecan maintains efficacy in this patient population. In addition, 
the response rate does not seem to differ between this patient population and those who received 
prior pertuzumab (57.1% vs. 62.0%). 
DS8201-A-U302 is designed to compare trastuzumab deruxtecan versus T-DM1 in the same line 
of therapy for which T-DM1 was approved. 
1.3. 
Risks and Benefits for Study Subjects 
Trastuzumab deruxtecan is under development for the treatment of HER2-expressing cancers 
and HER2-mutant tumors.  The DS8201-A-U201 study was initiated based on preliminary 
clinical observations in the Phase 1 study (DS8201-A-J101) (see Section 1.1.1.6).  In this study, 
trastuzumab deruxtecan demonstrates antitumor activity in HER2 expressing cancers including 
breast cancer and gastric cancer.  
As of 01 Feb 2019, from the ongoing DS8201-A-J101 study, the overall efficacy results in 
subjects with HER2-positive breast cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed 
ORR by Independent Committee Review (ICR) of 52.5%.  Among the subjects with HER2-low 
breast cancer, confirmed ORR by ICR was 37.0%.  The overall efficacy results in subjects with 
HER2-positive gastric/gastroesophageal junction cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated 
a confirmed ORR by ICR of 29.5%.  The overall efficacy results in subjects with other cancers 
demonstrated a confirmed ORR by ICR of 29.5%.  
As of 08 Jun 2019, based on the cumulative review of the safety data, including available 
nonclinical, clinical, and epidemiologic information and scientific literature (published and 
unpublished) and taking into consideration biological plausibility, ILD, anemia, neutrophil count 
decrease including febrile neutropenia, and platelet count decrease are classified as important 

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identified risks.  LVEF decrease is classified as an important potential risk.  Infusion related 
reactions, which were previously classified as an important potential risk, are reclassified as an 
identified risk.  QT prolongation is no longer considered an important potential risk and has been 
removed from the list of safety concerns for trastuzumab deruxtecan. 
In the trastuzumab deruxtecan clinical program, the inclusion/exclusion criteria and 
monitoring/management guidelines are currently in place in all protocols to mitigate the 
important identified risks of ILD, anemia, neutrophil count decrease including febrile 
neutropenia, and platelet count decrease, and important potential risk of LVEF decrease.  
ILD is a known serious risk of trastuzumab deruxtecan, and cases with fatal outcomes have been 
reported.  Most events were Grade 1 or Grade 2 and were manageable by dose modification and 
following clinical treatment guidelines for drug-induced ILD, with specific recommendations 
including close monitoring of signs/symptoms of ILD (eg, cough, fever, and dyspnea) to identify 
potential ILD and proactively managing ILD with dose modification and treatment (eg, steroids).  
ILD requires proper monitoring, dose modification, and supportive care instituted in a timely 
fashion.  
Other identified risks of trastuzumab deruxtecan in order of descending frequencies are nausea, 
decreased appetite, alopecia, vomiting, fatigue, constipation, diarrhoea, WBC count decrease, 
stomatitis, aspartate aminotransferase increased, cough, headache, abdominal pain, alanine 
aminotransferase increased, hypokalaemia, epistaxis, dyspnoea, dyspepsia, dizziness, dry eye, 
upper respiratory tract infection, asthenia, and infusion related reactions.   
These identified risks were generally manageable through dose modification and routine clinical 
practice.   
Trastuzumab deruxtecan has demonstrated a generally acceptable safety profile in the treated 
populations.  
In conclusion, given the data available on the efficacy and safety of trastuzumab deruxtecan, the 
overall benefit/risk remains positive for clinical development. 
For current assessments of risks and benefits to subjects, please refer to the current IB for 
trastuzumab deruxtecan.10 

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2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
The primary objective is to compare the PFS benefit of trastuzumab deruxtecan to T-DM1 for 
HER2-positive, unresectable and/or metastatic breast cancer subjects previously treated with 
trastuzumab and taxane. 
2.1.2. 
Key Secondary Objective 
The secondary objective is to compare the OS benefit of trastuzumab deruxtecan to T-DM1. 
2.1.3. 
Other Secondary Objectives 
Other secondary objectives are: 
 To evaluate efficacy of trastuzumab deruxtecan compared to T-DM1 on: 
 Confirmed ORR; 
 DoR. 
 To further determine PK of trastuzumab deruxtecan; 
 To further evaluate safety of trastuzumab deruxtecan compared to T-DM1; 
 To evaluate Health Economic and Outcomes Research (HEOR) endpoints for 
trastuzumab deruxtecan compared to T-DM1. 
2.1.4. 
Exploratory Objectives 
The exploratory objectives are: 
 To evaluate efficacy of trastuzumab deruxtecan compared to T-DM1 by clinical 
benefit rate (CBR) and progression-free survival on the next line of therapy (PFS2). 
 To evaluate potential biomarkers of response/resistance (eg, serum 
HER2-extracellular domain [HER2ECD]). 
 To evaluate exposure-response relationships for efficacy and safety endpoints. 
2.2. 
Study Hypothesis 
Trastuzumab deruxtecan confers a significant benefit in PFS compared with T-DM1 in 
HER2-positive breast cancer patients who have previously received trastuzumab and taxane. 
2.3. 
Study Endpoints 
The efficacy endpoints will be based on central assessments unless otherwise stated. 

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2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS as determined by blinded independent central review 
(BICR).  
2.3.2. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is OS. 
2.3.3. 
Other Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
 ORR based on BICR and investigator assessment (confirmation of complete response 
[CR]/partial response [PR] is required) 
 DoR based on BICR  
 PFS based on investigator assessment 
2.3.4. 
Exploratory Efficacy Endpoints  
The exploratory efficacy endpoints are: 
 Time to response based on BICR  
 Best percent change in the sum of the diameter of measurable tumors based on BICR  
 CBR based on BICR  
 PFS2 based on investigator assessment  
2.3.5. 
Health Economic and Outcomes Research Endpoints 
The HEOR endpoints include: 
 European Organization for Research and Treatment of Cancer (EORTC) quality of 
life questionnaire (QLQ)-C30 
 EORTC QLQ-BR45 
 EuroQol-5 dimensions-5 levels of severity (EQ-5D-5L) 
 Hospitalization-related endpoints 
2.3.6. 
Pharmacokinetic/Biomarker Endpoints 
2.3.6.1. 
Pharmacokinetic Endpoints 
The PK endpoints include:  
 Serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody, and 
MAAA-1181a 

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2.3.6.2. 
Biomarker Endpoints 
The biomarker endpoints include: 
 Serum biomarkers (eg, HER2ECD)  
 Other potential biomarkers (eg, cell free deoxyribonucleic acid [cfDNA], RNA 
profiling) 
2.3.7. 
Safety Endpoints 
The safety endpoints include: 
 Serious adverse events (SAEs)  
 TEAEs  
 Adverse events of special interest (AESIs) 
 TEAEs associated with discontinuation of study treatment 
 Physical examination findings (including Eastern Cooperative Oncology Group 
Performance Status [ECOG PS])  
 Vital sign measurements 
 Standard clinical laboratory parameters  
 Electrocardiogram (ECG) parameters  
 Echocardiogram (Echo)/multigated acquisition scan (MUGA) findings  
 Anti-drug antibodies (ADA) 

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3. 
STUDY DESIGN 
3.1. 
Overall Design 
This is a randomized, 2-arm, Phase 3, open-label, multicenter study designed to compare the 
safety and efficacy of trastuzumab deruxtecan versus T-DM1 in HER2-positive, unresectable 
and/or metastatic breast cancer subjects previously treated with trastuzumab and taxane. 
Figure 3.1 shows the study design. 
Trastuzumab deruxtecan for injection, 100 mg, will be administered IV at a starting dose of 
5.4 mg/kg.  
Randomization will be stratified by: 
 Hormone receptor status (positive, negative) 
 Prior treatment with pertuzumab (yes, no) 
 History of visceral disease (yes, no) 
For subjects randomized to T-DM1, the treatment will be in accordance to the approved label. 
The study treatment will be continued according to the dosing criteria in the absence of 
withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity (see 
Section 5.9). If the study treatment is delayed more than 28 d from the planned date of 
administration, the subject will be withdrawn from study treatment. 
History of past treatment with pertuzumab will be collected for all study subjects. 
Figure 3.1: 
Study Design Schema 
 
BC = breast cancer; HER2 = human epidermal growth factor receptor 2; T-DM1 = ado-trastuzumab emtansine. 
3.1.1. 
Duration of the Study 
Enrollment is planned to occur over approximately 22 mo. The end of the study 
hypothesis-testing period is the date when approximately 250 OS events have been observed. 
The total anticipated duration of the study is approximately 51 mo. 
The study team will monitor number of PFS events. The study statistician will make projections 
of the data cutoff date for PFS analysis, first quarterly and then monthly. The projection date will 
be made at a time when the number of reported PFS events is 90% or less of the planned 

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required number of events. PFS analysis will use all events accrued on or before the cutoff date. 
All data before or on the cutoff date will be used for analysis. Similar projections on data cutoff 
date will be performed for the OS analysis (as needed), and all data up to the data cutoff date will 
be used for OS analysis. 
For each subject there will be a 40-Day (+ 7 d) Follow-up after the last study treatment 
administration or before starting new anticancer treatment, whichever comes first, followed by 
Long-term/Survival Follow-up every 3 mo (± 14 d) from the date of 40-Day (+ 7 d) Follow-up, 
until death, withdrawal of consent, loss to follow-up, or study closure, whichever occurs first.  
The Sponsor may terminate the study at any time and study termination may also be requested by 
(a) competent authority(ies). 
3.1.2. 
Duration of Subject Participation 
The Screening period is up to 28 d. Each cycle of treatment will be 21 d. The number of 
treatment cycles with trastuzumab deruxtecan is not fixed. Upon commencing study treatment, 
subjects may continue receiving study treatment until the occurrence of any of the events defined 
in Section 5.9.1. 
After study treatment discontinuation, all subjects may be contacted every 3 mo until death or 
until follow-up data collection is no longer of scientific value or otherwise needed (at the 
Sponsor’s discretion), to obtain information about subsequent treatment(s) and survival status 
(Section 5.9.2). 
3.1.3. 
Definition of the End of the Study 
The end of the study hypothesis-testing period is defined as the date when approximately 250 OS 
events have been observed. The study closure is defined as the date when the last subject 
discontinues study treatment and applicable follow-up occurs, or the study is ended by the 
Sponsor. 
3.2. 
Discussion of Study Design 
This study will be conducted in approximately 175 study sites including but not limited to: North 
America, Asia, and Europe. 
The target sample size will be approximately 500 subjects, randomized in a 1:1 ratio into 
2 treatment groups (trastuzumab deruxtecan versus T-DM1). 

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4. 
STUDY POPULATION 
Each subject will sign Study Informed Consent Form(s) (ICF) provided by the site. A subject is 
considered enrolled in the study upon the investigator or designee obtaining written informed 
consent from the subject (Section 15.3) at the time of Screening and upon determination that all 
inclusion and exclusion criteria have been satisfied. 
Investigators will maintain a confidential Screening Log of all potential study candidates that 
includes limited subject information and outcome of Screening process (ie, enrollment in the 
study, reason for ineligibility, withdrew consent). 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification (SID) code list. This confidential 
list of the names of all subjects, allocated study numbers on enrolling in the study, allows the 
investigator to reveal the identity of any subject when necessary. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study:  
1. Must be competent and able to comprehend, sign, and date an Institutional Review Board 
(IRB) or Ethics Committee (EC) approved ICF before performance of any study-specific 
procedures or tests. 
2. Adults ≥18 y old. (Please follow local regulatory requirements if the legal age of consent 
for study participation is >18 y old.) 
3. Pathologically documented breast cancer that: 
a. is unresectable or metastatic. 
b. has confirmed HER2-positive expression as determined according to American 
Society of Clinical Oncology – College of American Pathologists guidelines 
evaluated at a central laboratory.23 
c. was previously treated with trastuzumab and taxane in the advanced/ metastatic 
setting or progressed within 6 mo after neoadjuvant or adjuvant treatment involving a 
regimen including trastuzumab and taxane. 
4. Documented radiologic progression (during or after most recent treatment or within 6 mo 
after completing adjuvant therapy). 
5. Subjects must be HER2-positive as confirmed by central laboratory assessment of most 
recent tumor tissue sample available. If archived tissue is not available, a fresh biopsy is 
required.   
6. Presence of at least 1 measurable lesion per modified Response Evaluation Criteria in 
Solid Tumors (mRECIST) version 1.1 (see Section 17.4).24 
a. Brain lesions will be considered as non-target lesions only. 
7. ECOG PS 0 or 1. 

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8. Adequate bone marrow function, within 14 d before randomization, defined as: 
 Absolute neutrophil count ≥ 1.5 × 109/L (granulocyte colony-stimulating factor 
administration is not allowed within 1 wk prior to Screening assessment); 
 Platelet count ≥ 100 × 109/L (Platelet transfusion is not allowed within 1 wk prior to 
Screening assessment); 
 Hemoglobin level ≥ 9.0 g/dL (Red blood cell transfusion is not allowed within 1 wk 
prior to Screening assessment). 
9. Adequate renal function within 14 d before randomization, defined as: 
 Creatinine clearance ≥ 30 mL/min, as calculated using the Cockcroft-Gault equation 
(CLcr (mL/min) =  
[140 - age (years)] × weight (kg)
72 × serum creatinine (mg/dL)   {× 0.85 for females}; Section 17.2). 
10. Adequate hepatic function within 14 d before randomization, defined as: 
 Total bilirubin ≤ 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 metastases at baseline, and 
 Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 3 × ULN 
11. Adequate blood clotting function within 14 d before randomization, defined as: 
 International normalized ratio/prothrombin time ≤ 1.5 × ULN and either partial 
thromboplastin or activated partial thromboplastin time ≤ 1.5 × ULN 
12. Female subjects of reproductive/childbearing potential must agree to use a highly 
effective form of contraception or avoid intercourse during and upon completion of the 
study and for at least 7 mo after the last dose of trastuzumab deruxtecan and 7 mo after 
the last dose of T-DM1. Male subjects must agree to inform all potential female partners 
that they are participating in a clinical trial of a drug that may cause birth defects. Male 
subjects must also agree to either avoid intercourse or that they and/or any female 
partners of reproductive/childbearing potential will use a highly effective form of 
contraception during and upon completion of the study and for at least 4.5 mo after the 
last dose of trastuzumab deruxtecan or 4 mo after the last dose of T-DM1. Methods 
considered as highly effective methods of contraception include:  
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 

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 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence defined as refraining from heterosexual intercourse 
during and upon completion of the study and for at least 7 mo for female subjects 
(4.5 mo for male subjects)after the last dose of trastuzumab deruxtecan or 7 mo after 
the last dose of T-DM1. True abstinence must be in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (calendar, symptothermal, postovulation 
methods) is not an acceptable method of contraception. 
Non-childbearing potential is defined as pre-menopausal females with a documented 
tubal ligation or hysterectomy; or postmenopausal defined as 12 mo of spontaneous 
amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating 
hormone > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use 1 of the contraception methods outlined for women of 
childbearing potential if they wish to continue their HRT during the study. Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status prior to study 
enrollment. For most forms of HRT, at least 2 to 4 wk will elapse between the cessation 
of therapy and the blood draw; this interval depends on the type and dosage of HRT. 
Following confirmation of their postmenopausal status, they can resume use of HRT 
during the study without use of a contraceptive method. 
13. Male subjects must not freeze or donate sperm throughout the study period beginning at 
Cycle 1 Day 1 and for at least 4.5 mo after the last dose of trastuzumab deruxtecan or 
4 mo after the last dose of T-DM1. Preservation of sperm should be considered prior to 
enrollment in this study. 
14. Female subjects must not donate ova or retrieve them for their own use from the time of 
Screening and throughout the study treatment period, and for at least 7 mo after the last 
dose of trastuzumab deruxtecan or 7 mo after the last dose of T-DM1. 
15. Has adequate treatment washout period before randomization/enrollment, defined as 
chloroquine/hydroxychloroquine >14 days 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Prior treatment with an anti-HER2 ADC (such as T-DM1) in the metastatic setting. Prior 
treatment in the adjuvant/neoadjuvant setting would be allowed if progression of disease 
did not occur within 12 mo of end of adjuvant therapy. 
2. Uncontrolled or significant cardiovascular disease, including any of the following: 
a. History of myocardial infarction within 6 mo before randomization;  

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b. History of symptomatic congestive heart failure (New York Heart Association Class 
II to IV); 
c. Troponin levels consistent with myocardial infarction as defined according to the 
manufacturer within 28 d prior to randomization;  
d. Corrected QT interval (QTc) prolongation to > 470 ms (females) or >450 ms (male) 
based on average of Screening triplicate 12-lead ECG;  
e. LVEF < 50% within 28 d prior to randomization 
3. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
Screening. 
4. Spinal cord compression or clinically active central nervous system (CNS) metastases, 
defined as untreated or symptomatic, or requiring therapy with corticosteroids or 
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 wk must have elapsed between the end of whole brain radiotherapy 
and study enrollment. 
5. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
6. History of severe hypersensitivity reactions to other mAbs.  
7. Substance abuse or medical conditions such as clinically significant cardiac or pulmonary 
diseases or psychological conditions, that may, in the opinion of the investigator, 
interfere with the subject’s participation in the clinical study or evaluation of the clinical 
study results. 
8. Social, familial, or geographical factors that would interfere with study participation or 
follow-up. 
9. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.  
10. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C 
infection.  Subjects positive for hepatitis C (HCV) antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. Subjects should be tested for HIV 
prior to randomization if required by local regulations or IRB/EC. 
11. Multiple primary malignancies within 3 y, except adequately resected non-melanoma 
skin cancer, curatively treated in situ disease, or contralateral breast cancer. 
12. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to Grade ≤ 1 or baseline. Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the investigator after consultation with the 
Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy). 

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13. Therapeutic radiation therapy or major surgery within 4 wk before randomization or 
palliative stereotactic radiation therapy within 2 wk before randomization. 
14. Systemic treatment with anticancer therapy (immunotherapy [non-antibody-based 
therapy], retinoid therapy, or hormonal therapy) within 3 wk before randomization; 
antibody-based-anticancer-therapy within 4 wk before randomization; or treatment with 
nitrosoureas or mitomycin C within 6 wk before randomization; or treatment with 
small-molecule targeted agents within 2 wk or 5 half-lives before randomization, 
whichever is longer. 
16. Participation in a therapeutic clinical study within 3 wk before randomization (for 
small-molecule targeted agents, this non-participation period is 2 wk or 5 half-lives, 
whichever is longer), or current participation in other investigational procedures. 
17. Pregnant, breastfeeding, or planning to become pregnant. 
18. Subject must not be an immediate family member of study site personnel working for the 
investigator or of Sponsor personnel. 
19. Otherwise considered inappropriate for the study by the investigator. 
20. Prior participation in a study involving an antibody drug conjugate produced by Daiichi 
Sankyo.  
21. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (ie, pulmonary emboli 
within 3 months of the study enrollment, severe asthma, severe chronic obstructive 
pulmonary disease [COPD], restrictive lung disease, pleural effusion etc), and any 
autoimmune, connective tissue or inflammatory disorders with pulmonary involvement 
(ie, rheumatoid arthritis, Sjögren’s, sarcoidosis etc), or prior pneumonectomy 

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5. 
STUDY TREATMENTS 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Groups 
There will be 2 treatment groups: trastuzumab deruxtecan and T-DM1 
5.1.2. 
Method of Treatment Allocation 
Prior to randomization of a subject, all eligibility criteria must be met and a signed informed 
consent obtained. 
Subjects will be randomized into 1 of the 2 treatment groups (trastuzumab deruxtecan versus 
T-DM1) in a 1:1 ratio. The randomization will be stratified by hormone receptor status (positive, 
negative), prior treatment with pertuzumab (yes, no), and history of visceral disease (yes, no). 
Randomization will be managed through an Interactive Web/Voice Response System (IXRS) for 
subjects meeting all eligibility criteria. The directions on how to use the system will be provided 
in the IXRS Quick Reference Manual. 
The system will assign a unique SID number and treatment arm for that subject (ie, trastuzumab 
deruxtecan versus T-DM1). 
5.1.3. 
Blinding 
It is not feasible to blind treatment allocations for individual subjects because of different 
administration protocols and different AE profiles between trastuzumab deruxtecan and T-DM1. 
The primary endpoint of BICR-assessed PFS is a robust endpoint and bias due to lack of blinding 
should be minimal. The study team will not perform or have access to efficacy analysis/summary 
during the study. 
An independent biostatistician, not otherwise part of the Sponsor study team, will generate the 
randomization schedule. 
5.1.4. 
Emergency Unblinding Procedure 
Not applicable 
5.2. 
Trastuzumab Deruxtecan 
5.2.1. 
Description 
Lyophilized powder (Lyo-DP) 
Trastuzumab deruxtecan for injection 100 mg will be provided as a lyophilized powder 
containing 100 mg of trastuzumab deruxtecan in a glass vial. Each glass vial should be 
reconstituted to a concentration of 20 mg/mL. Each vial is designed for single-use only and is not 
to be used to treat more than 1 subject.  

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5.2.2. 
Labeling and Packaging 
Trastuzumab deruxtecan for injection 100 mg will be supplied by the Sponsor. Trastuzumab 
deruxtecan for injection 100 mg will be packaged and labeled in compliance with regulatory 
requirements. The packaging will clearly display the name of the study treatment, the lot 
number, storage condition, and other required information in accordance with local regulations. 
5.2.3. 
Preparation 
Trastuzumab deruxtecan for IV infusion is prepared by dilution of the required volume of the 
study treatment calculated based on the subject’s body weight to a 100 mL or 250 mL infusion 
bag. Prepared study drug solutions should be used as directed in the pharmacy instructions. The 
preparation will be conducted in accordance with the pharmacy instructions provided by the 
Sponsor. Procedures for proper handling and disposal of anticancer drugs should be followed in 
compliance with the standard operating procedures (SOPs) of the study site.  
5.2.4. 
Storage 
Trastuzumab deruxtecan for injection 100 mg must be stored in a secure, limited access storage 
area under the storage conditions listed below: 
 Stored at 2°C to 8°C (protected from light) for lyophilized powder  
If storage conditions are not maintained per specified requirements, the Sponsor or contract 
research organization (CRO) should be contacted. 
See pharmacy instructions for storage conditions of the infusion solution. 
5.3. 
Control Treatment (T-DM1) 
5.3.1. 
Description 
Lyophilized powder in single-use vials containing 100 mg per vial. 
5.3.2. 
Labeling and Packaging 
T-DM1 will be packaged and labeled in compliance with local regulatory requirements.  
5.3.3. 
Preparation 
T-DM1 should be prepared following the pharmacy instructions. 
5.3.4. 
Storage 
Storage for all medications must follow the locally approved label. 
T-DM1 lyophilized powder must be stored in a secure, limited access storage area under the 
storage conditions listed below: 
 Stored at 2°C to 8°C 

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5.4. 
Administration of either Trastuzumab Deruxtecan or T-DM1 
The study treatment will be administered initially as an IV infusion over 30 to 90 min every 21 d 
(± 2 d). The initial dose of study treatment will be infused for approximately 90 min. If there is 
no infusion related reaction, after the initial dose, the next doses of study treatment will be 
infused for a minimum of 30 min. The subject’s weight at Screening (baseline) will be used to 
calculate the initial dose. If during the course of treatment, the subject’s weight changes by 
≥± 10% of the baseline weight, the subject’s dose will be recalculated based on the subject’s 
updated weight. Refer to the pharmacy instructions for detailed information about administration 
of study treatment. 
Trastuzumab deruxtecan should only be initiated by a physician or healthcare professional 
experienced in the administration of cytotoxic chemotherapy. Medicinal products to treat 
allergic/anaphylactic infusion reactions, as well as emergency equipment, should be available for 
immediate use. 
For subjects randomized to T-DM1, the treatment administration and monitoring of subjects will 
be in accordance with the locally approved label. 
5.5. 
Drug Accountability 
When a drug shipment is received from the Sponsor, the investigator or designee will check the 
amount and condition of the drug, check for appropriate local language in the label, check drug 
expiration date, and acknowledge receipt in IXRS. In addition, the investigator or designee shall 
contact Sponsor as soon as possible if there is a problem with the shipment.  
A Drug Accountability Record will be provided for study treatment (trastuzumab 
deruxtecan/T-DM1). The record must be kept current and should contain the following: 
 dates and quantities of drug received,  
 subject’s SID and/or initials or supply number (as applicable),  
 the date and quantity of study treatment dispensed and remaining (if from individual 
subject drug units),  
 the initials of the dispenser.  
At the study closure, as per local laws and/or directed by Sponsor, all unused study treatment 
will be returned or destroyed as per local laws or site policy and only after the study monitor has 
completed a final inventory. As applicable, the study site must file a copy of the appropriate 
institution policy within their investigator site file and provide a copy to the Sponsor. At the 
study closure, a final study treatment reconciliation statement must be completed by the 
investigator or designee and provided to the Sponsor. See pharmacy instructions for details.  
Unused drug supplies may be destroyed by the investigator when approved in writing by Sponsor 
and Sponsor has received copies of the study site’s drug handling and disposition SOPs and it is 
assured that the Sponsor will receive copies of the certificate of destruction which is traceable to 
the study treatment. 
All investigational product inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and Regulatory Agency inspectors.  

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5.6. 
Dose Interruptions and Reductions 
The investigator will evaluate which toxicities are attributed to the study treatment and adjust the 
dose of the drug as recommended below for trastuzumab deruxtecan. Dose adjustments for 
T-DM1 should be made in accordance with the locally approved label. All dose modifications 
should be based on the worst preceding toxicity (Common Toxicology Criteria for Adverse 
Events [CTCAE] version 5.0). All interruptions or modifications must be recorded on the AE 
and drug administration electronic case report form (eCRF). Appropriate clinical experts should 
be consulted as deemed necessary.  
Investigators may consider dose reductions or discontinuations of the study treatment according 
to the subject’s condition and after discussion with and approval from the Sponsor Medical 
Monitor or designee. 
For Grade 3 or Grade 4 events assessed as related to use of trastuzumab deruxtecan by the 
investigator(s), monitoring (including local laboratory tests when appropriate) should be 
performed at intervals no greater than 7 d until the AE is determined to be resolving. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to study treatment should also be reported and managed as an 
SAE. 
Prophylactic or supportive treatment for expected toxicities, including management of study 
treatment-induced AEs will be as per treating physician discretion and institutional guidelines. 
5.6.1. 
Dose Reduction and Interruption Guidelines 
NOTE: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified below 
in Table 5.3. 
The starting dose of trastuzumab deruxtecan Lyo-DP formulation will be 5.4 mg/kg. The starting 
dose of T-DM1 will be 3.6 mg/kg. Two dose reductions will be permitted (Table 5.1 and 
Table 5.2). 
Table 5.1: 
Dose Reduction Levels of Trastuzumab Deruxtecan 
Starting Dose 
Dose Level -1 
Dose Level -2 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
Table 5.2: 
Dose Reduction Levels of T-DM1 
Starting Dose 
Dose Level -1 
Dose Level -2 
3.6 mg/kg 
3.0 mg/kg 
2.4 mg/kg 
Once the dose of study treatment has been reduced because of toxicity, all subsequent cycles 
should be administered at that lower dose level unless further dose reduction is required. If 
toxicity continues after 2 dose reductions, then the subject will be withdrawn from study 
treatment. Study treatment dose increases are not allowed in the study. 

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Dose can be interrupted for up to 28 d from the planned date of administration. If a subject is 
assessed as requiring a dose delay longer than 28 d (49 d from the last infusion date), the subject 
will permanently discontinue study treatment and will be followed for survival. 
Treatment cycles for a subject for whom study treatment dosing was temporarily withheld for 
any reason may have future cycles scheduled based on the date of the last study treatment dose. 
Investigators may contact the Sponsor Medical Monitor or designee to discuss questions 
regarding dose modification or discontinuation of study treatment. 
5.6.1.1. 
Dose Modifications 
Dose adjustments for T-DM1 should be made in accordance with the approved label for T-DM1.  
Specific criteria for interruption, re-initiation, dose reduction, and/or discontinuation of 
trastuzumab deruxtecan are listed in table below, which are applicable only to TEAEs that are 
assessed as related to use of trastuzumab deruxtecan by the investigator(s). For non-drug-related 
TEAEs, follow standard clinical practice. Appropriate clinical experts should be consulted as 
deemed necessary.   
All confirmed or suspected coronavirus disease 2019 (COVID-19) infection events must be 
recorded in the eCRF.  Please refer to Section 17.8 for additional information on dose 
modification. 
Dose adjustments guidelines for trastuzumab deruxtecan are shown in Table 5.3. 
Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
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, 
hypotension) is observed during administration, the infusion rate 
should be reduced by 50% and subjects 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 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Grade 2 (Therapy or 
infusion interruption 
indicated but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, 
nonsteroidal anti-
inflammatory drugs 
(NSAIDs), narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤ 24 h) 
 
Administration of trastuzumab deruxtecan should be interrupted 
and symptomatic treatment started (eg, antihistamines, NSAIDs, 
narcotics, IV fluids). 
 
If the event resolves or improves to Grade 1, infusion can be 
re-started 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 trastuzumab deruxtecan should be 
discontinued immediately and permanently. 
 
Urgent intervention indicated. Antihistamines, steroids, 
epinephrine, bronchodilators, vasopressors, IV fluid therapy, 
oxygen inhalation etc, should be administered. 
Hematologic Toxicity 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3 (Neutrophils: <1.0 
to 0.5 × 109/L,  
WBCs: <2.0 to 1.0 × 109/L) 
 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 (Neutrophils: <0.5 
× 109/L, WBCs: <1.0 to 1.0 
× 109/L)  
 
Delay dose until resolved to ≤ Grade 2 
 
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 h) 
 
Delay dose until resolved 
 
Reduce dose by 1 level 
Lymphocyte Count Decreased 
Grade 1 to Grade 3 
lymphopenia 
 
No dose modification 
Grade 4 (< 0.2 × 109/L) 
 
Delay dose until resolved to ≤ Grade 2: 
 
If resolved in ≤ 14 d from day of onset, maintain dose 
 
If resolved in > 14 d from day of onset, reduce dose 1 level 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Anaemia 
Grade 3 (Hemoglobin [Hb] 
<8.0 g/dL); transfusion 
indicated 
 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 (Hb <8.0 g/dL) 
Life-threatening 
consequences; urgent 
intervention indicated 
 
Delay dose until resolved to ≤ Grade 2, then reduce dose 1 level 
Platelet Count Decreased 
Grade 3 
(platelets <50 to 25 × 
109/L) 
 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 4 
(platelets < 25 × 109/L) 
 
Delay dose until resolved to ≤ Grade 1, then reduce dose 1 level 
Cardiac Toxicity 
Symptomatic congestive 
heart failure 
 
Discontinue subject from study treatment 
Decrease in LVEF 10-20% 
(absolute value), but LVEF 
> 45% 
 
Continue treatment with trastuzumab deruxtecan 
LVEF 40% to ≤ 45% and 
decrease is < 10% (absolute 
value) from baseline 
 
Continue treatment with trastuzumab deruxtecan 
 
Repeat LVEF assessment within 3 wk 
LVEF 40% to ≤ 45% and 
decrease is 10-20% 
(absolute value) from 
baseline 
 
Interrupt trastuzumab deruxtecan dosing 
 
Repeat LVEF assessment within 3 wk 
 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue subject from study treatment 
 
If LVEF recovers to within 10% from baseline, resume study 
drug treatment and maintain dose 
LVEF < 40% or > 20% 
(absolute value) drop from 
baseline 
 
Interrupt trastuzumab deruxtecan dosing 
 
Repeat LVEF assessment within 3 wk 
 
If LVEF < 40% or > 20% drop from baseline is confirmed, 
discontinue subject from study treatment 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Electrocardiogram QT Prolonged 
Grade 3 (Average QTc 
> 500 ms or >60 ms change 
from baseline) 
 
Delay dose until resolved to ≤ Grade 1 (QTc ≤ 480 ms), 
determine if another medication the subject was taking may be 
responsible and can be adjusted or if there are any changes in 
serum electrolytes that can be corrected, then 
 
if attributed to trastuzumab deruxtecan, reduce dose 1 level 
Grade 4 (Torsade de 
pointes or polymorphic 
ventricular tachycardia or 
signs/symptoms of serious 
arrhythmia) 
 
Discontinue subject from study treatment 
Troponin Increased 
Grade 1 (Levels above the 
ULN and below the level of 
myocardial infarction as 
defined by the 
manufacturer) 
If troponin levels are above the upper limit of normal and below the 
level of myocardial infarction (CTCAE Grade 1) at baseline, no repeat 
testing is required if the troponin level is not Grade 3. 
For new diagnosed Grade 1 detected on study, repeat troponin testing at 
3 h ± 1 h after initial troponin test. 
 
If repeat troponin level at 3 ± 1 h rises significantly per 
institutional guidelines,  
 
Perform ECG in triplicate 
 
Repeat troponin testing at 6 h ± 1 h  
 
Follow institutional guidelines for management of detectable 
troponin testing. 
 
If repeat troponin level at 3 ± 1 h does not rise significantly per 
institutional guidelines,  
 
Repeat troponin testing 6 h ± 1 h or 24 h ± 2 h after initial 
troponin test.  
 
Continue treatment with trastuzumab deruxtecan. 
Grade 3 (Levels consistent 
with myocardial infarction 
as defined by the 
manufacturer) 
 
Perform ECG in triplicate 
 
Repeat troponin testing at 6 h (± 1 h) and 12 h (± 1 h) after initial 
troponin test. 
 
Follow institutional guidelines for management of detectable 
troponin testing.  
 
If acute myocardial infarction is confirmed, discontinue subject 
from study treatment. 
 
Otherwise, delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Pulmonary Toxicity 
If a subject develops radiographic changes potentially consistent with 
ILD or develops an acute onset of new or worsening pulmonary or other 
related signs/symptoms such as dyspnea, cough or fever, rule out 
ILD/pneumonitis.  
If the AE is confirmed to have an etiology other than ILD/pneumonitis, 
follow the management guidance outlined in the “Other Non-laboratory 
Adverse Events” dose modification section below. 
If the AE is suspected to be ILD/pneumonitis, treatment with study drug 
should be interrupted pending further evaluations.  
Evaluations should include: 
 
High resolution computed tomography (CT)  
 
Pulmonologist consultation (infectious disease consultation as 
clinically indicated) 
 
Blood culture and Complete Blood Count (CBC). Other blood 
tests could be considered as needed 
 
Consider bronchoscopy and bronchoalveolar lavage if clinically 
indicated and feasible 
 
Pulmonary function tests and pulse oximetry (SpO2)  
 
Arterial blood gases if clinically indicated  
 
One blood sample collection for PK (central) analysis as soon as 
ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered as needed. Radiation applications 
utilized for the monitoring and management of potential ILD are not 
specific to this study; routine CT scans should be performed.  
If the AE is confirmed to be ILD/pneumonitis, follow the management 
guidance as outlined below. 
All events of ILD regardless of severity or seriousness will be followed 
until resolution including after drug discontinuation. 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Grade 1 
The administration of trastuzumab deruxtecan must be interrupted for any 
ILD events regardless of grade.  
 
Monitor and closely follow-up in 2 to 7 days for onset of clinical 
symptoms and pulse oximetry 
 
Consider follow-up imaging in 1-2 weeks (or as clinically 
indicated). 
 
Consider starting systemic steroids (eg, at least 0.5 mg/kg/day 
prednisone 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.* 
For Grade 1 events, trastuzumab deruxtecan can be restarted only if the 
event is fully resolved to Grade 0: 
 
If resolved in ≤ 28 d from day of onset, maintain dose 
 
If resolved in > 28 d from day of onset, reduce dose 1 level 
However, if the Grade 1 ILD/pneumonitis occurs beyond cycle Day 22 
and has not resolved within 49 d from the last infusion, the study 
treatment should be discontinued. 
* If subject is asymptomatic, then subject should still be considered as 
Grade 1 even if steroid treatment is given. 
Grade 2 
Permanently discontinue subject from study treatment.  
 
Promptly start and treat with systemic steroids (eg, at least 
1 mg/kg/day prednisone or equivalent) for at least 14 days or 
until complete resolution of clinical and chest CT findings, then 
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 5 days,  
 Consider increasing dose of steroids (eg, 2 mg/kg/day 
prednisone or equivalent) and administration may be 
switched to intravenous (eg, methylprednisolone). 
 Re-consider additional work-up for alternative etiologies as 
described above. 
 
Escalate care as clinically indicated. 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
 
Hospitalization required. 
 
Promptly initiate empiric high-dose methylprednisolone IV 
treatment (eg, 500-1000 mg/day for 3 days), followed by at least 
1.0 mg/kg/day of prednisone (or equivalent) for at least 14 days 
or until complete resolution of clinical and chest CT findings, 
then followed by a 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 immuno-suppressants and/or treat per local 
practice. 
Ocular 
Grade 3 
 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 4 
 
Discontinue subject from study treatment 
Blood Creatinine Increased 
Grade 3 (> 3.0 to 6.0 × 
ULN) 
 
Delay dose until resolved to ≤ Grade 2 or baseline, then reduce 
dose 1 level 
Grade 4 (> 6.0 × ULN) 
 
Discontinue subject from study treatment 
Hepatic Toxicity 
AST or ALT With Simultaneous Total Bilirubin Increased 
AST/ALT ≥3.0 × ULN 
with simultaneous total 
bilirubin >2.0 × ULN 
 
Delay study medication until drug-induced liver injury can be 
ruled out.  
 
If drug-induced liver injury is ruled out, the subject should be 
treated accordingly, and resumption of study treatment may 
occur after discussion between the investigator and Sponsor.  
 
If drug-induced liver injury cannot be ruled out from diagnostic 
work-up, permanently discontinue study treatment. 
 
Monitor AST/ALT and total bilirubin twice weekly until 
resolution or return to baseline. 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
AST or ALT Increased 
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 subjects without liver 
metastases and subjects 
with liver metastases and 
baseline level ≤ 3 × ULN: 
 
Repeat testing within 3 d. Delay dose until resolved to ≤ Grade 1 
if baseline ≤ 3 × ULN, otherwise delay dose until resolved to 
≤baseline, then: 
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, 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 subjects with liver 
metastases, if the baseline 
level was > 3 × ULN 
 
Repeat testing within 3 d. Delay dose until resolved to ≤ baseline 
level, then: 
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 4 (> 20 × ULN if 
baseline was normal; >20.0 
× baseline if baseline was 
abnormal) 
 
Discontinue subject from study treatment 
Total 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 until resolved to ≤ Grade 1: 
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 
 
If documented Gilbert’s syndrome or liver metastases at 
baseline, continue study treatment 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
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 d. Delay dose until resolved to ≤ 
Grade 1: 
 
If resolved in ≤ 7 d from day of onset, reduce dose 1 level 
 
If resolved in > 7 d from day of onset, discontinue 
trastuzumab deruxtecan 
 
If documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 d. Delay dose until resolved to < 
Grade 2: 
 
If resolved in ≤ 7 d from day of onset, reduce dose 1 level 
 
If resolved in > 7 d from day of onset, discontinue 
trastuzumab deruxtecan 
Grade 4 (> 10.0 × ULN if 
baseline was normal; >10.0 
×baseline if baseline was 
abnormal) 
 
Discontinue subject from study treatment 
Blood Alkaline Phosphatase Increased 
Grade 3(>5.0 to 20.0 × 
ULN if baseline was 
normal; >5.0 to 20.0 × 
ULN 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 until resolved to ≤ Grade 1  
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Diarrhea/Colitis 
Grade 3 
 
Delay dose until resolved to ≤ Grade 1 
 
If resolved in ≤ 3 d from day of onset, maintain dose 
 
If resolved in > 3 d from day of onset, reduce dose 1 level 
Grade 4 
 
Discontinue subject from study treatment 

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Table 5.3: 
Dose Modification for Trastuzumab Deruxtecan (Continued) 
Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Other Laboratory Adverse Events 
Grade 3 
 
Delay dose until resolved to ≤ Grade 1 or baseline level:  
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 4 
 
Discontinue subject from study treatment 
Other Non-laboratory Adverse Events 
Grade 3 
 
Delay dose until resolved to ≤ Grade 1 or baseline:  
 
If resolved in ≤ 7 d from day of onset, maintain dose 
 
If resolved in > 7 d from day of onset, reduce dose 1 level  
Grade 4 
 
Discontinue subject from study treatment 
All dose modifications should be based on the worst preceding toxicity.  
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CBC = complete blood 
count; CT = high resolution computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; Hb = hemoglobin; ILD = interstitial lung disease; IV = intravenous; LVEF = left 
ventricular ejection fraction; NSAID = nonsteroidal anti-inflammatory drug; PK = pharmacokinetic; 
QTc = corrected QT interval; SpO2 = peripheral oxygen saturation; ULN = upper limit of normal; WBC = white 
blood cell. 
In addition, investigators may consider dose reductions or discontinuations of the study treatment 
according to the subject’s condition and after discussion with the Sponsor Medical Monitor or 
designee. 
5.7. 
Method of Assessing Treatment Compliance 
Trastuzumab deruxtecan and T-DM1 will be administered by IV only to subjects participating in 
the study and under the supervision of clinical study personnel at the site. Start and stop times of 
injection and amount of drug administered are to be recorded by clinical study personnel. 
5.8. 
Concomitant Medications (Drugs and Therapies) 
Medications used from the time the subject signs the ICF to 40 d (+ 7 d) after the last 
administration of study treatment will be recorded. Concomitant medications and therapies 
include all prescription, over-the-counter (OTC), and herbal remedies. All concomitant 
medications will be recorded on the eCRF. 
Hematopoietic growth factors may be used for prophylaxis or treatment based on the clinical 
judgment of the investigator, except for within 1 wk prior to Screening (see Section 4.1). 
Prophylactic or supportive treatment of study treatment-induced AEs will be otherwise as per 
investigator’s discretion and institutional guidelines.  
Based on the currently available clinical safety data, it is recommended that subjects receive 
prophylactic anti-emetic agents prior to infusion of trastuzumab deruxtecan and on subsequent 

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days.  Antiemetics such as 5-hydroxytryptamine receptor antagonists or Neurokinin-1 receptor 
antagonists and/or steroids (eg, dexamethasone) should be considered and administered in 
accordance with the prescribing information or institutional guidelines. 
Concomitant use of dietary supplements, medications not prescribed by the investigator, and 
alternative/complementary treatments is discouraged, but not prohibited.  Concomitant use of 
e-cigarettes and vaping is strongly discouraged but not prohibited. 
Prohibited Medications and Treatments 
With the exception of medications that are under investigation in the study (eg, standard of care, 
comparators, or combination therapies), the following medications, treatment and procedures 
will be prohibited during the treatment period (see Section 4.2 for required washout periods).  
The Sponsor must be notified if a subject receives any of these during the study. 
 Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, 
antibody, retinoid, or anticancer hormonal treatment (concurrent use of hormones for 
noncancer-related conditions [eg, insulin for diabetes and hormone replacement 
therapy] is acceptable);  
 Use of bisphosphonates or RANKL pathway inhibitors for the prevention or 
treatment of skeletal-related events is acceptable. 
 Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during 
the study treatment. Refer to Section 17.8 for further details.; 
 Other investigational therapeutic agents; 
 Radiotherapy (except for palliative radiation to known metastatic sites as long as it 
does not affect assessment of response or interrupt treatment for more than the 
maximum time specified in dose modification section); 
 Radiotherapy to the thorax; 
 Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing AEs; (inhaled steroids or intra 
articular steroid injections are permitted in this study.) 
 Subjects with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study.  
For subjects randomized to T-DM1: 
 Refer to the approved local label for T-DM1 for medications prohibited during 
treatment with the applicable product. 
5.9. 
Study Drug Discontinuation and Discontinuation from the Study 
5.9.1. 
Discontinuation of Study Drug 
Subjects may be withdrawn from study treatment for the following reasons:  
 PD per criteria set forth in mRECIST version 1.1 (Section 17.4);  

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 Clinical progression (definitive clinical signs of PD), but a recent radiographic 
assessment did not meet the criteria for PD according to mRECIST version 1.1; 
 AE; 
 Death; 
 Pregnancy; 
 Withdrawal of consent by subject (to discontinue study drug) Note: this section only 
refers to withdrawal from treatment with study drug, which is not the same thing as a 
complete withdrawal from the study.  Discuss with the subject that they will remain 
in the study (ie, continue with study visits and assessments, including survival 
follow-up); 
 Lost to follow-up; 
 Protocol deviation; 
 Physician decision; 
 Study terminated by Sponsor; 
 Other, specify. 
Procedures for Discontinuation from Study Drug 
If there is evidence that the subject is receiving benefit from treatment even though the subject 
has met a criterion for discontinuation as listed above, the subject may remain on study treatment 
after discussion with and approval from the Sponsor Medical Monitor. 
All subjects who are withdrawn from study treatment should complete protocol-specified 
withdrawal procedures (Section 5.9.2) and follow-up procedures (Section 6.6).  The investigator 
or sub-investigator must discuss with the subject that even though study treatment has stopped, 
the subject will continue into the follow-up period for study visits.  If a subject withdraws 
consent from study treatment, the investigator or sub-investigator must discuss with the subject 
that their decision to permanently discontinue study treatment does not mean follow-up visits 
should be discontinued as well. 
Record the reason for any subject who discontinues study treatment on the eCRF. Discontinued 
subjects will be followed for survival, either through direct contact or by collecting public 
records (eg, death certificates) as allowed by local laws.  If a subject discontinues treatment for 
reasons other than disease progression or death, every attempt should be made to collect tumor 
assessments until disease progression and the scans be sent for central review even if the subject 
has started another anticancer therapy. 
If the subject is withdrawn because of an AE, the investigator will follow the subject until the AE 
has resolved or stabilized. 
If a subject does not agree to continue to come to the study site, then a modified follow-up must 
be arranged to ensure the continued collection of endpoints and safety information.  Options for 
modified follow-up are noted below. 

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Modified Follow-up Options 
The following modified follow-up options can be offered to the subject who does not agree to 
study visits at the study site. 
 Study personnel contacting the subject by telephone to collect study information 
based on the follow-up schedule 
 Study personnel contacting an alternative person (eg, family member, spouse, partner, 
legal representative, physician, or other healthcare provider) 
 Study personnel accessing and reviewing the subject’s medical information 
(eg, doctor’s notes, hospital records) at the study site or other location) 
Dates of the modified follow-up contact(s) should be recorded.  See Section below, (Subject 
Withdrawal/Discontinuation from the Study) for definition of withdrawal by subject from the 
study (ie, withdrawal of consent). 
Subject Withdrawal/Discontinuation from the Study The duration of subject participation in the 
study will be until 1 of the following occurs: 
 Subject dies; 
 Study termination;  
 Withdrawal by subject (from the study)  Note: This indicates that the subject 
withdraws consent and refuses to undergo any further study procedures or be 
followed for long-term survival; 
 Subject is lost to follow-up; 
 Other, specify. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation (ie, from the interventional portion and follow-up): 
 Attendance at study visits per protocol 
 Study personnel contacting the subject by telephone 
 Study personnel accessing and reviewing the subject’s medical information (at study 
site or other location) 
If the subject refuses all of the above methods of follow-up, the investigator or sub-investigator 
should personally speak to the subject to ensure the subject understands all of the potential 
methods of follow-up.  If the subject continues to refuse all potential methods of follow-up, the 
investigator or sub-investigator will document this as a withdrawal of consent (from the 
interventional portion and follow-up).  
5.9.2. 
Withdrawal Procedures 
If a subject is withdrawn from the study, the investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of last 
treatment and the reason for withdrawal. 

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If the subject is withdrawn due to an AE, the investigator will follow the subject until the AE has 
resolved or stabilized. 
All subjects who are withdrawn from the study should complete protocol-specified withdrawal 
procedures. Protocol-specified withdrawal procedures will be obtained during the End of 
Treatment (EOT) assessments (+ 7 d) and the 40-Day (+ 7 d) Follow-up assessments conducted 
after the last administration of study treatment (Section 6.5 and Section 6.6.1). 
5.9.3. 
Subject Replacement 
Randomized subjects will not be replaced. 
5.9.4. 
Subject Re-screening Procedures 
Re-screening is permitted for any subject who failed to meet eligibility criteria upon initial 
screening. The SID number must remain the same at the time of re-screening. The initial 
screening information and the reason why the subject was ineligible for the initial evaluation will 
be recorded on the Screening Log. No data from the initial evaluation will be entered into the 
clinical database for a subject who was re-screened (see Study Manual for details). 

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6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Table 17.1 for the Tissue Screening and 
Screening period and in Table 17.2 for the treatment and follow-up periods. 
6.1. 
Tissue Screening 
To determine eligibility, subjects must have breast cancer that has confirmed HER2-positive 
expression as determined according to American Society of Clinical Oncology – College of 
American Pathologists guidelines23 evaluated at a central laboratory. 
Note: Subjects may continue on prior therapy while HER2 testing takes place.  
Please refer to the study laboratory manual for required tumor sample specifications and 
shipping instructions.  
The following procedures will be conducted: 
 Obtain a signed and dated written Tissue Screening ICF from the subject prior to 
collecting tissue.  .  
 Obtain adequate archived or recent tumor tissue sample for HER2 testing. Refer to 
study laboratory manual for preparation, number of slides required, storage, and 
shipment procedures. If the most recent tissue sample is unavailable: 
 Document the reason why the most recent tissue sample  is unavailable and 
submit another prior tissue specimen. 
 If archival tissue is not available, collect fresh tissue sample. 
 If a tumor biopsy is needed, report any SAEs directly related to tissue screening 
procedure (ie, tumor biopsy) along with any associated treatment. Unless 
documentation of other AEs is required by local law, only SAEs directly related to 
tumor biopsy will be recorded during tissue screening.  
 Send the samples to the central laboratory to confirm HER2 status. 
 Assign SID. 
6.2. 
Screening 
Obtain a signed and dated Main ICF before any study-related procedures or assessments are 
conducted.   
The following activities and/or assessments will be performed within 28 d before 
randomization during the Screening period: 
 Perform an HIV antibody test if required by local regulations or IRB/ECs. 
 Perform hepatitis B surface antigen/hepatitis C antibody test. 
 Perform ophthalmologic assessments including visual acuity testing, slit lamp 
examination, and fundoscopy. 

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 Perform an Echo or MUGA (note: the same test must be used for the subject 
throughout the study).  
 Perform tumor assessment by computed tomography (CT) or magnetic resonance 
imaging (MRI) scans of the chest, abdomen, pelvis, and any other sites of disease. A 
CT or MRI of the brain is to be included for all subjects.  
 Note: Radiation applications utilized to assess tumor burden are not specific to 
this study. Scans will be performed per the normal course of subject care 
 Additional slides for optional exploratory biomarker assessment are requested (see 
study laboratory manual).  It is preferred if the slides are from the same block as the 
tissue sample sent for central laboratory HER2 testing. 
If there are screening procedures that are performed within 28 days of randomization during the 
standard treatment of the subject, these procedure results can be used for the study even if 
conducted prior to consent because they were performed during the normal course of subject 
care. 
NOTE: To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use it as comparator for subsequent measurement. Therefore, all 
lesions (target and non-target) have to be assessed at Screening according to mRECIST version 
1.1 (Section 17.4). 
The following activities and/or assessments will be performed during the Screening period 
within 14 d before randomization except as indicated: 
 Confirm subject eligibility. 
 Obtain demographics (eg, birth date, sex, race, ethnicity), medical and surgical 
history, including all previous, now resolved, significant medical conditions, date of 
diagnosis, extent of disease, disease staging, estrogen/progesterone receptor status, 
previous cancer therapies (including prior radiation therapy) and oncology surgical 
history. 
 Perform a complete physical examination (see Section 9.11) including weight and 
height. 
 Assess functional status using the ECOG PS (Section 17.3). 
 Record concomitant medications, AEs, and hospitalization-related records at every 
visit (from the time the subject signed the Main ICF). For details on AE collection 
and reporting, refer to Section 9. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature; Section 9.9) and peripheral oxygen saturation (SpO2; 
Section 9.12.2). 
 Perform triplicate 12-lead ECG.  ECGs will be taken in close succession while in a 
supine/semi-recumbent position (Section 9.10). ECG should be performed prior to 
blood draws.  

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 Note that subsequent ECGs will be performed in triplicate only if an abnormality 
is noted. 
 Collect and send blood samples to the laboratory for the following tests (Section 9.8): 
 Hematology; 
 Chemistry; 
 Coagulation (should also be performed as clinically indicated throughout the 
study); 
 Troponins (preferably high-sensitivity troponin-T); the test used to test troponin 
should remain the same throughout the course of a subject’s time on study. In 
addition to the troponin sample that is tested locally, a sample should also be 
submitted for central laboratory troponin-T testing.  
 Serum biomarkers (eg, HER2ECD; Section 8.3.2; COVID-19 serology, 
Table 17.2). 
 Obtain urine sample for urinalysis (protein, glucose, blood, microscopy assessment 
[if indicated], and specific gravity; Section 9.8).  
 For women of childbearing potential (criteria for non-childbearing potential are 
defined in Section 4.1) perform a serum or urine pregnancy test and document the 
results. A positive urine pregnancy test result must be confirmed immediately using a 
serum test, with a confirmed negative test result within 72 hours prior to drug 
administration. For subjects who are of non-childbearing potential (as defined in 
Section 4.1), no pregnancy test will be required. 
6.3. 
Randomization 
Eligible subjects will be randomized by the IXRS in a 1:1 ratio into 1 of 2 treatment groups 
(trastuzumab deruxtecan versus T-DM1).  
Randomization will be stratified by hormone receptor status (positive, negative), prior treatment 
with pertuzumab (yes, no), and history of visceral disease (yes, no). 
A subject’s first dose/Cycle 1 Day 1 should occur within 7 d from the date the subject is 
randomized. 
6.4. 
Treatment Period 
6.4.1. 
Cycle 1 to 4 and Subsequent Cycles 
Treatment and procedures performed on Day 1 of Cycle 1 and beyond are specified in Table 17.2 
and further described below. Cycles for trastuzumab deruxtecan and T-DM1 are both 21 d in 
duration. 
6.4.1.1. 
Between -3 Days Through Immediately Before Infusion (All Cycles) 
 The subject must complete the HEOR outcomes, EORTC QLQ-C30 and EORTC 
QLQ-BR45, and EQ-5D-5L questionnaires before any other assessments or 

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procedures are done that day . Complete at Cycle 1 Day 1, Cycle 2 Day 1, Cycle 3 
Day 1 and then every 2 cycles thereafter (eg, Cycles 5, 7, 9, etc). 
 Perform 12-lead ECG.   
 If an abnormality is noted, perform triplicate ECG.  ECGs will be taken in close 
succession while in a supine/semi-recumbent position. ECGs should be performed 
before blood draws at respective time points. 
 Perform a physical examination (Section 9.11), including weight. More frequent 
examinations may be performed at the discretion of the investigator and if medically 
indicated.  
 Assess functional status using the ECOG PS Scale (Section 17.3). 
 Record concomitant medications, AEs, and hospitalization-related records at every 
visit. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) and SpO2. More frequent examinations may be performed at 
the discretion of the investigator and if medically indicated. 
 Collect and send blood samples to the laboratory for the following tests (Section 9.8): 
 Hematology 
 Chemistry 
 For all female subjects of childbearing potential (as defined in Section 4.1) perform a 
serum or urine pregnancy test within 72 h prior to the beginning of the infusion and 
document the results. A positive urine pregnancy test result must be confirmed 
immediately using a serum test, with a confirmed negative test result within 72 hours 
prior to drug administration. For subjects who are of non-childbearing potential (as 
defined in Section 4.1), no pregnancy test will be required. 
 Note: Vital signs (including SpO2) evaluations, clinical laboratory tests, physical 
examination, weight, ECG, HEOR outcomes, and ECOG PS determination need not 
be repeated if they were performed within 3 d of the first dose in each cycle. 
6.4.1.2. 
Day 1; Before Infusion (All Cycles, Unless Otherwise Noted) 
 Obtain blood samples for:  
 Pharmacogenetic assessment, Cycle 1 only, if the subject provides consent by 
signing the pharmacogenetics sample banking consent form. (This sample is not 
required for study participation.); 
 Serum biomarkers (eg, HER2ECD, COVID-19 serology [refer to Section 17.8]) 
assessment which will be collected on Cycle 3 Day 1 and every 2 cycles thereafter 
(Cycles 5, 7, 9, etc).  
 

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 COVID-19 testing will be performed only on the serology samples from 
Cycle 5 and every 4 cycles thereafter.  For subjects with suspected or 
confirmed COVID-19, follow the dose modifications in Section 17.8. 
 Only subjects randomized to trastuzumab deruxtecan: 
 PK assessment before infusion (BI) (within 8 h) on Day 1 of Cycles 1, 2, 3, 
4, 6, and 8;  
 ADA at Cycles 1, 2 and 4, then every 4 cycles (Cycles 8, 12, 16, etc); 
 Obtain blood samples for exploratory biomarkers, such as cfDNA analysis in plasma, 
before treatment on Day 1 of Cycle 1 and every 3 cycles thereafter until EOT (Cycles 
4, 7, etc). 
 Record concomitant medications, AEs, and hospitalization-related records at every 
visit. 
6.4.1.3. 
Day 1: Dosing and End of Infusion (All Cycles, Unless Otherwise Noted) 
 Administer study treatment IV infusion approximately 90 min for the initial dose and, 
if no infusion related reaction after the initial dose, infuse subsequent doses over a 
minimum of 30 min. Record start and stop times and amount of drug administered. 
Study treatment is to be administered every 21 d ± 2 d. 
 Trastuzumab deruxtecan should only be initiated by a physician or healthcare 
professional experienced in the administration of cytotoxic chemotherapy. 
Medicinal products to treat allergic/anaphylactic infusion reactions, as well as 
emergency equipment, should be available for immediate use.  
 Trastuzumab deruxtecan arm only: During and following the first infusion (Cycle 
1 Day 1), subjects will be observed for infusion related reaction until the PK 
collection time point, which is about 5 h (± 2 h) after the start of infusion of 
trastuzumab deruxtecan. 
 Administration and monitoring of subjects randomized to T-DM1 should occur per 
the locally approved label. Blood samples for PK analyses are not required at the end 
of infusion (EOI)/treatment for subjects randomized to T-DM1 as part of this study 
protocol. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) and SpO2. More frequent examinations may be performed at 
the discretion of the investigator and if medically indicated.  
 Trastuzumab deruxtecan arm only: At Cycle 1 Day 1, perform ECG testing at 5 h 
after the start of drug administration (± 2 h).  
 If an abnormality is noted, perform triplicate ECG.  ECGs will be taken in close 
succession while in a supine/semi-recumbent position.  ECG should be performed 
prior to blood draws. 
 Trastuzumab deruxtecan arm only: Collect blood samples for: 

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 PK analysis samples on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 should be collected as 
soon as possible after EOI and the actual time of sampling should be accurately 
recorded. In addition, for Cycle 1 Day 1 only, collect sample at 5 h after the start 
of drug administration (± 2 h). 
 If at any time a subject reports signs or symptoms suggesting congestive heart failure, 
myocardial infarction, or other causes of cardiac myocyte necrosis, collect blood 
samples for troponin (preferably high-sensitivity troponin-T) testing and perform 
ECG in triplicate. If ECG is abnormal, follow institutional guidelines. See details in 
Table 5.3. 
6.4.1.4. 
Day 8 (± 1 d) and Day 15 (± 1 d) (Cycle 1 Only) 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) and SpO2. More frequent examinations may be performed at 
the discretion of the investigator and if medically indicated. 
 Collect and send blood samples to the laboratory for the following tests (Section 9.8): 
 Hematology 
 Chemistry 
 Record concomitant medications, AEs, and hospitalization-related records at every 
visit. 
6.4.2. 
Every 2 Cycles after Cycle 3 
 The subject must complete the HEOR outcomes, EORTC QLQ-C30 and EORTC 
QLQ-BR45, and EQ-5D-5L questionnaires before any other assessments or 
procedures are done that day .  Collect HEOR outcomes on Day 1 at Cycles 1, 2, and 
3; thereafter, collect every 2 cycles (eg, Cycle 5, Cycle 7, Cycle 9, etc). 
6.4.3. 
Every 4 Cycles (± 7 d) after Cycle 1 
 Perform an Echo or MUGA every 4 cycles after Cycle 1 (Cycle 5, 9, 13, etc). (note: 
the same test must be used for the subject throughout the study).   
6.4.4. 
Every 6 Weeks (± 7 d) 
 Tumor assessments, based on sites of disease identified at Screening and any 
additional newly suspected sites of PD, will be conducted every 6 wk (± 7 d) from 
randomization, independent of treatment cycle. A CT and/or MRI (CT or MRI with 
≤ 5 mm cuts) of chest, abdomen, and pelvis should be used for tumor assessment 
unless another modality of disease assessment is necessary for the lesions. The same 
assessment modality should be used throughout the study for all assessments for each 
subject unless prior approval is obtained from Sponsor or its designee. Unscheduled 
tumor assessments may be performed if progression is suspected.  

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 A CT or MRI of the brain is mandatory for all subjects included with baseline stable 
brain metastases. Subjects without brain metastases do not need additional brain scans 
for tumor assessment unless clinically indicated. 
Imaging results will be reviewed by an independent radiologic facility. 
6.5. 
End of Treatment 
The EOT is defined as the date the investigator decides to discontinue study treatment (+ 7 d). 
All assessments required as part of EOT must occur within 7 days from the date the Investigator 
decides to discontinue study treatment. The following procedures will be performed as specified 
in the Schedule of Events (Table 17.2). However, if the EOT assessments have been performed 
within 30 d (± 7 d) of their last treatment, they can be considered to be the EOT data and there is 
no need to repeat them; otherwise, these assessments need to be repeated.  
 The subject must complete the HEOR outcomes, EORTC QLQ-C30 and EORTC 
QLQ-BR45, and EQ-5D-5L questionnaires before any other assessments or 
procedures are done that day. 
 Perform a physical examination (Section 9.11), including weight.  
 Ophthalmologic assessments to include visual acuity testing, slit lamp examination, 
and fundoscopy. 
 Assess functional status using the ECOG PS (Section 17.3). 
 Record concomitant medications, AEs, and hospitalization-related records at every 
visit. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) and SpO2. 
 Perform 12-lead ECG.   
 If an abnormality is noted, perform triplicate ECG.  Triplicate ECGs will be taken 
in close succession while in a supine/semi-recumbent position. ECG should be 
performed prior to blood draws. 
 Echo or MUGA (note: the same test must be used for the subject throughout the 
study). 
 Blood sample for troponin (preferably high-sensitivity troponin-T); in addition to the 
troponin sample that is tested locally, a sample should also be submitted for central 
laboratory troponin-T testing:  
 If troponin levels are consistent with myocardial infarction as defined according 
to manufacturer (CTCAE Grade 3), perform ECG testing in triplicate, repeat 
troponin testing 6 h (± 1 h) and 12 h (± 1 h) after initial troponin test was drawn, 
and follow institutional guidelines.  
 If troponin levels are new CTCAE Grade 1 (ie, levels at baseline were ≤ULN), 
repeat troponin testing at 3 h (± 1 h) after initial troponin test was drawn. If 
troponin level at 3 h after initial troponin test was drawn significantly increases 

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per institutional guidelines, then perform ECG in triplicate, repeat troponin testing 
at 6 h (± 1 h) and follow institutional guidelines. Otherwise, repeat troponin 
testing at 6 h (±1 h) or at 24 h (±2 h) after initial troponin test.  
 If at any time a subject reports signs or symptoms suggesting congestive heart 
failure, myocardial infarction, or other causes of cardiac myocyte necrosis, collect 
blood samples for troponin (preferably high-sensitivity troponin-T) testing and 
perform ECG in triplicate. 
 Collect sample for ADA, only in subjects randomized to trastuzumab deruxtecan. 
 Collect and send blood samples to the laboratory for the following tests (Section 9.8): 
 Hematology; 
 Chemistry;  
 Serum biomarkers (eg, HER2ECD; Section 8.3.2; COVID-19 serology; 
Section 17.8); 
 Coagulation. 
 Blood sample for exploratory biomarkers, such as cfDNA analysis in plasma, will be 
collected. 
 Serum or urine sample for pregnancy testing in women of childbearing potential. 
 Tumor assessments should include all sites of disease identified at Screening and any 
other locations where PD is suspected (eg, MRI of the brain if brain metastases are 
suspected) should also be imaged, per mRECIST version 1.1 (Section 17.4). If the 
previous scan was within the last 6 wk (± 7 d) from the date of EOT, this assessment 
does not need to be performed at EOT.  If a subject discontinues treatment for reasons 
other than disease progression, every attempt should be made to collect tumor 
assessments until disease progression and the scans be sent for central review even if 
the subject has started another anti-neoplastic therapy. 
 A CT or MRI of the brain is mandatory for all subjects included with baseline stable 
brain metastases. Subjects without brain metastases do not need brain scan for tumor 
assessment unless clinically indicated.  
6.6. 
Follow-up 
6.6.1. 
40-Day (+ 7 d) Follow-up 
Forty d (+ 7 d) after last study treatment administration or before starting new anticancer 
treatment, whichever comes first, the following procedures will be performed as specified in the 
Schedule of Events (Table 17.2). If EOT is > 40 d (+ 7 d) after last treatment, then the EOT 
assessments can also function as the 40-Day (+ 7 d) Follow-up assessments. 
 The subject must complete the HEOR outcomes, EORTC QLQ-C30 and EORTC 
QLQ-BR45, and EQ-5D-5L questionnaires before any other assessments or 
procedures are done that day. 

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 Perform a physical examination (Section 9.11), including weight.  
 Assess functional status using the ECOG PS Scale (Section 17.3).  
 Record concomitant medications, AEs, and hospitalization-related records. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) and SpO2. 
 Collect and send blood samples to the laboratory for the following tests (Section 9.8): 
 Hematology; 
 Chemistry; 
 Coagulation. 
 Obtain blood samples for ADA, only for subjects randomized to trastuzumab 
deruxtecan. 
 For subjects with positive ADA at the follow-up visit, additional serum ADA samples 
may be collected every 3 mo (± 1 mo) up to 1 y from the last dose of study treatment, 
or until the ADA becomes negative, or until the ADA titer becomes less than baseline 
(applicable when preexisting ADA is observed), or until the subject starts another 
therapy for cancer, or withdraws consent from the study, whichever occurs first. 
 Serum or urine sample for pregnancy testing in women of childbearing potential.  
6.6.2. 
Long-term/Survival Follow-up Visits 
After completion of the 40-Day (+ 7 d) Follow-up assessments, the Long-term/Survival 
Follow-up assessments will be performed every 3 mo (± 14 d), from the date of 40-Day (+ 7 d) 
Follow-up assessments, until death, withdrawal of consent from the study, loss to follow-up, or 
study closure, whichever occurs first.  
The following activities will take place during Long-term/Survival Follow-up at the study site or 
by telephone contact:  
 The subject must complete the HEOR outcomes, EORTC QLQ-C30 and EORTC 
QLQ-BR45, and EQ-5D-5L questionnaires before any other assessments or 
procedures are done that day (only at first 3 mo, which will be the last data collection 
point for both questionnaires); 
 Record subsequent anticancer treatments, their outcomes, and survival;  
 Further follow-up may be required for ongoing AEs (see Section 9). 
If direct contacts are not possible due to withdrawal of consent or the subject becomes lost to 
follow-up, the site must make every effort to collect survival status from public records 
(eg, death certificates) in accordance with local laws. See Section 5.9.2 for further details on how 
subjects will be followed for survival status if they withdraw consent. 

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7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoints 
7.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS based on BICR. Progression-free survival based on BICR 
is defined as the time from the date of randomization to the earliest date of the first objective 
documentation of radiographic disease progression per BICR according to mRECIST version 1.1 
or death due to any cause. Subjects who are alive with no objective documentation of 
(radiographic) disease progression by the data cutoff date for PFS analysis will be censored at 
the date of their last evaluable tumor assessment. Detailed censoring rules for PFS based on 
BICR will be specified in the Statistical Analysis Plan (SAP).  
7.1.2. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is OS, defined as the time from the date of randomization 
to the date of death for any cause. If there is no death reported for a subject before the data cutoff 
for OS analysis, OS will be censored at the last contact date at which the subject is known to be 
alive.  The definition and additional details for the last contact date will be specified in the SAP.  
7.1.3. 
Secondary Efficacy Endpoints 
Other secondary efficacy endpoints noted below will be assessed by BICR review based on 
mRECIST version 1.1. Secondary efficacy endpoints include: 
 ORR, defined as the proportion of subjects who achieve a best overall response of CR 
rate and PR rate, based on BICR and based on investigator assessment. Confirmation 
of CR/PR is required for this study; 
 DoR, defined as the time from the date of the first documentation of objective 
response (CR or PR) to the date of the first documentation of disease progression, 
based on BICR. Duration of response will be measured for responding subjects (PR 
or CR) only. Subjects who are progression-free at the time of the analyses will be 
censored at the date of the last evaluable tumor assessment; 
 PFS (based on investigator assessment), defined as the time from the date of 
randomization to the earliest date of the first objective documentation of radiographic 
disease progression via investigator-assessed disease progression according to 
mRECIST version 1.1 (Section 17.4) or death due to any cause. Subjects who are 
alive with no objective documentation of (radiographic) disease progression by the 
data cutoff date for PFS analysis will be censored at the date of their last evaluable 
tumor assessment.  
Detailed censoring rules for secondary efficacy endpoints will be specified in the SAP. 

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7.1.4. 
Exploratory Efficacy Endpoints 
 Time to response, defined as the time from the date of randomization to the date of 
the first documentation of objective response (CR or PR), based on BICR. Time to 
response will be measured for responding subjects (CR or PR) only. 
 Best percent change in the sum of the diameter of measurable tumors based on BICR. 
 CBR, defined as the sum of CR rate, PR rate, and more than 6 mo SD rate, based on 
BICR. 
 PFS2, defined as the time from date of randomization to the first documented 
progression on next line therapy* or death due to any cause, whichever occurs first. 
The first documented progression on next-line therapy is based on investigator 
assessment of PD.  PFS2 will be censored if no PFS2 event is observed during next 
line therapy before the analysis cutoff date; censoring date will be the last contact 
date.  In case a second anti-neoplastic therapy is introduced prior to a PFS2 event, the 
PFS2 date will be censored at the end date of the first next line therapy. 
 Any death occurring prior to the start of next line therapy will be considered a 
PFS2 event. 
 Any death following the next line of therapy will be a PFS2 event if no second 
new line of therapy is initiated. 
 PFS and PFS2 may be identical in the case that a patient starts the next line 
anti-neoplastic therapy prior to progression on the trial therapy and tumor 
assessments continue after start of the new therapy. 
* Next line therapy is defined as the first new systemic anti-neoplastic therapy initiated 
after discontinuation of study treatment, regardless of EOT reason. 
7.2. 
Appropriateness of Selected Efficacy Assessments 
The primary endpoint of this study is PFS based on mRECIST version 1.1 which will be 
determined by independent review of baseline and follow-up assessments obtained every 6 wk. 
Progression-free survival has served as the basis of several recent approvals in the mBC setting 
including pertuzumab (CLEOPATRA study),3 palbociclib (PALOMA studies),25,26 ribociclib 
(MONALEESA-2),27 and abemaciclib (MONARCH 2).28  While PFS is a well-accepted measure 
to demonstrate clinical benefit in this setting, OS provides additional evidence of clinical 
efficacy and is the key secondary endpoint.  Sample size has been calculated to ensure the study 
is adequately powered to detect a clinically meaningful PFS and OS benefit. 
Patients with mBC face an illness associated with significant symptoms. Moreover, they are also 
aware that despite the availability of various treatments, it is ultimately incurable. The success of 
modern therapies in achieving better disease control and prolonged survival means that more 
women with mBC can receive several lines of treatment and in the process the key goals are to 
prolong survival and to improve health-related quality of life (QoL) (Section 10). That is why it 
is particularly valuable to involve subjects in clinical studies by asking them to provide 
assessment of their health and quality of life. In recent years a growing number of clinical studies 
in mBC have been reporting on health-related QoL, the most common patient reported outcome 

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(PRO) being used is the EORTC QLQ-C30 with or without the breast cancer supplement 
EORTC QLQ-BR45, followed by FACT-B.29  
The index scores from the PROs will be used to show changes in overall health-related quality of 
life and clinically meaningful changes in specific aspects of subject’s well-being over time.  In 
addition, the outcomes will be used in additional analyses and economic models to generate 
evidence to support access and reimbursement. 

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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic Assessments 
Blood samples for PK assessments will be collected only from subjects randomized to 
trastuzumab deruxtecan at multiple time points in the study, as outlined in Table 8.1 and 
Table 17.2. In addition, if feasible, a blood sample should be collected for PK analysis as soon as 
possible when a subject is suspected of having ILD/pneumonitis. 
Table 8.1: 
Blood Sampling for Pharmacokinetic Analysis 
Cycle 
Day 
Sampling Time Point (Acceptable Ranges) 
Cycle 1 
Day 1 
BI (within 8 h)  
EOI a 
5 h after the start of drug administration (± 2 h) 
Cycles 2, 3, 4, 6, 
and 8 
Day 1 
BI (within 8 h) 
EOI a 
BI = before infusion; EOI = end of infusion 
a The tissue sample should be collected as soon as possible after EOI and the actual time of sampling should be 
accurately recorded. 
At each time point, blood will be collected for trastuzumab deruxtecan, total anti-HER2 
antibody, and MAAA-1181a PK analysis. The actual time of study treatment administration and 
the exact time of blood sampling for PK analysis must be recorded on the eCRF.  
Details for blood sampling, processing, storage and shipment to central laboratory for PK 
samples will be provided in the study laboratory manual. 
Serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody, and MAAA-1181a 
will be measured using validated assays at the bioanalytical laboratory. 
If chloroquine or hydroxychloroquine are administered for COVID-19 infection, additional PK 
serum samples should be collected from each subject who provides consent and as described in 
Section 17.8 and at the time points specified in the Schedule of Events (Section 17.1) 
8.2. 
Pharmacodynamic Assessment 
Not applicable 
8.3. 
Biomarker Assessments 
Samples for biomarker testing will be collected from all subjects at the time points specified in 
Table 17.2. In this study biomarker analyses will be used to investigate the effect of trastuzumab 
deruxtecan at the molecular and cellular level as well as to determine how changes in the 
markers may relate to exposure and clinical outcomes. The sample collection information as 
required should be recorded on the eCRF page(s) and central laboratory requisition form(s). 
Detailed instructions for the collection, handling, and shipping of biomarker samples are outlined 
in the study laboratory manual. 

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8.3.1. 
Tumor Sampling 
In addition to the tumor sample required for confirmation of HER2 status, if the subject agrees, 
additional slides for optional exploratory biomarker analysis are requested. The detailed 
instructions for the handling and shipping of tumor samples are included in the study laboratory 
manual. 
8.3.2. 
Blood Sampling 
The HER2ECD in serum may be measured by a central laboratory. Other exploratory 
biomarkers, such as cfDNA in plasma, may be measured. 
8.3.3. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, optional exploratory biomarker 
research may be conducted on available additional samples. These studies would extend the 
search for other potential biomarkers that may correlate with clinical benefit. This may include 
the development of ways to detect, monitor or treat cancer. These additional investigations 
would be dependent upon clinical outcome, reagent and sample availability. If the subject agrees, 
the remaining samples (tumor tissues, blood and plasma) may be stored for up to 15 y and further 
analyzed to address scientific questions related to trastuzumab deruxtecan and/or cancer.  
8.3.4. 
Disclosure of the Results of Additional Biomarker Assessments 
See ICF for details on disclosure. 
8.4. 
Immunogenicity 
Blood samples for ADA analyses will be collected only for subjects randomized to trastuzumab 
deruxtecan and at the time points specified in Table 17.2. A blood sample will be drawn at each 
time point. Serum concentrations of trastuzumab deruxtecan and/or total anti-HER2 antibody 
may be measured using the same ADA samples for purpose of ADA assessment.  
Details for ADA serum sampling, processing, storage and shipment for ADA samples will be 
provided in the study laboratory manual. 
The ADA testing will be performed using a validated ADA assay following tiered assay steps 
including screening, confirmatory, and titer determination testing. Samples confirmed positive 
will be analyzed by neutralizing antibody assay. 
8.5. 
Pharmacogenetic Analysis 
8.5.1. 
Genomic or Genetic Banking and Analysis 
A single blood sample for pharmacogenetics analysis will be collected from each subject, who 
consents to this test, predose on Day 1 of Cycle 1. Participation in this part of the study is 
optional for all subjects. 
The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjects' blood samples. Pharmacogenetic samples may be analyzed 
for genes involved in absorption, distribution, metabolism, elimination, safety, and efficacy of 

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trastuzumab deruxtecan. Additionally, samples may be analyzed for genes involved in 
trastuzumab deruxtecan related signaling pathways, or to examine diseases or physiologic 
processes related to trastuzumab deruxtecan. DNA samples will not be immortalized or sold to 
anyone. This information may be useful in increasing the knowledge of differences among 
individuals in the way they respond to the study treatment, as well as helping in the development 
of new drugs or improvement of existing drugs. 
Specimen shipping and handling details will be included in the study laboratory manual. 
8.5.1.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
See ICF for details on disclosure. 
8.5.1.2. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until the genetic material has been exhausted or until the Sponsor 
instructs the laboratory for sample storage and/or analysis to destroy the sample (in accordance 
with laboratory procedures). During the period of storage, the genetic samples will not be 
immortalized or sold to anyone. Subjects will have the right to withdraw consent and have their 
sample destroyed at any time.  
However, the data will not be discarded if genetic analysis has been completed before the subject 
withdraws consent.  

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9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoints 
Safety endpoints will include SAEs, TEAEs, AESI, DAEs, physical examination findings 
(including ECOG PS), vital sign measurements, standard clinical laboratory parameters, ECG 
parameters, Echo/MUGA findings, and ADAs. All AEs will be categorized using the Medical 
Dictionary for Regulatory Activities (MedDRA). Adverse events and abnormal laboratory test 
results, if applicable, will be graded using National Cancer Institute (NCI)-CTCAE version 5.0. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics. 
9.2. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 9.4.1 for definitions) occurring after the subject signs the Main ICF 
and up to 40 d (+ 7 d) after last treatment (ie, the follow-up period), whether observed by the 
investigator or reported by the subject, will be recorded on the AE eCRF page. All SAEs 
occurring after subject signs the Main ICF and up to 40 d (+ 7 d) after last treatment will be 
recorded on the eCRF. Medical conditions (including laboratory values/vital signs that are out of 
range) that were diagnosed or known to exist prior to informed consent will be recorded as part 
of medical history.  
If a tumor biopsy is needed, report any SAEs directly related to tissue screening procedure (ie, 
tumor biopsy) along with any associated treatment. Unless documentation of other AEs is 
required by local law, only SAEs directly related to tumor biopsy will be recorded during tissue 
screening. 
All AEs, SAEs, and AESI are to be reported according to the procedures in Section 9.5. 
All laboratory results, vital signs, and ECG results or findings should be appraised by the 
investigator to determine their clinical significance. Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study treatment discontinuation, dose interruption or reduction, 
require corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
subject. Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject at each study visit. Subjects should be questioned in a general way, 
without asking about the occurrence of any specific symptoms. The investigator must assess all 
AEs to determine seriousness, severity, and causality, in accordance with the definitions in 
Section 9.4. The investigator’s assessment must be clearly documented in the site’s source 
documentation with the investigator’s signature. 
The investigator should always report the diagnosis as the AE or SAE term. When a diagnosis is 
unavailable, the primary sign or symptom should be reported as the AE or SAE term with 
additional details included in the narrative until the diagnosis becomes available. If the signs and 
symptoms are distinct and do not suggest a common diagnosis, they should be reported as 
individual entries of AE or SAE. 

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For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE. Preplanned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for preexisting conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 for definitions). 
For deaths, the underlying or immediate cause of death should always be reported as an SAE. 
Disease progression is a study endpoint and consequently, should not be reported as an AE/SAE. 
However, when a subject dies from PD with no other immediate causes, “disease progression” 
should be reported as an SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to study treatment should also be reported and managed as an 
SAE. 
9.3. 
Adverse Events of Special Interest 
For the trastuzumab deruxtecan clinical program, based on the available pre-clinical data, review 
of the cumulative literature, reported toxicities for the same class of agents and biological 
plausibility, ILD and LVEF decrease are considered to be AESIs. 
9.3.1. 
Interstitial Lung Disease/Pneumonitis 
9.3.1.1. 
Clinical Summary 
Interstitial lung disease/pneumonitis is considered an important identified risk based on a 
comprehensive cumulative review of the available safety data from the clinical development 
program as well as the results of potential ILD/pneumonitis cases reviewed by the independent 
ILD AC, 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.10  
9.3.1.2. 
Management Guidance 
Interstitial lung disease/pneumonitis should be ruled out if a subject develops radiographic 
changes potentially consistent with ILD or develops an acute onset of new or worsening 
pulmonary or other related signs/symptoms such as dyspnea, cough or fever. If the AE is 
confirmed to have an etiology other than ILD/pneumonitis, follow the management guidance 
outlined in the designated “Other Non-laboratory Adverse Events” dose modification section of 
the study protocol (Section 5.6).  
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 (infectious disease consultation as clinically indicated), blood culture and CBC 
(other blood tests could be considered as needed), bronchoscopy and bronchoalveolar lavage if 
clinically indicated and feasible should be considered, pulmonary function tests and SpO2, 
arterial blood gases if clinically indicated, and one blood sample collection for PK (central) 
analysis as soon as ILD/pneumonitis is suspected, if feasible. Other tests could be considered, as 
needed.  

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If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in the 
designated “Pulmonary Toxicity” dose modification section of the study protocol (Table 5.3). 
All events of ILD regardless of severity or seriousness will be followed until resolution including 
after drug discontinuation. 
9.3.1.3. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD AC for the trastuzumab deruxtecan program is responsible for reviewing all 
cases of potential ILD/pneumonitis. To ensure adequate and relevant independent evaluation, 
systematic additional data collection will be conducted for all cases that will be brought for 
adjudication. These additional data collection will cover a more in-depth relevant medical history 
(eg, smoking, radiation, COPD and other chronic lung conditions), diagnostic evaluation, 
treatment and outcome of the event. This data collection will be triggered for AEs reported using 
the selected 42 preferred terms (PTs) (all from the ILD Standardised MedDRA Query [SMQ]) 
plus the 2 PTs of acute respiratory failure and respiratory failure. 
9.3.2. 
Left Ventricular Ejection Fraction Decrease 
9.3.2.1. 
Clinical Summary 
LVEF decrease in association with trastuzumab deruxtecan are considered to be an important 
potential risk based on the available nonclinical data, literature and available safety information 
for drugs of similar class. Refer to the current IB for a summary of preliminary clinical study 
data.10 
For broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of Cardiac 
Failure and Myocardial Infarction are included for enhanced data collection; additional data for 
these AEs are collected via targeted questionnaires of heart failure or myocardial infarction. 
9.3.2.2. 
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 EOT and as needed based on subject-reported cardiac signs and 
symptoms suggesting congestive heart failure, myocardial infarction, or other causes of cardiac 
myocyte necrosis. ECGs will be performed, and standard ECG parameters will be measured, 
including RR, PR, QT intervals, and QRS duration. All ECGs must be evaluated by investigator 
or delegated physician for the presence of abnormalities. Whether or not measurement is 
performed, date performed, results, and findings for each parameter will be recorded in the 
eCRF. 
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and does not necessarily have to have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 

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whether or not considered related to the medicinal product (International Council on 
Harmonisation [ICH] E2A Guideline: Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting, Oct 1994).30  
It is the responsibility of investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 
9.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994).30  
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the subject or may require 
intervention to prevent 1 of the other outcomes listed in the definition above. Examples include 
allergic bronchospasm, convulsions, and blood dyscrasias or development of drug dependency or 
drug abuse. 
Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE. 
 Preplanned (prior to signing the ICF) procedures or treatments requiring 
hospitalization for preexisting conditions that do not worsen in severity are not SAEs. 
9.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest NCI-CTCAE version 5.0: 
 Grade 1 Mild AE 
 Grade 2 Moderate AE 
 Grade 3 Severe AE 
 Grade 4 Life-threatening consequences; urgent intervention indicated 
 Grade 5 Death related to AE 

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Severity versus Seriousness: Severity is used to describe the intensity of a specific event, 
however, the event itself may be of relatively minor medical significance (such as severe 
headache). Seriousness of an event is based upon a universal and global regulatory definition for 
reporting SAEs to regulatory agencies. For example, Grade 4 (life-threatening consequences; 
urgent intervention indicated) is assessed based on unique clinical descriptions of severity for 
each AE, and these criteria may be different from those used for the assessment of AE 
seriousness. An AE assessed as Grade 4 may or may not be assessed as serious based on the 
seriousness criteria. Overall, the severity of an event may be graded by the investigator as 
Grade 1 or 2, but if the subject presents to the emergency facility for evaluation and is 
hospitalized overnight for observation that immediately makes the event serious based upon 
hospitalization without regard to the investigator assessment of severity. 
9.4.4. 
Causality Assessment 
The investigator should assess causal relationship between an AE and the study treatment on the 
basis of his/her clinical judgment and the following definitions. The causality assessment must 
be made based on the available information and can be updated as new information becomes 
available. 
 Related 
 The AE follows a reasonable temporal sequence from study treatment 
administration, and cannot be reasonably explained by the subject’s clinical state 
or other factors (eg, disease under study, concurrent diseases, and concomitant 
medications). 
or 
 The AE follows a reasonable temporal sequence from study treatment 
administration, and is a known reaction to the drug under study or its chemical 
group, or is predicted by known pharmacology. 
 Not Related 
 The AE does not follow a reasonable sequence from study treatment 
administration, or can be reasonably explained by the subject’s clinical state or 
other factors (eg, disease under study, concurrent diseases, and concomitant 
medications).  
9.4.5. 
Action Taken Regarding Study treatments 
 Dose Not Changed 
 No change in study treatment dosage was made. 
 Drug Withdrawn 
 The study treatment was permanently stopped. 
 Dose Reduced 
 The dosage of study treatment was reduced. 

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 Drug Interrupted 
 The study treatment was temporarily stopped. 
 Not Applicable 
 Subject died, study treatment had been permanently discontinued prior to 
reaction/event, or reaction/event occurred prior to start of study treatment. 
9.4.6. 
Other Action Taken for Event 
 None 
 No treatment was required. 
 Medication required 
 Prescription and/or OTC medication was required to treat the AE. 
 Other 
9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
 Unknown should be used if subject is lost to follow-up before an outcome can be 
determined. 
9.5. 
Adverse Events Reporting–Procedure for Investigators 
All AEs, SAEs, AESIs, and overdoses will be reported in the eCRF. 
Additional relevant information regarding the AESIs ILD/pneumonitis and LVEF decrease for 
the trastuzumab deruxtecan clinical program regardless of seriousness is to be collected through 
the targeted questionnaires built within the clinical study database.   

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For broad surveillance of LVEF decrease, relevant AEs under the MedDRA SMQs of Cardiac 
Failure and Myocardial Infarction are included for enhanced data collection; additional data for 
these AEs are collected via targeted questionnaires of heart failure or myocardial infarction. 
For the trastuzumab deruxtecan arm, all targeted questionnaires are to be completed. For the 
comparator arm, only the ILD/pneumonitis targeted questionnaire is to be completed. For broad 
surveillance of ILD/pneumonitis, the selected 42 PTs (all from the ILD SMQ) plus the 2 PTs of 
respiratory failure and acute respiratory failure are included for enhanced data collections. 
Serious events that are also efficacy endpoints (eg, PD) and/or safety endpoints will be exempted 
from SAE processing and expedited reporting. Disease progression should not be reported as an 
AE/SAE. However, when a subject dies from PD with no other immediate causes, “disease 
progression” should be reported as an SAE and captured on designated eCRF. These events are 
clinically anticipated events in the target treatment population, and will be periodically reviewed 
by the Daiichi Sankyo safety teams to ensure prompt identification of any clinically concerning 
safety issues. 
The following types of events should be reported by the investigator in electronic data capture 
(EDC) within 24 h of awareness: 
 SAEs (see Section 9.4.2 for definition)  
 All potential ILD cases should be reported within 24 hours; including both serious 
and non-serious potential ILD cases (potential ILD is defined by the Event 
Adjudication Site Manual List of PTs). 
 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 total 
bilirubin > 2 × ULN that may occur either at different time points or simultaneously 
during the study. A targeted questionnaire is built within the eCRF to collect relevant 
additional information for these potential cases. 
 Overdose, defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. An “excessive and 
medically important” overdose includes any overdose in which either an SAE, a 
non-serious AE, or no AE occurs and is considered by the investigator to be clinically 
relevant; ie, poses an actual or potential risk to the subject.  
 Overdose is always serious. By definition, an overdose is medically important, 
which meets the seriousness criterion of important medical event. An overdose 
can occur with or without an AE. AEs can either be serious or non-serious. 
Details of the overdose including trastuzumab deruxtecan dosage, clinical course, 
associated AEs, and outcome must be captured in the Narrative form of the eCRF 
within electronic data capture. 
All events (serious and non-serious) must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the study treatment. A detailed narrative 
summarizing the course of the event, including its evaluation, treatment, and outcome should be 
provided. Specific or estimated dates of event onset, treatment, and resolution should be included 
when available. Medical history, concomitant medications, and laboratory data that are relevant 

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to the event should also be summarized in the narrative. For fatal events, the narrative should 
state whether an autopsy was or will be performed, and include the results if available. Source 
documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow- up. In the event that eCRF is unavailable, report 
SAEs by faxing the paper Serious Adverse Event Report (SAVER) Form to the CRO using the 
provided fax cover sheet and the appropriate fax number provided for your country. Once eCRF 
becomes available, please enter SAEs reported on the SAVER Form into eCRF as soon as 
possible. Please refer to eCRF Completion Guide for additional instructions. 
Please call the local SAE Hotline (see Study Manual) or your study monitor for any questions on 
SAE reporting. 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
Daiichi Sankyo and/or CRO will inform investigators, IRBs/ECs, and Regulatory Authorities of 
any suspected unexpected serious adverse reactions (SUSARs) occurring in other study sites or 
other studies of the study treatments, as appropriate per local reporting requirements. Daiichi 
Sankyo and/or CRO will comply with any additional local safety reporting requirements. 
In the US, upon receipt of the Sponsor’s notification of SUSARs that occurred with the study 
treatment, unless delegated to the Sponsor, it is the investigator’s responsibility to inform the 
IRB per Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
ECs and Regulatory Authorities. 
9.7. 
Exposure In Utero During Clinical Studies 
Daiichi Sankyo must be notified of any subject or their female partner who becomes pregnant 
while receiving or within 7 mo of discontinuing the study treatment.  
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome. This information is important for both drug safety and public health 
concerns. It is the responsibility of the investigator, or designee, to report any pregnancy in a 
female subject using the Exposure In Utero (EIU) Reporting form. Please contact your study 
monitor to receive the EIU Reporting form upon learning of a pregnancy, including normal 
delivery and induced abortion. An adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures. The investigator should make every 
effort to follow the subject until completion of the pregnancy. If the outcome of the pregnancy 
meets the criteria for immediate classification as a SAE (ie, post-partum complications, 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly, including that in an 
aborted fetus), the investigator should follow the procedures for reporting SAEs outlined in 
Section 9.5. 

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9.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed: 
1. Hematology tests 
 Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
2. Blood chemistry tests 
 Total protein, albumin, alkaline phosphatase, ALT, AST, TBL, blood urea nitrogen 
(BUN)/urea, calcium, chloride, serum creatinine, lactate dehydrogenase (LDH), 
magnesium, potassium, sodium. 
 A coagulation test will be performed (prothrombin time and either partial 
thromboplastin or activated partial thromboplastin time). 
 Creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation 
(Section 17.2). 
 Troponin will be analyzed for each sample at Screening, EOT, and as needed based 
on subject-reported signs or symptoms.  
3. Urinalysis 
 Protein, glucose, blood, microscopy assessment (if indicated), and specific gravity. 
In addition, the following parameters will be analyzed at the visits indicated in the Schedule 
of Events (Table 17.1 and Table 17.2).  
 Pregnancy test (serum or urine) for all female subjects of childbearing potential must 
be performed during the Screening period within 72 h prior to the beginning of 
infusion on Day 1 of each cycle, at EOT, and at the 40-Day Follow-up assessments. A 
positive urine pregnancy test result must be confirmed immediately using a serum 
test. 
All laboratory values must be appraised by the investigator as to clinical significance and 
used to take appropriate clinical management measures. All abnormal laboratory values 
considered clinically significant by the investigator should be recorded on the AE page of the 
eCRF. If the abnormal laboratory value constitutes an SAE, relevant procedures must be 
followed (see Section 9.5). Abnormal laboratory values (NCI-CTCAE Grade 3 or 4) 
occurring during the clinical study will be followed until repeat test results return to normal 
(or baseline), stabilize, or are no longer clinically significant. 
9.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and body temperature.  

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9.10. 
Electrocardiograms 
ECGs will be taken in triplicate at screening.  Thereafter, singular ECGs will be performed. If an 
abnormality is noted, ECGs should then be performed in triplicate.  Standard 
supine/semi-recumbent 12-lead ECGs will be taken prior to blood draws and will be performed 
as described in the Schedule of Events (Table 17.1 and Table 17.2).  When taken in triplicate, 
ECGs should be taken in close succession).  Standard ECG parameters will be measured, 
including RR, PR, QT intervals, and QRS duration. All ECGs must be evaluated by investigator 
or delegated physician for the presence of abnormalities. 
9.11. 
Physical Examinations 
Physical examination findings will evaluate the following body systems/organs: general 
appearance; dermatological; head; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and neurological. 
Weight and height will also be recorded in kilograms and centimeters, respectively. 
9.12. 
Other Examinations 
9.12.1. 
Cardiac Assessments 
Either Echo or MUGA will be performed as described in the Schedule of Events (Table 17.1 and 
Table 17.2). LVEF will be measured. 
9.12.2. 
Pulmonary Assessments 
The SpO2 will be measured at Screening, BI and EOI on Day 1 of each cycle, Days 8 and 15 of 
Cycle 1, EOT and at the 40-Day (+ 7 d) Follow-up assessments. For more details please refer to 
Section 6 of the protocol. 
An ILD AC will review all cases of (potential) ILD on an ongoing basis. Description of the ILD 
AC is available in Section 9.3.1.3. 

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10. 
OTHER ASSESSMENTS 
10.1. 
Patient Reported Outcomes 
Patient reported outcomes will be used to evaluate study treatment. The impact of breast cancer 
symptoms will be assessed based upon the EORTC QLQ-BR45 and EORTC QLQ-C30 
(version 3.0) and EQ-5D-5L questionnaires (Section 17.6 and Section 17.7, respectively). 
10.1.1. 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaires C30 and BR45  
The QLQ-C30 is a QoL instrument for cancer patients developed in 1987 by EORTC. Since then 
it has undergone several revisions and its current version is 3.0. 
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items. Each 
of the multi-item scales includes a different set of items - no item occurs in more than 1 scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
Thus, a high score for a functional scale represents a high/healthy level of functioning, a high 
score for the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatology/problems. 
Due to limitations inherent in its generic focus, the EORTC QLQ-C30 is supplemented by 
disease specific modules such as the EORTC QLQ-BR45, which are designed to be administered 
in addition to the core questionnaire. The EORTC QLQ-BR45 is specific for breast cancer. 
The EORTC QLQ-C30 with EORTC QLQ-BR45 will be used in the study as the disease- 
specific instruments to assess the health-related QoL of subjects. They will be administered 
before any other assessments or procedures are done that day.  Complete at  Cycle 1 Day 1, 
Cycle 2 Day 1, Cycle 3 Day 1, and then every 2 cycles thereafter (eg, Cycles 5, 7, 9, etc) and at 
the EOT as defined in the protocol. Subjects will be followed up at Day 40 (+ 7 d) and at the first 
Long-term/Survival Follow-up assessments 3 mo after that (last measurement). Reporting will 
follow closely the Consolidated Standards of Reporting Trials (CONSORT) extension on 
reporting PROs.31  
Changes from baseline over time will be assessed in the global QoL scale, each of the 
functioning scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, 
nausea/vomiting, and pain), 6 single-item scales (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, and financial impact) of the EORTC QLQ-C30 and in each of the 
subscales (breast symptoms, arm symptoms, body image, sexual functioning, and systemic 
therapy side effects) of the EORTC QLQ-BR45.  
Further, time to deterioration on the ‘breast symptoms’ and ‘arm symptoms’ subscales of the 
EORTC QLQ-BR45 and the pain symptom subscale of the EORTC QLQ-C30 will be assessed. 
On the basis of previously published research on clinically meaningful changes in the EORTC 
QLQ-BR45 and the QLQ-C30, deterioration is defined as an increase of 10 points or more on 
these symptom subscale scores. 

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Further details on the scoring of these scales, including missing items, will be provided in the 
SAP. 
10.1.2. 
EuroQoL Five Dimensions Five Levels (EQ-5D-5L) Patient Reported Outcome 
Questionnaire 
Study subjects will be asked to complete the EQ-5D-5L questionnaire, a generic measure of 
standardized health status, before any other study procedures are performed at Cycle 1 Day 1, 
Cycle 2 Day 1, Cycle 3 Day 1, and then every 2 cycles thereafter (eg, Cycles 5, 7, 9, etc) and at 
the EOT assessments. Data collection will continue at the 40-Day (+ 7 d) Follow-up assessments 
and the first Long-term/Survival Follow-up assessments 3 mo later, which will be the last data 
collection point for both questionnaires. 
The EQ-5D-5L is self-administered and consists of 2 parts, the EQ-5D-5L descriptive system, 
and the EQ-visual analogue scale (VAS). The descriptive system comprises 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems.32 The respondent is asked to indicate his/her health state by ticking (or placing a cross) 
in the box against the most appropriate statement in each of the 5 dimensions. This decision 
results in a 1-digit number expressing the level selected for that dimension. The digits for 
5 dimensions can be combined in a 5-digit number describing the respondent’s health state. The 
numerals 1 to 5 have no arithmetic properties and should not be used as a cardinal score.  
The EQ-VAS records the respondent’s self-rated health on a 20 cm vertical, VAS with endpoints 
labeled “the best health you can imagine” and “the worst health you can imagine.” This 
information can be used as a quantitative measure of health as judged by the individual 
respondents.  
The EQ-5D-5L will be administered before the first cycle and every 2 cycles after that until EOT 
as defined in the protocol. Subjects will be followed up at Day 40 (+ 7 d) and at the first 
Long-term/Survival Follow-up visit 3 mo after that (last measurement). Reporting will follow 
closely the CONSORT extension on reporting PROs.31  
10.2. 
Health-related QoL Endpoints 
10.2.1. 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Endpoints 
 Changes from baseline over time will be assessed in the global QoL scale, each of the 
functioning scales (physical, role, emotional, cognitive, and social), symptom scales 
(fatigue, nausea/vomiting, and pain), and the 6 single-item scales (dyspnea, sleep 
disturbance, appetite loss, constipation, diarrhea, and financial impact) of the EORTC 
QLQ-C30.  
 Time to deterioration on the pain symptom subscale of the EORTC QLQ-C30 will be 
assessed. 
 Changes from baseline over time will be assessed in each of the subscales (breast 
symptoms, arm symptoms, body image, sexual functioning, and systemic therapy side 
effects) of the EORTC QLQ-BR45.  

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 Time to deterioration on the ‘breast symptoms’ and ‘arm symptoms’ subscales of the 
EORTC QLQ-BR45 will be assessed. 
 On the basis of previously published research on clinically meaningful changes in the 
EORTC QLQ-BR45 and the QLQ-C30, deterioration is defined as an increase of 
10 points or more on these symptom subscale scores.33  
10.2.2. 
EuroQoL Five Dimensions Five Levels Endpoints 
 VAS as a measure of self-rated health status 
 Response by dimension 
 Index score change from baseline using UK value set 
 Index score by disease state 
10.3. 
Pharmacoeconomic Assessments 
10.3.1. 
Hospitalization-Related Endpoint 
Time to hospitalization will be assessed. Each hospitalization event will prompt the completion, 
by the site, of a detailed hospitalization eCRF containing the following components: 
 Date of admission to hospital. 
 Date of discharge from hospital. 
 Primary reason for hospitalization. 
 Discharge status from hospital (died, discharged home, discharged to home health 
care, discharged to nursing home care, discharged to long-term care, other). 
 Use of intensive care unit (ICU) services in hospital (Yes/No). 
 If yes, date of admission to ICU. 
 If yes, date of discharge from ICU. 

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11. 
STATISTICAL METHODS  
11.1. 
General Statistical Considerations 
The primary analyses for PFS based on BICR will be performed.  An interim and a final analysis 
for PFS is planned in this trial. The interim analysis will be performed when approximately 
234 BICR-assessed PFS events (70% information fraction) have been observed. If the trial is not 
statistically significant at this interim analysis, the final PFS analysis will be performed after 
observing 335 BICR-assessed PFS events. 
Projections of total number of PFS or OS events for interim or final analysis (as appropriate) will 
be performed as the trial progresses to monitor the number of PFS events for data cutoff. Data 
cutoff date for primary analysis will be at approximately the projected date of the 234th event for 
the interim analysis or the 335th PFS event if the study proceeds to final analysis. 
Starting 2 wk before and ending by the projected date for the PFS and OS analysis data cutoff, a 
data sweep will be conducted to collect information such as survival and clinical progression (to 
be described in a separate PFS/OS event sweep plan).Analysis of the data will be inclusive of all 
data collected up to the data cutoff date, and the database will be comprised of the primary 
analysis and submission data sets. 
Long-term/Survival Follow-up, as specified in Section 6.6.2, will continue after primary 
analysis. 
Summary statistics will be presented by treatment group. Continuous variables will be 
summarized by the number of observations, mean, standard error, median, minimum, and 
maximum values. Categorical variables will be summarized using frequency counts and 
percentages. 
Assessment of change from baseline to posttreatment or the ratio of posttreatment to baseline 
will include only those subjects with both baseline and posttreatment measurements. The last 
non-missing value of a variable taken before the first dose of the study treatment will be used as 
the baseline value, unless otherwise specified. In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified. 
Efficacy analyses will be performed on the Full Analysis Set (FAS). Primary efficacy analyses 
may also be performed on the Per-protocol Analysis Set (PPS). Safety analyses will be 
performed using the Safety Analysis Set. PK analysis will be based on the PK Analysis Set. All 
other exploratory analyses will be performed based on the FAS unless otherwise specified. 
11.2. 
Analysis Sets 
11.2.1. 
Full Analysis Set 
The FAS will include all randomized subjects. Following the intent-to-treat principle, subjects 
will be analyzed according to the treatments and strata they were assigned at randomization. 
11.2.2. 
Safety Analysis Set 
The Safety Analysis Set will include all randomized subjects who received at least 1 dose of 
study treatment. Subjects will be summarized according to treatment actually received.  

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11.2.3. 
Per-protocol Analysis Set 
The PPS will include all subjects from the FAS without any of the SAP-specified major protocol 
deviations and who received at least one dose of study treatment. Additional details will be 
specified in the SAP. 
11.2.4. 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects who received at least 1 dose of trastuzumab 
deruxtecan and had any measurable post-dose serum concentrations of trastuzumab deruxtecan, 
total anti-HER2 antibody, and MAAA-1181a. 
11.3. 
Study Population Data 
Subject disposition will be summarized for subjects in the FAS. The total number of subjects for 
each defined analysis population will also be tabulated. The demographic and baseline 
characteristics will be summarized descriptively for the FAS. Some baseline characteristics may 
also be summarized for Safety Analysis Set and PPS. Study treatment exposure and treatment 
duration will be summarized using descriptive statistics for the Safety Analysis Set. 
11.4. 
Statistical Analysis  
11.4.1. 
Efficacy Analyses 
11.4.1.1. Primary Efficacy Analyses 
The primary efficacy endpoint is PFS based on BICR. An interim and a final analysis for PFS is 
planned in this trial. The interim analysis will be performed when approximately 234 
BICR-assessed PFS events (70% information fraction) have been observed. If the trial is not 
statistically significant at this interim analysis, the final PFS analysis will be performed after 
observing 335 BICR-assessed PFS events. 
The primary efficacy analyses will be performed for the Full Analysis Set that consists of all 
randomized subjects. Following Intent-to-Treat principles, patients will be analyzed according to 
the treatment and the strata they were randomized as recorded in IXRS.  
The primary efficacy analysis will be the comparison of the survival distribution of PFS based on 
BICR between the 2 treatment groups, using a stratified log-rank test stratified by the 
randomization stratification factors as recorded by IXRS, at an overall 2-sided significance level 
of 0.05.  
One interim analysis for superiority is planned after at least 234 of the targeted 335 PFS events 
(70% information fraction) have been documented and after enrollment is completed. The 
primary intent of the interim analysis is to demonstrate superiority of the primary efficacy 
endpoint of PFS only and a formal futility evaluation is not planned. If superiority is not 
demonstrated at the interim analysis, final PFS analysis is planned after approximately 335 PFS 
events have been documented. A group sequential design, utilizing a Haybittle-Peto efficacy 
boundary36, 37, will be used to control the type I error rate for the primary efficacy analysis. 
Additional details of the interim analysis can be found in Section 11.5. 

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The survival distribution of PFS will be estimated by Kaplan-Meier method for each treatment 
group and results will be presented graphically. The median PFS time and the 2-sided 95% CI 
for the median will be provided using Brookmeyer and Crowley method for each treatment 
group. In addition, Kaplan-Meier estimates of PFS rate at fixed time points (eg, 3, 6, 9, 12 mo) 
along with their 2-sided 95% CIs will be provided for each treatment group. The treatment effect 
hazard ratio (HR) and its 95% CI will be estimated, using stratified Cox proportional hazards 
regression model stratified by the randomization stratification factors as recorded by the IXRS. 
11.4.1.2. Secondary Efficacy Analyses 
The key secondary efficacy endpoint is OS. Two interim analyses and a final analysis of OS are 
planned. The first OS interim analysis is planned at time of the PFS interim analysis, and the 
second OS interim analysis is planned at time of the final PFS analysis. Approximately 96 and 
153 of the planned 250 OS events (38.4% and 61.2% of information fractions) will be expected 
to be documented by time of the first and the second OS interim analyses, respectively. Final OS 
analysis is planned after approximately 250 OS events have been documented.  
A three-look design is considered for OS. OS will be hierarchically tested in the following way: 
1. The first potential OS analysis will be at the time of the PFS interim analysis after 
96 expected deaths. If PFS is statistically significant at this stage, OS will also be tested. 
If OS is not statistically significant at this stage, the second OS interim analysis will be 
planned after 153 deaths. If OS is not statistically significant at the second interim 
analysis, a final analysis is planned after 250 deaths have been recorded. 
2. If PFS is not statistically significant at the time of the interim analysis of PFS, then OS 
will not be tested at the time of the interim analysis of PFS. If PFS is statistically 
significant at the time of the final analysis, then OS will also be tested. If OS is not 
statistically significant at this stage, further testing will be carried out when a total of 
250 deaths have been recorded. 
3. If PFS is not statistically significant after the final analysis for PFS is performed, then OS 
will not be tested. 
The type I error rate will be controlled by using a separate Lan-DeMets alpha spending function 
with O’Brien-Fleming boundary independent of the one used for the primary efficacy analysis 
of PFS at the 2-sided significance level of 0.05. This guarantees the protection of the overall 
significance level across the 2 hypotheses and the repeated testing of the OS hypotheses in the 
interim and the final analyses.34 
Overall survival will be compared between the 2 treatment groups, using a stratified log-rank test 
stratified by the randomization stratification factors as recorded by IXRS, at 2-sided significance 
level of 0.05, provided superiority in PFS is demonstrated at either interim or final analysis. The 
survival distribution of OS will be estimated by Kaplan-Meier method and results will be 
presented graphically. The median survival time and the 2-sided 95% CI for the median will be 
provided using Brookmeyer and Crowley method for each treatment group. In addition, 
Kaplan-Meier estimates of OS rate at fixed time points (eg, 3, 6, 9, 12 mo) along with their 
2-sided 95% CIs will be provided for each treatment group. The treatment effect HR and its 95% 
CI will be estimated, using stratified Cox proportional hazards regression model stratified by the 
randomization stratification factors as recorded by the IXRS. 

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Other secondary efficacy endpoints include ORR based on BICR and investigator assessment, 
DoR based on BICR, and PFS based on investigator assessment.  
Cochran-Mantel-Haenszel tests stratified by the randomization stratification factors will be used 
to compare ORR (based on BICR and investigator assessment) between the treatment groups. 
ORR will be summarized by treatment group along with their 2-sided 95% CIs using 
Clopper-Pearson methods. 
Duration of response (DoR, based on BICR) will be summarized with median event time and the 
2-sided 95% CI using Brookmeyer and Crowley method for each treatment group. Detailed 
censoring rules for DoR will be specified in the SAP. 
The survival distribution of PFS based on investigator assessment will be estimated using the 
Kaplan-Meier method and will be presented graphically by treatment group.  The median PFS 
and its two-sided 95% CI using Brookmeyer and Crowley method will be provided for each 
treatment group.  PFS rates at fixed time points (e.g., 3, 6, 9, 12 months) and the two-sided 95% 
CIs will be provided for each treatment group. The treatment effect hazard ratio and its two-sided 
95% CI will be estimated using stratified Cox proportional hazards regression model with the 
same stratification factors as the randomization stratification factors taken from IXRS. The 
survival distribution of PFS based on investigator assessment between the two treatment groups 
will be compared at a two-sided significance level of 0.05, using a stratified log-rank test 
stratified by the randomization stratification factors as recorded by IXRS, at the time when 
primary analysis of PFS per BICR is statistically significant. 
11.4.1.3. Exploratory Efficacy Analyses 
11.4.1.3.1. Subgroup Analyses  
Subgroup analyses for PFS (based on BICR) and OS will be performed for the FAS if the 
primary analysis is statistically significant. Subgroups will include: 
 Hormone receptor status (positive, negative) 
 ERs (positive, negative) 
 Lines of prior systemic therapy not including hormone therapy (<3, ≥3) 
 Prior treatment with pertuzumab (yes, no) 
 Lines of therapy prior to pertuzumab treatment (<3 line, ≥3 line) 
 Renal impairment at baseline (within normal range, mild/moderate impairment) 
 Hepatic impairment at baseline (within normal range, mild impairment) 
 History of visceral disease (yes, no) 
 Clinically inactive CNS metastases (CNS metastases, no CNS metastases) 
 Age (< 65, ≥ 65 y) 
 Race (Asian, Rest of World) 
 Region (Asia, North American, Europe, RoW) 
 ECOG PS (0, 1) 

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The subgroups are based on baseline values (ie, the last non-missing values before the first drug 
administration). In each subgroup defined above, the analysis will be carried out using the same 
type of methodology as described for the overall analysis of the corresponding endpoint but not 
adjusted by stratification. No inferential statistics (p-values) will be presented for the subgroups. 
These results will be considered exploratory because of smaller sample sizes. Subgroup analyses 
will be performed only if at least 10 events in each subgroup. 
11.4.1.3.2. Analyses of Exploratory Efficacy Endpoints 
Time to response based on BICR, best percent change in the sum of the diameter of measurable 
tumors based on BICR, and CBR based on BICR will be evaluated and considered as exploratory 
efficacy endpoints. 
Descriptive statistics for the best percent change from baseline to minimum post-baseline sum of 
the diameter (based on BICR) and for time to response (based on BICR) will be provided by 
treatment group. A waterfall plot of the best percent change (baseline to post-baseline minimum) 
in the sum of the diameter for each subject will be presented for each treatment group with 
vertical lines representing the sorted values of percent changes. 
CBR based on BICR will be summarized by treatment group along with their 2-sided 95% CIs 
using Clopper-Pearson methods. 
The survival distribution of PFS2 will be estimated using the Kaplan-Meier method and will be 
presented graphically by treatment group.  The median PFS2 and its 2-sided 95% CI using the 
Brookmeyer and Crowley method will be provided for each treatment group.  PFS2 rates at fixed 
time points (eg, 3, 6, 9, 12 months) and the 2-sided 95% CIs will be provided for each treatment 
group.  The treatment effect hazard ratio and its 2-sided 95% CI will be estimated using a 
stratified Cox proportional hazards regression model with the treatment group as model factor 
and the randomization stratification factors taken from IXRS as strata variables.  
Exposure-response relationships will be explored. 
11.4.2. 
Analyses of Health Economic and Outcomes Research Endpoints 
Health economic and outcomes research endpoints based on the hospitalization-related data 
collection form and the following PRO questionnaires will be summarized by treatment group: 
EORTC QLQ-C30, EORTC QLQ-BR45, and EQ-5D-5L. 
The global health status/QoL scale of the EORTC QLQ-C30 questionnaire is the primary HEOR 
measurement. A score of the global health status/QoL at each assessment will be calculated per 
“EORTC QLQ-C30 Scoring Manual.” Primary analysis of the global health status/QoL score 
will use mixed model for repeated measurements. The primary analysis will be detailed in the 
SAP. Additional analyses of HEOR endpoints are in Section 11.4.2.1 through Section 11.4.2.3. 
11.4.2.1. EuroQoL Five Dimensions Five Levels 
Based on results of the EQ-5D-5L assessment, the EQ-5D-5L summary index score across 
disease states will be assessed. Descriptive statistics for the actual value and change from 
baseline will be computed for the EQ-5D-5L health profile utilities and EQ-VAS by scheduled 

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time of evaluation (including EOT) for all subjects using the EQ-5D Analysis Set. Results of the 
EQ-VAS will be presented as a measure of overall self-rated health status. 
11.4.2.2. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 and BR45 
Changes from baseline over time will be assessed in the global QoL scale, each of the 
functioning scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, 
nausea/vomiting, and pain), and 6 single-item scales (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhea, and financial impact) of the EORTC QLQ-C30 and in each of the 
subscales (breast symptoms, arm symptoms, body image, sexual functioning, and systemic 
therapy side effects) of the EORTC QLQ-BR45.  
Time to deterioration on the ‘breast symptoms’ and ‘arm symptoms’ subscales of the EORTC 
QLQ-BR45 and the pain symptom subscale of the EORTC QLQ-C30 will also be assessed. On 
the basis of previously published research on clinically meaningful changes in the EORTC 
QLQ-BR45 and the QLQ-C30, deterioration is defined as an increase of 10 points or more on 
these symptom subscale scores. Time to definitive deterioration will be compared between the 
2 treatment groups in the FAS using the stratified log-rank test with the same stratification 
factors as the randomization stratification factors taken from IXRS at 2-sided significance level 
of 5%. The survival distributions will be estimated by Kaplan-Meier method and results will be 
presented graphically for each treatment. The median time to definitive deterioration and the 
proportion of patients without definitive deterioration at specific time points will be reported 
along with the 2-sided 95% CIs for the medians. The treatment effect HR of time to definitive 
deterioration and its 95% CIs will be estimated using a stratified Cox proportional hazards 
regression model stratified by the randomization stratification factors as recorded by the IXRS. 
Further details on the scoring of these scales, including missing items, will be provided in the 
SAP. 
11.4.2.3. Hospitalization-Related Endpoints 
For hospitalization-related endpoints: time to hospitalization as well as reason, discharge 
diagnosis, ICU stay, and length of stay will be reported. 
11.4.3. 
Pharmacokinetic/Pharmacodynamic/Biomarker Analyses 
11.4.3.1. Pharmacokinetic Analyses 
Descriptive statistics will be provided for all serum concentration data (trastuzumab deruxtecan, 
total anti-HER2 antibody and MAAA-1181a) at each time point.   
The population PK (pop-PK) analysis to evaluate the effect of intrinsic and extrinsic factors of 
trastuzumab deruxtecan, and if appropriate, total anti-HER2 antibody, and MAAA-1181a will be 
characterized including available PK data.  After establishment of the pop-PK model, a 
pop-PK/pharmacodynamic model may be developed to evaluate the relationship between 
exposure and efficacy and toxicity.  The results of the nonlinear mixed effects of pop-PK and 
pop-PK/pharmacodynamic models may be reported separately from the clinical study report. 

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11.4.3.2. Pharmacodynamic Analyses 
Not applicable 
11.4.3.3. Biomarker Analyses 
Archived tissue will be requested for re-analysis of HER2 status by immunohistochemistry 
and/or in situ hybridization as well as exploratory for biomarker analyses. Biomarkers will be 
summarized by treatment group using descriptive statistics. 
11.4.4. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set and subjects will be analyzed 
according to their actual treatment received. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics. 
11.4.4.1. Adverse Event Analyses 
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 study drug up until 47 days after last dose 
of the study drug.  SAEs with an onset 48 days or more after the last dose of study drug, if 
considered related to the study treatment, are also TEAEs. Treatment-emergent AEs will be 
coded using MedDRA and assigned grades based on version 5.0 of NCI-CTCAE. The number 
and percentage of subjects reporting TEAEs will be tabulated by System Organ Class (SOC), PT, 
relationship to the study treatment, and the worst CTCAE grade. Similarly, the number and 
percentage of subjects reporting serious TEAEs will be tabulated by treatment group, as well as 
TEAEs leading to discontinuation of the study treatments. 
A by-subject AE (including TEAE) data listing including but not limited to the verbatim terms, 
SOC, PT, NCI-CTCAE grade, and relationship to study treatment will be provided. Deaths, other 
SAEs, AESIs, and other significant AEs, including those leading to discontinuation of the study 
treatments, will be listed.  
Treatment-emergent AEs will also be summarized by treatment group for the subgroups 
described in the SAP. 
11.4.4.2. Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory test results and changes from 
baseline by treatment group at each scheduled time of evaluation, including EOT, maximum 
posttreatment value, and minimum posttreatment value. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing. A shift table, presenting 
2-way frequency tabulation for baseline and the worst posttreatment value according to 
NCI-CTCAE grade, will be provided for clinical laboratory tests. 
All clinical laboratory test results and abnormal clinical laboratory test results deemed of clinical 
significance or of Grade 3 or 4 will be listed.  

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11.4.4.3. Vital Sign Analyses 
Descriptive statistics will be provided by treatment group for the vital sign measurements and 
changes from baseline by scheduled time of evaluation, including EOT and the maximum and 
minimum posttreatment values. All vital sign data will also be listed.  
11.4.4.4. Electrocardiogram Analyses 
Descriptive statistics will be provided by treatment group for ECG parameters and changes from 
baseline by scheduled time of evaluation, including EOT and the maximum posttreatment value. 
In addition, the number and percentage of subjects with ECG interval values meeting the criteria 
will be tabulated (eg, QTc ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms). The 
QT intervals will be corrected for heart rate by Fridericia’s formula (QTcF; QTcF = QT/[RR]1/3). 
ECG data will also be listed. 
11.4.4.5. Physical Examination Analyses 
Physical examination findings will be listed. 
11.4.4.6. Concomitant Medication Analyses 
Concomitant medications will be coded using the World Health Organization drug dictionary. 
Number and percentage of subjects taking concomitant medications will be summarized. 
Concomitant medications will also be listed. 
11.4.4.7. Immunogenicity (Anti-Drug Antibody) Analyses 
Immunogenicity will be assessed through characterization of incidence and titer of ADA.  A 
summary table by scheduled visit will be provided for incidence of ADA. The raw values for 
ADA titers for ADA positive subjects will be listed and summarized using descriptive statistics 
by scheduled visit. 
The number and percentage of the treatment-emerging ADA incidence will be calculated. 
Treatment-emergent ADA positive subject will be defined as subjects who are ADA negative at 
baseline and become ADA positive posttreatment, or who are ADA positive at baseline and 
posttreatment, but have an increase in ADA titer from baseline to posttreatment, or those who 
have missing ADA data at baseline but become ADA positive posttreatment.  The number and 
percentage of subjects positive for neutralizing anti-drug antibody (NAB) of trastuzumab 
deruxtecan, if analyzed, will also be determined.  A listing of all ADA/NAB assessments will be 
provided.  Further details will be provided in the SAP.   
11.4.4.8. Other Safety Analyses 
All other safety endpoints (eg, physical examination findings including ECOG PS and 
Echo/MUGA) will be listed. 
11.5. 
Interim Analyses 
An interim analysis of PFS for superiority is planned after at least 234 PFS events (70% 
information fraction) have been documented.  The primary intent of the interim analysis is to 
demonstrate superiority of the primary efficacy endpoint of PFS only, and a formal futility 

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evaluation is not planned. If the study continues to the final PFS analysis, the final PFS analysis 
will be performed when approximately 335 PFS events have been documented. A group 
sequential design, utilizing a 2-look Haybittle-Peto stop boundary36, 37, will be used to construct 
the efficacy stopping boundaries35 with an overall 2-sided significance level of 0.05.  
If the PFS interim analysis is carried out exactly after 70% of events, the efficacy boundary at the 
interim analysis is calculated as 0.000204 in p-value (2-sided) scale or 0.615 in HR scale; the 
observed 2-sided p-value/HR has to be less than these efficacy boundaries to conclude superior 
efficacy at the interim analysis. If the interim analysis of PFS is carried out exactly after 70% of 
events, and the study continues until the final analysis with exactly 335 PFS events, the observed 
2-sided p-value will have to be less than 0.049998 to declare statistical significance at final 
analysis.  
OS will be compared between the 2 treatment groups, provided superiority in PFS is 
demonstrated at either interim or final analysis. A hierarchical testing procedure, as described in 
Section 11.4.1.2, will be adopted in this study and the OS analyses will be performed only if the 
primary efficacy endpoint PFS is statistically significant. Two interim analyses are planned for 
OS, at the time of the interim and final analyses for PFS. Approximately 96 and 153 of the 
planned 250 OS events are expected to be observed (38.4% and 61.2% of information fractions) 
by time of the first and second OS interim analyses, respectively. Final OS analysis is planned 
after approximately 250 OS events have been documented if the superiority is not demonstrated 
at either OS interim analysis. 
A group sequential design, utilizing 3-look Lan-DeMets alpha spending function with 
O’Brien - Fleming stop boundary will be used to construct the efficacy stopping boundaries35 
with an overall 2-sided significance level of 0.05. The trial allows for the stopping of the study 
for a superior OS result, provided the primary endpoint PFS has already been shown to be 
statistically significant. The exact nominal p-values that will need to be observed to declare 
statistical significance at the time of these analyses for OS will depend on the number of OS 
events that have been observed at the time of these analyses and the significance level for OS 
already spent at the time of earlier analyses. 
If the interim and final analyses are carried out with exactly 96, 153, and 250 OS events 
respectively, the efficacy boundaries in p-value scale (HR scale) at the interim and final analyses 
are calculated as p = 0.001, 0.008, and 0.047 (2-sided) and HR = 0.496, 0.652, and 0.778, 
respectively. Efficacy stopping boundaries and the power at each analysis of the group sequential 
design for PFS and OS are summarized in Table 11.1. 

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Table 11.1: 
Efficacy Stopping Boundaries for PFS/OS Interim and Final Analyses 
Endpoint 
Median PFS: 13.7 mo for trastuzumab 
deruxtecan arm, 9.6 mo for T-DM1 arm 
(HR = 0.7) 
Median OS: 42.7 mo for trastuzumab 
deruxtecan arm, 29.9 mo for T-DM1 arm 
(HR = 0.7) 
PFS 
OS 
PFS 
events 
(IF) 
Boundary 
Cumulative 
Power 
OS 
Events 
(IF) b 
Boundary 
Cumulative 
Power f 
P-valuea 
HR 
P-
valuea 
HR 
IA 
1st IA 
234 
(70%) 
0.000204 
0.615 
15.9% 
96 
(38.4%)c 
0.001 
0.496 
4.48% 
FA 
2nd IA 
335 
(100%) 
0.049998 
0.807 
90.5% 
153 
(61.2%)d 
0.008 
0.652 
31.89% 
 
Final 
-- 
-- 
-- 
 
250 
(100%)e 
0.047 
0.778 
 
PFS = progression-free survival; OS = overall survival; IA = interim analysis; HR = hazard ratio; IF: Information 
Fraction 
The interim analysis for PFS at IF = 70% to stop for efficacy with 2-look Haybittle-Peto stop boundary. The interim 
analyses for OS at IF = 38.4% and 61.2% to stop for efficacy with 3-look Lan-DeMets alpha spending function with 
O’Brien-Fleming stop boundary. A total of 500 subjects will be enrolled. 
a P-values are 2-sided 
b The summary is based on 10,000 simulations in EAST 6.4 
c To be performed if the interim analysis for PFS was statistically significant 
d To be performed if the interim analysis for PFS was statistically significant but first interim analysis for OS is not 
statistically significant or if the final analysis for PFS was statistically significant 
e To be performed only if either the interim or the final analysis for PFS was statistically significant and neither the 
interim analyses for OS was statistically significant 
f Power conditional on PFS being significant 
Since the observed number of events at the PFS or OS interim analyses may not be exactly equal 
to the planned number of events, the efficacy boundaries will need to be recalculated based on 
the actual number of observed events using the pre-specified alpha spending function. If the 
study continues to final analysis, the efficacy stopping boundary used to declare statistical 
significance at the final analysis will be based on the actual number of PFS or OS events 
documented at the cutoff date for the final analysis and the significance level already spent at the 
interim analyses.  
For the interim analysis of PFS, an independent statistician will perform the analyses for the 
DMC.  At the time of the interim analysis for PFS, an interim analysis for OS will be performed 
if PFS is significant.  Unblinded results from the interim analysis for PFS and corresponding 
interim analysis for OS will not be communicated to the sponsor’s clinical team or to any party 
involved in the study conduct (apart from the independent statistician and DMC members) until 
the DMC has determined that PFS analysis has crossed the pre-specified boundary for efficacy. 
Further details will be described in the DMC Charter.   
11.6. 
Sample Size Determination 
This is a prospectively randomized, open-label study comparing the primary endpoint of PFS and 
the key secondary endpoint of OS between the 2 treatment groups, trastuzumab deruxtecan and 
T-DM1.  

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Assuming a median PFS of 9.6 months in the T-DM1 arm based on the results of the EMILIA 
study, 4 it is hypothesized that treatment with trastuzumab deruxtecan will result in a HR of 0.7, a 
30% reduction in the hazard rate of PFS (disease progression or death) that would correspond to 
a 43% improvement in median PFS from 9.6 months in the T-DM1 arm to 13.7 months in the 
trastuzumab deruxtecan arm under the exponential model assumption. 
A total of approximately 500 subjects will be randomized (250 subjects to trastuzumab 
deruxtecan and 250 subjects to T-DM1). The final PFS analysis will occur after approximately 
335 PFS events have been documented, if superiority is not demonstrated at the interim analysis. 
An interim analysis that allows the study to declare superiority of the primary efficacy endpoint 
is planned after approximately 234 (70%) of the targeted PFS events are documented. With 
335 PFS events, the study will have approximately 90.4% power to detect an HR of 0.70 in PFS 
at an overall 2-sided significance level of 0.05 to reject the null hypothesis (HR =1) using a 
log-rank test and a 2-look group sequential design with Haybittle-Peto efficacy boundary36, 37.  
A Monte-Carlo simulation based on 10,000 samples was carried out to characterize the 
probability of the study outcomes under various assumptions of the true hazard ratios 
(Table 11.2).  If the alternative hypothesis is true, that is, the true hazard ratio is 0.7, then there is 
90. 5% probability that the study will be successful at the time of either the interim analysis or 
the final analysis.   
Table 11.2: 
Probability of Study Outcomes Under Various True Hazard Ratios 
True Hazard Ratio 
(mPFS) 
Power at the Interim 
Analysisa 
Cumulative Power 
at the Final 
Analysisa 
% Non-successa,b 
0.5 (9.6 vs 19.2) 
93.6% 
100% 
0% 
0.6 (9.6 vs 16) 
57.1% 
99.8% 
0.2% 
0.7 (9.6 vs 13.7) 
15.9% 
90.5% 
9.5% 
mPFS = median progression-free survival 
The PFS interim analysis at IF = 70% in each scenario to stop for efficacy with 2-look Haybittle-Peto boundary.  A 
total of 500 subjects will be enrolled. 
a Based on 10,000 simulations using EAST 6.5 
b The study was not statistically significant at the PFS final analysis 
OS will be compared between the 2 treatment groups, provided that the test of the primary 
endpoint PFS is statistically significant. Assuming a median OS of 29.9 months in the T-DM1 
arm based on the results of the EMILIA study4, it is hypothesized that treatment with 
trastuzumab deruxtecan will result in a hazard ratio of 0.7 in OS that would correspond to a 43% 
improvement in median OS from 29.9 months in the T-DM1 arm to 42.7 months in the 
trastuzumab deruxtecan arm under the exponential model assumption. With 250 OS events, the 
study will have approximately 80% power (conditional on PFS being significant) to detect a HR 
of 0.70 in OS at an overall 2-sided significance level of 0.05 to reject the null hypothesis (HR 
=1) using a log-rank test and a 3-look group sequential design with Lan-DeMets alpha spending 
function with O’Brien-Fleming efficacy boundary. Based on the same number of subjects that 
are planned to be enrolled in this study to detect the primary endpoint (PFS), it is estimated that 
final OS analysis will occur at approximately 51 months from the date of first subject 
randomized when 250 OS events have been documented.  If the true hazard ratio is 0.7, it is 

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estimated that approximately 96 (38.4%) and 153 (61.2%) of the targeted OS events will be 
documented at the timing of the 2 OS interim analyses. The sample size calculation was 
conducted using EAST v6.4 software. 
11.7. 
Statistical Analysis Process 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, study 
treatment exposure, and prior and concomitant medications. The SAP will also include a 
description of how missing, unused, and spurious data will be addressed. 
All statistical analyses will be performed using SAS® version 9.3 or higher (SAS Institute Inc., 
Cary, NC 27513). 

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12. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The investigator/investigational site will permit study-related monitoring, audits, IRB/EC review 
and regulatory inspections by providing direct access to source data/documents. Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
12.1. 
Monitoring and Inspections 
The Sponsor, CRO monitor and Regulatory Authority inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and, upon request, 
inspecting the various records of the study (eg, eCRFs, source data, and other pertinent 
documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH Good Clinical Practices (GCP) and local regulations on the conduct 
of clinical research will be accomplished through a combination of onsite visits by the monitor 
and review of study data remotely. The frequency of the monitoring visit will vary based on the 
activity at each study site. The monitor is responsible for inspecting the eCRFs and ensuring 
completeness of the study essential documents. The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the eCRFs. 
Detailed information will be provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor. Audit of study site facilities (eg, pharmacy, drug storage 
areas, laboratories) and review of study-related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements. 
The investigator should respond to audit findings. In the event that a Regulatory Authority 
informs the investigator that it intends to conduct an inspection, the Sponsor shall be notified 
immediately. 
12.2. 
Data Collection 
All relevant observations and data related to the study, as per the study protocol, will be recorded 
on eCRF pages. A representative of Daiichi Sankyo or their designee will provide instruction for 
completing the eCRF. Adequate and accurate case records should be maintained, including the 
evaluation of inclusion and exclusion criteria, medical history, physical examinations, clinical 
assessments, a record of clinical safety laboratory sample collection drug administration, AEs, 
and final evaluation.  
The eCRF should be kept current to enable the monitor to review the subject’s status throughout 
the course of the study.  

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An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedures. For subjects who are screened but not randomized, minimal data will be recorded on 
the eCRF, including demography, subject status, and AEs (or SAEs as appropriate). All 
study-related data for these subjects will be maintained in the medical records at the site. 
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature. These signatures will indicate that the investigator inspected or reviewed the 
data on the eCRF, the data queries, and the site notifications, and agrees with the content. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or Designee. Data will be vetted both electronically and manually for eCRFs and the 
data will be electronically vetted by programmed data rules within the application. Queries 
generated by rules and raised by reviewers will be generated within the EDC application. During 
this review, subject data will be checked for consistency, completeness and any apparent 
discrepancies. 
Data received from external sources such as central labs will be reconciled to the clinical 
database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs will be coded using MedDRA.  
All concomitant medications and prior cancer therapies will be coded using the World Health 
Organization Drug Reference List Dictionary. 
Data that may potentially unblind the treatment assignment (ie, study treatment serum 
concentrations, ADA, treatment allocation, and study treatment preparation/accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent audits. 
12.4. 
Study Documentation and Storage 
The investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties. All persons authorized to make entries and/or corrections on 
eCRFs will be included on the Signature List. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained. These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 

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Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study treatment, regulatory documents (eg, protocol and amendments, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (Trial Master File). Source 
documents include all recordings and observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical study. These 
records will be retained in a secure file for the period required by the institution or study site 
policy. Prior to transfer or destruction of these records, the Sponsor must be notified in writing 
and be given the opportunity to further store such records. 
12.5. 
Record Keeping 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (Trial Master File) of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from the Sponsor and/or applicable Regulatory 
Authorities. Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting copies of source 
documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the IRB/EC and the Sponsor. 
 Records related to the study treatment(s) including acknowledgment of receipt at 
study site, accountability records and final reconciliation and applicable 
correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All study-related essential documentation will be retained by the investigator until at least 2 y 
after the last approval of a marketing authorization in an ICH region and until there are no 
pending or contemplated marketing authorizations in an ICH region or at least 2 y have lapsed 
since the formal discontinuation of clinical development of the investigational drug. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. It is the responsibility of the 
Sponsor to inform the investigator/institution as to when these documents no longer need to be 
retained. 
Subject medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private 
practice.  
No study document should be destroyed without prior written agreement between Sponsor and 
the investigator. Should the investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor in writing of the new responsible 
person and/or the new location. 

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13. 
FINANCING AND INSURANCE 
13.1. 
Finances 
Prior to starting the study, the investigator and/or institution will sign a clinical study agreement 
with the Sponsor or the CRO. This agreement will include the financial information agreed upon 
by the parties. 
13.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 

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14. 
PUBLICATION POLICY 

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15. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
15.1. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
 US Food and Drug Administration GCP Regulations: Code of Federal Regulations 
Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March, 1997 
and/or; 
 Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of GCP in the conduct of clinical trials on 
medicinal product for human use and/or; 
 Other applicable local regulations. 
15.2. 
Subject Confidentiality 
The investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
The investigator must ensure that the subject’s anonymity is maintained. On the eCRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identifier as designated by the Sponsor. Documents that are not for submission to the 
Sponsor or the CRO (eg, signed ICF) should be kept in strict confidence by the investigator. 
In compliance with ICH GCP Guidelines, it is required that the investigator and institution 
permit authorized representatives of the company, of the Regulatory Agency(ies), and the 
IRB/EC direct access to review the subject’s original medical records for verification of 
study-related procedures and data. The investigator is obligated to inform the subject that his/her 
study-related records will be reviewed by the above-named representatives without violating the 
confidentiality of the subject. 
15.3. 
Informed Consent  
Before a subject’s participation in the study, it is the investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study treatments are administered. Subjects should be given the opportunity to 
ask questions and receive satisfactory answers to their inquiries, and should have adequate time 
to decide whether or not to participate in the study. The written ICF should be prepared in the 
local language(s) of the potential subject population. 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 

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have their origin in the Declaration of Helsinki. The consent form and any revision(s) should be 
approved by the EC/IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records. 
The ICF should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the investigator). The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed consent form 
should be provided to the subject. The date and time (if applicable) that informed consent was 
given should be recorded on the eCRF. 
15.4. 
Regulatory Compliance 
The study protocol, subject information and consent form, the IB, any subject written 
instructions to be given to the subject, available safety information, subject recruitment 
procedures (eg, advertisements), information about payments and compensation available to the 
subjects, and documentation evidencing the investigator’s qualifications should be submitted to 
the EC or IRB for ethical review and approval according to local regulations, prior to the study 
start. The written approval should identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The investigator and/or Sponsor must submit and, where necessary, obtain approval from the EC 
or IRB for all subsequent protocol amendments and changes to the ICF. The investigator should 
notify the EC or IRB of deviations from the protocol or SAEs occurring at the study site and 
other AE reports received from the Sponsor/CRO, in accordance with local procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation. If changes to 
the initial protocol and other relevant study documents are made, this representative will also 
ensure that any revised documents required for submission are submitted to Regulatory 
Authorities and implementation of these changes are made after approval by the relevant 
regulatory bodies, as needed. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.  
In addition, the investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of any 
suspected/actual serious GCP non-compliance that the investigator becomes aware of. 
15.5. 
Protocol Deviations 
The investigator should conduct the study in compliance with the protocol agreed to by Sponsor 
and, if required, by the Regulatory Authority(ies), and which was given approval/favorable 
opinion by the IRBs/ECs. 

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A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. Sponsor must be 
notified of all intended or unintended deviations to the protocol (eg, inclusion/exclusion criteria, 
dosing, missed study visits) on an expedited basis. 
The investigator, or person designated by the investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at least 
1 administration of study treatment, data should be collected for safety purposes. 
 If applicable, the investigator should notify the IRB/EC of deviations from the 
protocol in accordance with local procedures. 
15.6. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all investigators involved in the clinical study, 
IRBs/ECs, and Regulatory Authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study. The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study.  
If the subject information is revised, it must be re-approved by the IRB/EC. The investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information. The investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
15.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the investigator by Daiichi Sankyo or the CRO. Also, the Sponsor will 
ensure the timely submission of amendments to Regulatory Authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of the 
world. Such amendments will be incorporated into a revised protocol document. Changes made 
by such amendments will be documented in a Summary of Changes document. These protocol 
amendments will undergo the same review and approval process as the original protocol.  
A local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country. Sponsor approval of local amendments will be clearly documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
Regulatory Authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 

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15.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may also be 
requested by (a) competent authority(ies). 
15.9. 
Data Monitoring Committee  
An independent data monitoring committee (DMC) will be created to further protect the rights, 
safety, and well-being of subjects who will be participating in this study by monitoring the 
progress and results. The DMC will comprise qualified physicians and scientists who are not 
investigators in the study and not otherwise directly associated with the Sponsor. 
The DMC will periodically review unblinded safety data in this study. The DMC will also 
review the efficacy results from the interim analysis for PFS and OS analysis performed at the 
time of the interim analysis of PFS if PFS is significant. The details about the reviews of the 
study data and other DMC processes will be described in the DMC charter. 
The DMC may recommend modification of the study protocol or study to the Steering 
Committee based on pre-specified rules described in the DMC charter. 
15.10. 
Address List 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
regularly updated as necessary. 

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