A Phase 3, Multicenter, Randomized, Open-label, Active-controlled Study of Trastuzumab Deruxtecan (DS-8201a), an Anti-HER2-antibody Drug Conjugate, Versus Treatment of Investigator's Choice for HER2-positive, Unresectable and/or Metastatic Breast Cancer Subjects Previously Treated With T-DM1
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 
TREATMENT OF INVESTIGATOR’S CHOICE FOR 
HER2-POSITIVE, UNRESECTABLE AND/OR 
METASTATIC BREAST CANCER SUBJECTS 
PREVIOUSLY TREATED WITH T-DM1 
(DESTINY-Breast02) 
DS8201-A-U301 
IND/EudraCT NUMBERS 127553/2018-000221-31 
VERSION 8.0, 24 Apr 2023 
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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Protocol DS8201-A-U301 
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DOCUMENT HISTORY 
Version Number 
Version Date 
8.0 
24 Apr 2023 
7.0 
17 Mar 2022 
6.0 
05 Aug 2020 
5.0 
23 Apr 2020 
4.0 
26 Apr 2019 
3.0 
08 Mar 2019 
2.0 
20 Jun 2018 
1.0 
23 Mar 2018 
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Protocol DS8201-A-U301 
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INVESTIGATOR AGREEMENT 
A Phase 3, multicenter, randomized, open-label, active-controlled study of trastuzumab 
deruxtecan (DS-8201a), an anti-HER2-antibody drug conjugate, versus treatment of 
investigator’s choice for HER2-positive, unresectable and/or metastatic breast cancer 
subjects previously treated with T-DM1 
Investigator’s Signature: 
I have fully discussed the objectives of this study and the contents of this protocol with the 
Sponsor’s representative. 
I understand that information contained in or pertaining to this protocol is confidential and 
should not be disclosed, other than to those directly involved in the execution or the ethical 
review of the study, without written authorization from the Sponsor. It is, however, permissible 
to provide information to a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki, 
International Council for Harmonisation guidelines on Good Clinical Practice (ICH E6), and 
applicable regional regulatory requirements. 
I agree to make available to Sponsor personnel, their representatives and relevant Regulatory 
Authorities, my subjects’ study records in order to verify the data that I have entered into the 
case report forms. I am aware of my responsibilities as a Principal Investigator as provided by 
the Sponsor. 
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study, I will communicate my intention 
immediately in writing to the Sponsor. 
Print Name 
Signature 
Title 
Date (DD MMM YYYY) 
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Protocol DS8201-A-U301 
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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 8.0 (dated 24 Apr 2023) vs. 
protocol Version 7.0 (dated 17 Mar 2022) for actual changes in text. The summary of changes 
below is a top-line summary of major changes in the current DS8201-A-U301 clinical study 
protocol (Version 8.0) by section. 
Amendment Rationale: The study concluded positively for the primary and secondary efficacy 
endpoints of the primary analysis, which was conducted 18 months after data cutoff for the last 
subject randomized. Since the study treatments are approved drugs, it is now justified to align a 
number of on-treatment or follow-up procedures with recommendations for routine practice for 
subjects who continue to receive protocol treatment and thereby reduce the burden on subjects 
and study site personnel. Key changes include updates to frequency of tumor assessments, 
removal of anti-drug antibody (ADA) and biomarker sample collection for on-treatment subjects, 
and updates to the adverse event management guidelines. At the same time, given the high 
relevance of the problem of developing drug resistance, it is justified to introduce into the 
protocol the possibility of obtaining an optional biopsy at the time of end of treatment with 
further central evaluation of the collected biopsy sample. 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
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 (Study Duration) 
3.1.3. Definition of the End of the 
Study 
Provided the end of study 
definition.  
To maintain internal consistency 
across the T-DXd program. 
Table 17.2 Schedule of Events-
Treatment and Follow-up Period 
 
Added option to provide subjects 
the opportunity to transition to 
separate study 
Allow subjects continued 
administration of T-DXd after study 
closure, if otherwise available. 
3.1. Overall Design 
Table 5.2. Dose Modification for 
Trastuzumab Deruxtecan 
5.4.1. Dose Reduction and 
Interruption Guidelines 
 
Updated drug delay for adverse 
event management or medical 
intervention to 7 weeks from the 
last dose of investigator’s choice 
drug and 18 weeks from the last 
T-DXd dose. Criteria involving 
CT/MRI scans before resuming 
drug were added.  
To maintain internal consistency 
across the T-DXd program. 
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Section # and Title 
Description of Change 
Brief Rationale 
Table 5.2. Dose Modification of 
Trastuzumab deruxtecan 
9.3.1.2. Management Guidance 
Added pulmonary function tests 
and blood tests. Updated 
pulmonary toxicity guidelines, 
including timeline of monitoring 
Grade 1 ILD/pneumonitis  
To maintain internal consistency 
across the T-DXd program. 
5.4.1. Dose Reduction and 
Interruption Guidelines 
5.7.1. Discontinuation of Study Drug 
6.2. Screening 
6.5. End of Treatment 
Updated modified RECIST 
(mRECIST) to RECIST 
To maintain internal consistency 
across the T-DXd program. 
5.6. Concomitant Medications 
(Drugs and Therapies)  
Updated guidance in regard to 
prophylactic administration of 
anti-emetic medications for all 
subjects.  
To maintain internal consistency 
across the T-DXd program. 
6.4.1.1. Between -3 Days Through 
Immediately Before Infusion (All 
Cycles) 
6.4.3. Every 4 Cycles (±7 d) after 
Cycle 1 
6.5. End of Treatment 
9.3. Adverse Events of Special 
Interest 
9.3.2.1. Clinical Summary 
9.3.2.2. Management Guidance 
9.10. Electrocardiograms 
17.1. Schedule of Events-Tissue 
Screening and Screening Period 
17.2. Schedule of Events-Treatment 
and Follow-up 
Updates made to cardiac function 
assessments, including ECGs and 
ECHO/MUGA 
Based on a comprehensive review 
of the cumulative safety data for all 
cardiac events, risk for cardiac 
events is considered negligible. 
ECHO/MUGA and ECG 
assessments will take place at 
regular intervals during treatment as 
clinically indicated (and at end of 
treatment [EOT] for 
ECHO/MUGA). Please reference 
the IB for more information. 
6.4.1.2 Day 1; Before Dosing (All 
Cycles, Unless Otherwise Noted) 
Table 17.2 Schedule of Events-
Treatment and Follow-Up Period 
Removed biomarker sampling for 
on-treatment assessment after 
Cycle 3 Day 1. 
All subjects who remain on 
treatment have > 24 months of 
treatment duration; additional on-
treatment samples beyond this time 
point are not needed. 
 
6.4.1.2 Day 1; Before Dosing (All 
Cycles, Unless Otherwise Noted) 
6.6.1. 40-day (+7 d) Follow-up 
Table 17.2 Schedule of Events-
Treatment and Follow-Up Period 
Removed ADA sampling for 
those with positive ADA at the 
follow-up visit and after protocol 
version 8 is implemented. 
All subjects who remain on 
treatment have > 24 months of 
treatment duration and have 
provided immunogenicity samples, 
and results from the primary 
analysis indicate low prevalence of 
treatment-emergent ADAs with no 
impact on subject safety. 
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Section # and Title 
Description of Change 
Brief Rationale 
6.4.1.2 Day 1; Before Dosing (All 
Cycles, Unless Otherwise Noted) 
Table 17.2 Schedule of Events-
Treatment and Follow-Up Period 
Removed exploratory biomarker 
sampling during treatment for 
subjects after protocol version 8 is 
approved. 
All subjects who remain on 
treatment have > 24 months of 
treatment duration; additional on-
treatment samples beyond this time 
point are not needed. 
6.4.3. Every 6 weeks (12 weeks upon 
approval of version 8 ±7 d) 
6.5 End of Treatment 
Table 17.2 Schedule of Events-
Treatment & Follow-up Period 
17.4.2.5. Frequency of Tumor Re-
Evaluation 
The following language was 
added to the tumor assessment 
schedule: “Tumor assessments, 
based on sites of disease 
identified at Screening and any 
additional newly suspected sites 
of progressive disease, will be 
conducted every 6 weeks (±7 
days) from randomization, until 
protocol version 8 is approved by 
the site. After approval and 
implementation of this protocol 
version, tumor assessments will 
be conducted every 12 weeks (±7 
days), independent of treatment 
cycle.” 
Scan frequency is updated to align 
with standard of care and to reduce 
patient burden. 
6.5 End of Treatment 
8.3 Biomarker Assessments 
Table 17.2 Schedule of Events-
Treatment and Follow-Up Period 
Added an optional newly 
obtained tumor tissue biopsy 
collection for the T-DXd group. 
Collection of optional newly 
obtained biopsies at end of 
treatment was added for the purpose 
of biomarker analysis, including 
evaluation of mechanisms of 
resistance which may inform the 
clinical development of T-DXd. 
6.5 End of Treatment 
9.3.2.2 Management Guidance 
9.8 Clinical Laboratory Evaluations 
Table 17.2 Schedule of Events-
Treatment and Follow-Up Period 
 
Removed blood sample troponin 
assessment at end of treatment 
Based on a comprehensive review 
of the cumulative safety data for 
troponin levels, risk for increased 
troponin levels is considered 
negligible. Therefore, EOT troponin 
level assessments are no longer 
required and troponin level 
assessments should be performed 
only if clinically indicated. Please 
reference the IB for more 
information. 
6.5 End of Treatment 
Table 17.2: Schedule of Events-
Treatment and Follow-Up Period 
 
Removed ophthalmologic 
assessment at end of treatment. 
Based on a comprehensive review 
of the cumulative safety data for all 
ocular events, risk for ocular events 
is considered negligible. Therefore, 
EOT ophthalmologic assessments 
are no longer required and 
ophthalmologic assessments should 
be performed only if clinically 
indicated. Please reference the IB 
for more information. 
 
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Section # and Title 
Description of Change 
Brief Rationale 
7.1.1. Primary Efficacy Endpoint 
Added the language: “After the 
primary efficacy endpoint has 
been achieved, assessments by 
BICR (PFS, ORR, DoR, BOR, 
best percent change in the sum of 
the diameter of measurable 
tumors, and CBR) will be 
discontinued. Participants will 
continue with all other 
assessments as indicated in the 
SoE, including the assessment of 
tumor response and radiographic 
disease progression by 
investigators.” 
Scan frequency is updated to align 
with standard of care and to reduce 
patient burden. 
8.1 Pharmacokinetic Assessments 
17.2 Schedule of Events-Treatment 
& Follow-up Period 
17.8 Instructions Related to 
Coronavirus Disease 2019 (COVID-
19) 
Removed PK assessments if 
chloroquine or 
hydroxychloroquine is 
administered 
To maintain internal consistency 
across the T-DXd program. 
 
9.2 Adverse Event Collection and 
Reporting 
Updated instructions regarding 
the timepoint at which death is 
considered a serious adverse 
event 
Clarification of instructions. 
9.3.1.2 Management Guidance 
17.2. Schedule of Events-Treatment 
& Follow-up Period 
Added pulmonary function tests 
and blood tests  
To maintain internal consistency 
across the T-DXd program. 
9.5. Adverse Events Reporting-
Procedure for Investigators 
Added information regarding 
reporting of overdoses 
Clarification 
9.7 Exposure in Utero During 
Clinical Studies 
Updated information regarding 
exposure during pregnancy for 
those subjects taking investigator 
choice drugs and the timeline for 
informing the Sponsor of 
pregnancy 
Clarification of instructions 
regarding in utero exposure 
10.1.1. European Organization for 
Research and Treatment of Cancer 
Quality of Life Questionnaires C30 
and BR45 
Removed language regarding 
scoring 
To maintain internal consistency 
across the T-DXd program. 
Table 17.2 Schedule of Events-
Treatment & Follow-up Period 
 
Added the language: “After the 
primary efficacy endpoint has 
been achieved, the assessment of 
the scans by BICR is no longer 
required.” 
 
Scan frequency is updated to align 
with standard of care and to reduce 
patient burden. 
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Section # and Title 
Description of Change 
Brief Rationale 
Table 17.2 Schedule of Events-
Treatment & Follow-up Period 
Moved arrow from coagulation 
row to concomitant medications 
row for Cycle 3 to EOT 
Correction of an error 
17.8 Instructions Related to 
Coronavirus Disease 2019 (COVID-
19) 
Updated dose modification of 
T-DXd for COVID-19 symptom 
grades, timeline of monitoring of 
symptoms, and method of 
confirmation of COVID-19 
 
To maintain internal consistency 
across the T-DXd program. 
 
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Protocol DS8201-A-U301 
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PROTOCOL SYNOPSIS 
EudraCT: 
2018-000221-31 
IND Number: 
127553 
NCT Number: 
NCT03523585 
Protocol Number: DS8201-A-U301 (DESTINY-Breast02)  
Investigational 
Product: 
trastuzumab deruxtecan (DS-8201a) 
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 Treatment of Investigator’s Choice for HER2-Positive, Unresectable and/or 
Metastatic Breast Cancer Subjects Previously Treated with T-DM1 
(DESTINY-Breast02) 
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 investigator’s choice for HER2-positive, unresectable and/or 
metastatic breast cancer subjects previously treated with T-DM1. 
Key Secondary Objective: 
 
To compare overall survival (OS) benefit of trastuzumab deruxtecan to 
investigator’s choice for HER2-positive, unresectable and/or metastatic breast 
cancer subjects previously treated with T-DM1. 
Other Secondary Objectives: 
 
To evaluate efficacy of trastuzumab deruxtecan compared to investigator’s choice 
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 investigator’s 
choice. 
 
To evaluate Health Economics and Outcomes Research (HEOR) endpoints for 
trastuzumab deruxtecan compared to investigator’s choice. 
Exploratory Objectives: 
 
To evaluate efficacy of trastuzumab deruxtecan compared to investigator’s choice 
by clinical benefit rate (CBR) and progression-free survival on the next-line of 
therapy (PFS2). 
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 
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 the investigator’s choice in 
HER2-positive, unresectable and/or metastatic breast cancer subjects previously 
treated with standard of care HER2 therapies, including ado-trastuzumab emtansine 
(T-DM1). Approximately 600 subjects will be randomized 2:1 to trastuzumab 
deruxtecan versus the investigator’s choice of 
 
Trastuzumab/capecitabine, or 
 
Lapatinib/capecitabine 
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-U301 
 
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 30 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. 
End of the Study: 
Overall EOS will occur when any of the following conditions are met: 
 
The last subject’s last visit has occurred. 
 
An alternative study becomes available for subjects continuing to derive benefit 
from treatment with T-DXd, where the study drug is offered to these subjects. 
 
The study is discontinued by the Sponsor for other reasons (eg, administrative or 
safety related). 
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For clinical studies conducted in the European Union (EU) and under the EU clinical 
trial regulation (CTR), if the EOS in the last EU Member State occurs before the EOS 
in the last global country, the clinical study results summary will be submitted within 
12 months after the EOS in the final global country (ie, in such a situation, the 
submission will not be based on the EOS in the last EU Member State). Holding the 
submission until the study is complete globally is justified, because in situations when 
the clinical study is still ongoing in other countries and data from these other countries 
are not available, the full statistical analysis planned for the study is not feasible, and 
incomplete results are uninterpretable. 
Study Sites  
and Location: 
Approximately 230 sites including, but not limited to, North and South America, 
Europe, and Asia.  
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 T-DM1. 
 
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, 6 mo after the last dose of lapatinib/capecitabine, 
or 7 mo after the last dose of trastuzumab/capecitabine. 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 he and/or any 
female partner 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, 3 mo 
after the last dose of lapatinib/capecitabine, or 7 mo after the last dose of 
trastuzumab/capecitabine. 
 
Adequate renal function, defined as: 
 
Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault 
equation, 
 
Adequate hepatic function, defined as: 
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 
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/alanine transaminase ≤ 2.5 × ULN 
Key Exclusion Criteria: 
 
Ineligible for the comparator arm treatment for reasons including but not limited 
to the following: 
 
Prior treatment with capecitabine; 
 
History of any contraindication included in the approved local label for 
capecitabine or for both trastuzumab and lapatinib; 
 
Concurrent treatment with any medication prohibited in the applicable 
approved local label for capecitabine or for both trastuzumab and lapatinib. 
 
Prior participation in a study involving an antibody-drug conjugate produced by 
Daiichi Sankyo Inc 
 
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 weeks must have elapsed between the end of 
whole brain radiotherapy and study enrollment. 
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. 
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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. The study treatment will be administered as an IV infusion every 
21 d, initially for approximately 90 min, then, if there is no infusion related reaction, 
for a minimum of 30 min thereafter. 
Investigator’s choice comparative therapy will be administered in accordance with the 
locally approved label in cycles of every 21 d. The choice needs to be pre-defined at 
time of randomization from the following options: 
 
Trastuzumab/capecitabine 
 
Lapatinib/capecitabine 
Study Endpoints: Primary Efficacy Endpoint: 
 
PFS based on 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 
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 600 subjects, randomized in a 2:1 ratio 
into two treatment groups (trastuzumab deruxtecan versus investigator’s choice). 
Statistical 
Analyses: 
The primary analysis for PFS will be performed when approximately 372 BICR-
assessed PFS events are observed or 18 months from the last subject randomized, 
whichever comes first. 
Efficacy Analyses 
The primary efficacy analyses will be performed for the Full Analysis Set (FAS) that 
consists of all randomized subjects. The primary efficacy endpoint is PFS based on 
BICR. 
The primary efficacy analyses will compare PFS per BICR between the two treatment 
groups, using stratified log-rank test stratified by stratification factors per Interactive 
Web/Voice Response System (IXRS). 
PFS will be tested for statistical significance at an overall 2-sided alpha of 0.05. 
Kaplan-Meier estimates and survival curves will also be presented for each treatment 
group. The median survival times and 2-sided 95% confidence intervals (CIs) for the 
medians will be provided using Brookmeyer and Crowley method for each treatment 
group. The hazard ratio (HR) and its 95% CI will be estimated, using stratified Cox 
proportional hazards regression model stratified by stratification factors per IXRS. 
The key secondary efficacy endpoint is OS, and other secondary efficacy endpoints are 
confirmed 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. 
Group sequential testing will be used to compare OS between the two treatment 
groups hierarchically, provided PFS is significant. Kaplan-Meier estimates and 
survival curves will also be presented for each treatment group. The median survival 
times and 2-sided 95% CIs for the medians will be provided using Brookmeyer and 
Crowley method for each treatment group. In addition, Kaplan-Meier estimates at 
fixed time points along with their 2-sided 95% CIs will be provided for each treatment 
group. The HR and its 95% CI will be estimated, using stratified Cox proportional 
hazards regression model stratified by stratification factors per IXRS. Up to 3 analyses 
of OS could be performed: 
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 
First interim analysis at the time of the final analysis for PFS (provided PFS is 
significant), at which point a total of approximately 240 OS events 
(55% information fraction) are expected. 
 
If the OS interim analysis is not significant, a second interim analysis for OS 
is planned when approximately 304 OS events (70% information fraction) are 
expected. 
 
If the second OS interim analysis is not significant, a final analysis for OS 
after approximately 434 OS events have been observed (expected 71 months 
from date of first subject to be randomized). 
Cochran-Mantel-Haenszel tests stratified by stratification factors per IXRS will be 
used to compare ORR (based on BICR/investigator assessment) between the treatment 
groups. The estimates of ORR and the 2-sided 95% CIs will be provided using 
Clopper-Pearson method. 
Duration of response (based on BICR) will be summarized with median DoR and its 
2-sided 95% CI 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 2-sided 95% CI using Brookmeyer and Crowley method will 
be provided for each treatment group. PFS 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 HR and its 2-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 2-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, could be provided in the Statistical Analysis Plan. 
Descriptive analyses of HEOR endpoints based on the following patient-reported 
outcome questionnaires will be summarized. 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 EORTC 
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 EORTC QLQ-BR45, and the pain symptom subscale of the EORTC 
QLQ-C30 will also be assessed. 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 subjects 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. 
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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 pop-PK and pop-PK/pharmacodynamic models may be 
reported separately from the clinical study report. 
Biomarker Analyses 
Samples collected for biomarker analyses, such as tissue and blood, may be used for 
exploratory biomarker assessments. Biomarker data may be summarized by treatment 
group using descriptive statistics. 
Safety Analyses: 
Safety endpoints will include SAEs, TEAEs, AESIs, DAEs, 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.................................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................9 
LIST OF ABBREVIATIONS ........................................................................................................27 
1. 
INTRODUCTION ...........................................................................................................31 
1.1. 
Background ......................................................................................................................31 
1.1.1. 
Investigational Product ....................................................................................................32 
1.1.1.1. Name ................................................................................................................................32 
1.1.1.2. Description ......................................................................................................................32 
1.1.1.3. Intended Use Under Investigation ...................................................................................32 
1.1.1.4. Comparators (Investigator’s Choice) ..............................................................................32 
1.1.1.5. Nonclinical Studies of Trastuzumab Deruxtecan ............................................................33 
1.1.1.6. Clinical Experience .........................................................................................................33 
1.1.1.7. Summary of Clinical Pharmacokinetics ..........................................................................34 
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 ...............................................................................................................39 
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 ......................................................................................................42 
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 .............................................................................................43 
4. 
STUDY POPULATION ..................................................................................................44 
4.1. 
Inclusion Criteria .............................................................................................................44 
4.2. 
Exclusion Criteria ............................................................................................................47 
5. 
STUDY TREATMENTS ................................................................................................49 
5.1. 
Assigning Subjects to Treatments and Blinding .............................................................49 
5.1.1. 
Treatment Groups ............................................................................................................49 
5.1.2. 
Method of Treatment Allocation .....................................................................................49 
5.1.3. 
Blinding ...........................................................................................................................49 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................49 
5.2. 
Trastuzumab Deruxtecan .................................................................................................50 
5.2.1. 
Description ......................................................................................................................50 
5.2.2. 
Labeling and Packaging ..................................................................................................50 
5.2.3. 
Preparation .......................................................................................................................50 
5.2.4. 
Administration .................................................................................................................50 
5.2.5. 
Storage .............................................................................................................................50 
5.2.6. 
Drug Accountability ........................................................................................................51 
5.3. 
Control Treatment (Investigator’s Choice) .....................................................................51 
5.4. 
Dose Interruptions and Reductions .................................................................................52 
5.4.1. 
Dose Reduction and Interruption Guidelines ..................................................................53 
5.4.1.1. Dose Modifications .........................................................................................................54 
5.5. 
Method of Assessing Treatment Compliance ..................................................................64 
5.6. 
Concomitant Medications (Drugs and Therapies) ...........................................................64 
Prohibited Medications and Treatments ........................................................................................64 
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5.7. 
Study Drug Discontinuation and Discontinuation from the Study ..................................65 
5.7.1. 
Discontinuation of Study Drug ........................................................................................65 
Procedures for Discontinuation from Study Drug .........................................................................66 
Modified Follow-up Options .........................................................................................................66 
5.7.2. 
Withdrawal Procedures ...................................................................................................67 
5.7.3. 
Subject Replacement .......................................................................................................67 
5.7.4. 
Subject Re-screening Procedures ....................................................................................68 
6. 
STUDY PROCEDURES .................................................................................................69 
6.1. 
Tissue Screening ..............................................................................................................69 
6.2. 
Screening .........................................................................................................................69 
6.3. 
Randomization .................................................................................................................71 
6.4. 
Treatment Period .............................................................................................................71 
6.4.1. 
Cycle 1 to 4 and Subsequent Cycles ................................................................................71 
6.4.1.1. Between -3 Days Through Immediately Before Dosing (All Cycles): ...........................71 
6.4.1.2. Day 1; Before Dosing (All Cycles, Unless Otherwise Noted): .......................................72 
6.4.1.3. Day 1: Dosing and End of Infusion (All Cycles, Unless Otherwise Noted): ..................73 
6.4.1.4. Day 8 (± 1 d) and Day 15 (± 1 d) (Cycle 1 Only) ...........................................................74 
6.4.2. 
Every 2 Cycles after Cycle 3 ...........................................................................................74 
6.4.3. 
Every 6 Weeks (12 weeks upon approval of version 8 ±7 d) ..........................................74 
6.5. 
End of Treatment .............................................................................................................75 
6.6. 
Follow-up ........................................................................................................................76 
6.6.1. 
40-Day (+7 d) Follow-up.................................................................................................76 
6.6.2. 
Long-term/Survival Follow-up ........................................................................................77 
7. 
EFFICACY ASSESSMENTS .........................................................................................78 
7.1. 
Assessments for Efficacy Endpoints ...............................................................................78 
7.1.1. 
Primary Efficacy Endpoint ..............................................................................................78 
7.1.2. 
Key Secondary Efficacy Endpoint ..................................................................................78 
7.1.3. 
Other Secondary Efficacy Endpoints ..............................................................................78 
7.1.4. 
Exploratory Efficacy Endpoints ......................................................................................79 
7.2. 
Appropriateness of Selected Efficacy Assessments ........................................................79 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ...........................81 
8.1. 
Pharmacokinetic Assessments .........................................................................................81 
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8.2. 
Pharmacodynamic Assessment .......................................................................................81 
8.3. 
Biomarker Assessments ...................................................................................................81 
8.3.1. 
Tumor Sampling ..............................................................................................................81 
8.3.2. 
Blood Sampling ...............................................................................................................82 
8.3.3. 
Optional Newly Obtained Tumor Tissue Biopsy ............................................................82 
8.3.4. 
Additional Biomarker Assessments ................................................................................82 
8.3.5. 
Disclosure of the Results of Additional Biomarker Assessments ...................................82 
8.4. 
Immunogenicity ...............................................................................................................82 
8.5. 
Pharmacogenetic Analysis ...............................................................................................83 
8.5.1. 
Pharmacogenetic Analysis ...............................................................................................83 
8.5.2. 
Banking of Specimens .....................................................................................................83 
8.5.2.1. Storage and Disposal of Specimens ................................................................................83 
8.5.2.2. Disclosure of the Results of Future Analysis ..................................................................83 
9. 
SAFETY EVALUATION AND REPORTING ..............................................................84 
9.1. 
Assessment of Safety Endpoints .....................................................................................84 
9.2. 
Adverse Event Collection and Reporting ........................................................................84 
9.3. 
Adverse Events of Special Interest ..................................................................................85 
9.3.1. 
Interstitial Lung Disease/Pneumonitis .............................................................................85 
9.3.1.1. Clinical Summary ............................................................................................................85 
9.3.1.2. Management Guidance ....................................................................................................85 
9.3.1.3. Interstitial Lung Disease Adjudication Committee .........................................................86 
9.3.2. 
Left Ventricular Dysfunction ..........................................................................................86 
9.3.2.1. Clinical Summary ............................................................................................................86 
9.3.2.2. Management Guidance ....................................................................................................86 
9.4. 
Adverse Event .................................................................................................................87 
9.4.1. 
Definition of Adverse Event ............................................................................................87 
9.4.2. 
Serious Adverse Event ....................................................................................................87 
9.4.3. 
Severity Assessment ........................................................................................................88 
9.4.4. 
Causality Assessment ......................................................................................................88 
9.4.5. 
Action Taken Regarding Study treatments ......................................................................89 
9.4.6. 
Other Action Taken for Event .........................................................................................89 
9.4.7. 
Adverse Event Outcome ..................................................................................................89 
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9.5. 
Adverse Events Reporting-Procedure for Investigators ..................................................90 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee .................................................................................................91 
9.7. 
Exposure In Utero During Clinical Studies .....................................................................91 
9.8. 
Clinical Laboratory Evaluations ......................................................................................92 
9.9. 
Vital Signs .......................................................................................................................93 
9.10. 
Electrocardiograms ..........................................................................................................93 
9.11. 
Physical Examinations .....................................................................................................93 
9.12. 
Other Examinations .........................................................................................................93 
9.12.1. Cardiac Assessments .......................................................................................................93 
9.12.2. Pulmonary Assessments ..................................................................................................93 
10. 
OTHER ASSESSMENTS ...............................................................................................94 
10.1. 
Patient-Reported Outcomes .............................................................................................94 
10.1.1. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaires C30 and BR45 ........................................................................................94 
10.1.2. EuroQoL Five Dimensions Five Levels Patient-Reported Outcome 
Questionnaire ...................................................................................................................95 
10.2. 
Health-related QoL Endpoints .........................................................................................95 
10.2.1. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Endpoints .................................................................................................95 
10.2.2. EuroQoL Five Dimensions Five Levels Endpoints .........................................................96 
10.3. 
Pharmacoeconomic Assessments ....................................................................................96 
10.3.1. Hospitalization-Related Endpoints ..................................................................................96 
11. 
STATISTICAL METHODS ...........................................................................................97 
11.1. 
General Statistical Considerations ...................................................................................97 
11.2. 
Analysis Sets ...................................................................................................................97 
11.2.1. Full Analysis Set ..............................................................................................................97 
11.2.2. Safety Analysis Set ..........................................................................................................97 
11.2.3. Per-protocol Analysis Set ................................................................................................97 
11.2.4. Pharmacokinetic Analysis Set .........................................................................................97 
11.3. 
Study Population Data .....................................................................................................98 
11.4. 
Statistical Analysis ..........................................................................................................98 
11.4.1. Efficacy Analyses ............................................................................................................98 
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11.4.1.1. Primary Efficacy Analyses ..............................................................................................98 
11.4.1.2. Secondary Efficacy Analyses ..........................................................................................98 
11.4.1.3. Exploratory Efficacy Analyses ........................................................................................99 
11.4.2. Analyses of Health Economic and Outcomes Research Endpoints ..............................101 
11.4.2.1. EuroQoL Five Dimensions Five Levels ........................................................................101 
11.4.2.2. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 and BR45 ........................................................................................101 
11.4.2.3. Hospitalization-Related Endpoints ................................................................................101 
11.4.3. Pharmacokinetic/Pharmacodynamic/Biomarker Analyses............................................102 
11.4.3.1. Pharmacokinetic Analyses .............................................................................................102 
11.4.3.2. Pharmacodynamic Analyses ..........................................................................................102 
11.4.3.3. Biomarker Analyses ......................................................................................................102 
11.4.4. Safety Analyses .............................................................................................................102 
11.4.4.1. Adverse Event Analyses ................................................................................................102 
11.4.4.2. Clinical Laboratory Evaluation Analyses ......................................................................103 
11.4.4.3. Vital Sign Analyses .......................................................................................................103 
11.4.4.4. Electrocardiogram Analyses ..........................................................................................103 
11.4.4.5. Physical Examination Analyses ....................................................................................103 
11.4.4.6. Concomitant Medication Analyses ................................................................................103 
11.4.4.7. Immunogenicity (Anti-Drug Antibody) Analyses .........................................................103 
11.4.4.8. Other Safety Analyses ...................................................................................................104 
11.5. 
Interim Analyses ............................................................................................................104 
11.6. 
Sample Size Determination ...........................................................................................105 
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 
13. 
FINANCING AND INSURANCE ................................................................................109 
13.1. 
Finances .........................................................................................................................109 
13.2. 
Reimbursement, Indemnity, and Insurance ...................................................................109 
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14. 
PUBLICATION, PUBLIC DISCLOSURE POLICY, AND DATA SHARING ..........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 .......................................................................................................113 
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 .............................................................................................124 
17.3. 
Eastern Cooperative Oncology Group Performance Status ..........................................125 
17.4. 
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 ..........................................................................................127 
17.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease ..................................127 
17.4.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ..................................127 
17.4.2.3. Response Criteria ...........................................................................................................128 
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 
17.6.1. European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (version 3.0) ....................................................................................135 
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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) ..................................144 
17.9. 
Product Complaints .......................................................................................................145 
 
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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 .................................................53 
Table 5.2: Dose Modification for Trastuzumab Deruxtecan .......................................................55 
Table 8.1: Blood Sampling for Pharmacokinetic Analysis ..........................................................81 
Table 11.1: Efficacy Stopping Boundaries for OS ......................................................................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 ...........................125 
Table 17.4: Overall Response: Subjects with Target (+/–Non-target) Disease ...........................131 
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 
ADR 
adverse drug reaction  
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/dosing  
BICR 
blinded independent central review  
CBR 
clinical benefit rate 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum plasma/serum concentration 
CNS 
central nervous system 
COPD 
chronic obstructive pulmonary disease 
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 
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ABBREVIATION 
DEFINITION 
DoR 
duration of response  
EC 
Ethics Committee 
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) 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol-5 dimensions-5 levels of severity 
EU 
European Union 
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 
extracellular domain of HER2 
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 
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ABBREVIATION 
DEFINITION 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
Lyo-DP 
lyophilized powder 
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) 
NCCN 
National Comprehensive Cancer Network 
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 treatment  
PK 
pharmacokinetic 
pop-PK 
population pharmacokinetics 
PO 
oral(ly) 
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 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
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ABBREVIATION 
DEFINITION 
SAP 
Statistical Analysis Plan 
SAVER 
Serious Adverse Event Report 
SD 
stable disease 
SID 
subject identification 
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 These HER2-positive breast cancers have historically been 
associated with more aggressive disease and worse outcomes compared to HER2-negative breast 
cancers. Although anti-HER2 targeted therapies have improved outcomes, they are not curative 
in the metastatic setting. Treatment options for patients who have progressed after 2 lines of 
anti-HER2 therapy remain unclear and limited. Current options include: lapatinib + capecitabine, 
trastuzumab + capecitabine, trastuzumab + lapatinib, or trastuzumab + other agents.3 Reported 
response rates for these regimens when given as second lines of anti-HER2 therapy range from 
10% to 22%.4,5,6 It is expected that these response rates would be lower when given in a later line 
of therapy. 
The only study to report outcomes after 2 lines of anti-HER2 therapy was the TH3RESA study, 
which compared ado-trastuzumab emtansine (T-DM1) in the third-line setting to investigator’s 
choice therapies. The two prior lines of anti-HER2 therapy in this case were regimens containing 
trastuzumab and lapatinib. In this setting, although 81% of investigator’s choice treatments 
consisted of combining an anti-HER2 agent with chemotherapy, the objective response rate 
(ORR) for the investigator’s choice treatment was only 9% and the median progression-free 
survival (PFS) was 3.3 mo.6 
Treatment options for HER2-positive breast cancer, therefore, remain limited, with no targeted 
therapy specifically approved following trastuzumab, pertuzumab, and T-DM1 failure.7 In this 
setting, recommended treatment options include continuation of an anti-HER2 therapy in 
combination with a standard chemotherapy agent. Due to the lack of clear superiority, no specific 
combination is currently endorsed by the National Comprehensive Cancer Network (NCCN) 
guidelines, and consideration of palliative care is recommended after 3 lines of targeted therapy.3 
Therefore, a high unmet medical need exists, and new treatment options need to be developed to 
improve outcomes for patients with disease progression following the failure of trastuzumab, 
pertuzumab, and T-DM1 regimens. 
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 Phase 2 DS8201-A-U201 study in HER2-positive metastatic breast cancer previously 
treated with T-DM1. Trastuzumab deruxtecan (Enhertu®) is approved as a treatment in multiple 
markets globally; please refer to the IB for additional information. 
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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. MAAL-9001 
is an in-house humanized immunoglobulin G1 (IgG1) monoclonal antibody (mAb) having 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).8,9,10 This ADC achieves a high drug-to-antibody ratio 
(approximately 8) with homogeneous conjugation with MAAA-1181a.11 After binding to HER2 
and internalization, trastuzumab deruxtecan is cleaved by lysosomal enzymes and releases 
MAAA-1181a in the cytoplasm after it binds to the HER2 receptor and gets internalized in tumor 
cells. 
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)-O1 cell 
line (FL-DP1). To support new clinical studies, as well as commercial development, transition 
was made to MAAL-9001 production using a CHO-S cell line (FL-DP2). Analytic comparison 
of the two 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 two products. 
1.1.1.3. 
Intended Use Under Investigation 
This study will compare the activity of trastuzumab deruxtecan in subjects with HER2-positive, 
unresectable and/or metastatic breast cancer who are resistant or refractory to T-DM1 versus two 
potential investigator’s choice options that are currently part of guideline recommendations for 
this line of therapy. 
1.1.1.4. 
Comparators (Investigator’s Choice) 
The description of these can be found within their approved labels. 
 Trastuzumab/capecitabine 
 Lapatinib/capecitabine 
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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).12 
1.1.1.6. 
Clinical Experience 
As of 08 Jun 2021, trastuzumab deruxtecan is being evaluated in 27 company-sponsored clinical 
studies (18 monotherapy studies and 9 combination therapy studies). An estimated total of 
3462 subjects were treated with trastuzumab deruxtecan (alone or in combination with 
nivolumab or pembrolizumab) or were treated with a comparator.12 Seven studies are complete 
(have finalized clinical study reports presenting the results for the study primary objective), and 
20 studies are ongoing.12 For updated results, please also see the latest version of the IB.12 
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, three 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.13 Among 
the 184 subjects who received trastuzumab deruxtecan at the recommended dose of 5.4 mg/kg, 
the blinded independent central review (BICR) confirmed response rate was 60.9% (95% CI: 
53.4, 68.0); of these subjects, 6.0% had a complete response (CR), and 54.9% had a partial 
response.13 The disease control rate (DCR) was 97.3% (95% CI: 93.8, 99.1).13 The median time 
to response was 1.6 months (95% CI: 1.4, 2.6), and the median duration of response (DoR) was 
14.8 months (95% CI: 13.8, 16.9).13 The median PFS was 16.4 months (95% CI: 12.7, not 
reached).13 The 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.13 
As of 01 August 2019, among 184 subjects who received 5.4 mg/kg trastuzumab deruxtecan, 
99.5% had at least one adverse event (AE) and 57.1% had an AE of Grade 3 or higher.13 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%).13 AEs led to dose interruption in 35.3%, dose reduction in 23.4%, and dose 
discontinuation in 15.2% of subjects.13 A total of 25 deaths were reported, including seven that 
occurred during treatment as a result of either disease progression (in three subjects) or AEs 
(hemorrhagic shock, general physical health deterioration, pneumonia, and acute organ failure in 
one subject each).13 During survival follow-up (which was defined as 47 days after the end of 
treatment [EOT]), 18 of the 25 deaths occurred, two 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.13 
For further details related to the efficacy and safety of trastuzumab deruxtecan reported from 
clinical studies, please see the latest version of the IB.12 
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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. 
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 
(μg/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 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 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.14,15 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,15,16 gastric cancer,17,18 pancreatic cancer,19 lung cancer,20 colorectal cancer,21 and ovarian 
cancer.22 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 tracts as well as in the skin, breast, and placenta.23 
The current first line standard of care for HER2-positive metastatic breast cancer (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 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.24 
Additionally, the EMILIA study established T-DM1 as the standard for subsequent line of 
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.25 
The multitude of treatment options being used post-T-DM1 for HER2+ mBC reflect the unmet 
medical need in this setting and the absence of guideline specific recommendations. The NCCN 
has no recommendation, but offers lapatinib + capecitabine, trastuzumab + capecitabine, and 
trastuzumab + lapatinib as possibilities. The two most common regimens for HER2+ mBC 
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post-T-DM1 are trastuzumab + chemotherapy and lapatinib + chemotherapy, with capecitabine 
being the most common chemotherapy used in combination. Comparison of these regimens 
across studies, and in the limited data with direct comparisons, suggest that these two regimens 
were similar in terms of response rates and survival. This study therefore allows either 
trastuzumab + capecitabine or lapatinib + capecitabine to be chosen at the investigator’s 
discretion as a comparator to trastuzumab deruxtecan in the post-T-DM1 setting. 
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. 
Trastuzumab deruxtecan has a cytotoxic drug component with a different mechanism of action 
than that of T-DM1 and is expected to show activity in tubulin inhibitor insensitive tumors, so it 
is anticipated to be of benefit in the T-DM1-refractory patient population. 
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 with durable disease control. 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 reached 10.4 mo (95% confidence interval [CI]: 32.1, 
not reached). 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. These results compare favorably to the historical results described above 
despite use of trastuzumab deruxtecan in a later line of therapy. 
DS8201-A-U301 is designed to compare trastuzumab deruxtecan versus standard of care 
(investigator’s choice) in subjects with unresectable and/or metastatic breast cancer previously 
treated with T-DM1. 
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 completed 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 BICR of 52.5%. Among the subjects with HER2-low breast cancer, confirmed ORR by 
BICR was 37.0%. The overall efficacy results in subjects with HER2-positive 
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gastric/gastroesophageal junction cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed 
ORR by BICR of 29.5%. The overall efficacy results in subjects with other cancers demonstrated 
a confirmed ORR by BICR of 29.5%. 
Based on the cumulative review of nonclinical, clinical, and epidemiologic studies and the 
scientific literature on the safety profile of trastuzumab deruxtecan, ILD/pneumonitis and 
neutropenia (including febrile neutropenia) are classified as important identified risks as of 
08 Jun 2021. Left ventricular (LV) dysfunction and embryo-fetal toxicity are classified as 
important potential risks. 
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/pneumonitis and neutropenia (including febrile neutropenia), 
important potential risks of LV dysfunction and embryo-fetal toxicity, and other risks. 
ILD/pneumonitis and neutropenia are known adverse drug reactions (ADRs) of trastuzumab 
deruxtecan, and cases with fatal outcomes have been reported. Most events were Grade 1 or 
Grade 2 and were manageable by following clinical management guidelines, which included 
monitoring of signs/symptoms of ILD/pneumonitis (eg, cough, fever, and dyspnea) to identify 
potential ILD/pneumonitis and proactively managing events with appropriate intervention 
(including dose modification and treatment [eg, steroids]) and supportive care instituted in a 
timely fashion. 
Other ADRs of trastuzumab deruxtecan were primarily gastrointestinal or hematologic in nature. 
These identified risks were generally manageable through dose modification and routine clinical 
treatment. 
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 current assessments of risks and benefits to subjects, please refer to the current IB12 for 
trastuzumab deruxtecan. 
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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 investigator’s 
choice for HER2-positive, unresectable and/or metastatic breast cancer subjects previously 
treated with T-DM1. 
2.1.2. 
Key Secondary Objective 
The key secondary objective is to compare the OS benefit of trastuzumab deruxtecan to 
investigator’s choice for HER2-positive, unresectable and/or metastatic breast cancer subjects 
previously treated with T-DM1. 
2.1.3. 
Other Secondary Objectives 
The secondary objectives are: 
 To evaluate efficacy of trastuzumab deruxtecan compared to investigator’s choice on: 
 Confirmed ORR; 
 DoR. 
 To further determine PK of trastuzumab deruxtecan; 
 To further evaluate safety of trastuzumab deruxtecan compared to investigator’s 
choice; 
 To evaluate Health Economics and Outcomes Research (HEOR) endpoints for 
trastuzumab deruxtecan compared to investigator’s choice. 
2.1.4. 
Exploratory Objectives 
The exploratory objectives are: 
 To evaluate efficacy of trastuzumab deruxtecan compared to investigator’s choice 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 to investigator’s choice in 
HER2-positive breast cancer subjects previously treated with T-DM1. 
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2.3. 
Study Endpoints 
The efficacy endpoints will be based on central assessments unless otherwise stated. 
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is PFS based on BICR. 
2.3.2. 
Key Secondary Efficacy Endpoint 
The key secondary efficacy endpoint is OS. 
2.3.3. 
Other Secondary Efficacy Endpoints 
The other secondary efficacy endpoints are: 
 ORR based on BICR and investigator assessment (confirmation of 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 (Section 10.3.1) 
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 
2.3.7. 
Safety Endpoints 
The safety endpoints include: 
 Serious adverse events (SAEs) 
 TEAEs 
 Adverse events of special interest (AESIs) 
 TEAEs associated with discontinuations 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 (ADAs) 
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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 investigator’s choice in HER2-positive, 
unresectable and/or metastatic breast cancer subjects who are resistant or refractory to T-DM1. 
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. 
The comparator for this study is called investigator’s choice with the options being 1 of the 
following: 
 Trastuzumab/capecitabine 
 Lapatinib/capecitabine 
For subjects randomized to comparator, the treatment will be in cycles of every 21 d (± 2 d). 
Randomization will be stratified by: 
 Hormone receptor status (positive, negative) 
 Prior treatment with pertuzumab (yes, no) 
 History of visceral disease (yes, no) 
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 5.7). If the study treatment is delayed more than 49 d (7 wks) for the investigator’s 
choice group or 126 days (18 weeks) for the T-DXd group from the last infusion date, the subject 
will be withdrawn from the study treatment and will be followed for survival.  
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 
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3.1.1. 
Duration of the Study 
Enrollment is planned to occur over approximately 30 mo. 
The study team will monitor the 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 required number of events. Progression-free survival 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 interim and final OS 
analyses (as needed), and data after the data cutoff date will be considered for OS 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. For trastuzumab deruxtecan, 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 5.7.1. 
For subjects randomized to investigators choice, treatment cycles will be on the same 21 d 
cycles. 
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 5.7.1). 
3.1.3. 
Definition of the End of the Study 
Overall end of study (EOS) will occur when any of the following conditions are met: 
 The last subject’s last visit has occurred. 
 An alternative study becomes available for subjects continuing to derive benefit from 
treatment with T-DXd, where the study drug is offered to these subjects. 
 The study is discontinued by the Sponsor for other reasons (eg, administrative or 
safety related). 
For clinical studies conducted in the European Union (EU) and under the EU clinical trial 
regulation, if the EOS in the last EU Member State occurs before the EOS in the last global 
country, the clinical trial results summary will be submitted within 12 months after the EOS in 
the final global country (ie, in such a situation, the submission will not be based on the EOS in 
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the last EU Member State). Holding the submission until the study is complete globally is 
justified, because in situations when the clinical study is still ongoing in other countries and data 
from these other countries are not available, the full statistical analysis planned for the study is 
not feasible, and incomplete results are uninterpretable. 
3.2. 
Discussion of Study Design 
This study will be conducted in approximately 230 sites including, but not limited to, North and 
South America, Europe, and Asia. 
The target sample size will be approximately 600 subjects, randomized in a 2:1 ratio into 
2 treatment groups (trastuzumab deruxtecan versus investigator’s choice). 
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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 guidelines26 
evaluated at a central laboratory. 
c. was previously treated with T-DM1. 
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).27 
 Brain lesions will be considered as non-target lesions only. 
7. ECOG PS 0 or 1. 
8. Adequate bone marrow function, within 14 d before randomization, defined as: 
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 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) ≤ 2.5 × 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, 6 mo after the 
last dose of lapatinib/capecitabine, or 7 mo after the last dose of 
trastuzumab/capecitabine. 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 he and/or any 
female partner 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, 3 mo after the last dose of lapatinib/capecitabine, or 
7 mo after the last dose of trastuzumab/capecitabine. 
Methods considered as highly effective methods of contraception include: 
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral (PO) 
 Intravaginal 
 Transdermal 
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 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 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, 6 mo after 
the last dose of lapatinib/capecitabine for female subjects (3 mo for male subjects), or 
7 mo after the last dose of trastuzumab/capecitabine. 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. 
13. 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. 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, 3 mo after the last dose of lapatinib/capecitabine, or 7 mo 
after the last dose of trastuzumab/capecitabine. 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, 6 mo after the last dose of lapatinib/capecitabine, 
or 7 mo after the last dose of trastuzumab/capecitabine. 
15. Has adequate treatment washout period before randomization/enrollment, defined as 
chloroquine/hydroxychloroquine >14 days 
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4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Ineligible for the comparator arm treatment for reasons including but not limited to the 
following: 
a. Prior treatment with capecitabine; 
b. History of any contraindication included in the approved local label for capecitabine 
or for both trastuzumab and lapatinib; 
c. Concurrent treatment with any medication prohibited in the applicable approved local 
label for capecitabine or for both trastuzumab and lapatinib. 
2. Prior participation in a study involving an ADC produced by Daiichi Sankyo. 
3. Uncontrolled or significant cardiovascular disease, including any of the following: 
a. History of myocardial infarction within 6 mo before randomization; 
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. Left ventricular ejection fraction (LVEF) < 50% within 28 d prior to randomization. 
4. 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. 
5. 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. 
6. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
7. History of severe hypersensitivity reactions to other mAbs. 
8. 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. 
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9. Social, familial, or geographical factors that would interfere with study participation or 
follow-up. 
10. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.  
11. Known human immunodeficiency virus (HIV) infection or active hepatitis B or C 
infection. Subjects positive for hepatitis C virus (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. 
12. Multiple primary malignancies within 3 y, except adequately resected non-melanoma 
skin cancer, curatively treated in situ disease, or contralateral breast cancer. 
13. 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). 
14. Therapeutic radiation therapy or major surgery within 4 wk before randomization or 
palliative stereotactic radiation therapy within 2 wk before randomization. 
15. 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. 
17. 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. 
18. Pregnant, breastfeeding, or planning to become pregnant. 
19. Subject must not be an immediate family member of study site personnel working for the 
investigator or of Sponsor personnel. 
20. Otherwise considered inappropriate for the study by the investigator. 
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 investigator’s choice; within investigator’s choice there are 
2 options: 
 Trastuzumab/capecitabine 
 Lapatinib/capecitabine 
The option chosen must be declared before randomization. Once assigned, subjects will remain 
on study in their treatment group and will not change groups. Within investigator’s choice, the 
subject must remain on the declared option for their duration within the study. 
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 
investigator’s choice) in a 2:1 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. 
All subjects will have investigator’s choice treatment declared and recorded in the IXRS prior to 
randomization. 
5.1.3. 
Blinding 
It is not feasible to blind treatment allocations for individual subjects because of different routes 
of administration, different treatment schedules, and different AE profiles between trastuzumab 
deruxtecan and investigator’s choice therapy. The primary endpoint of PFS will be based on 
BICR. 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 
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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. 
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 treatment 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. 
Administration 
Trastuzumab deruxtecan will be administered initially as an IV infusion over 30 to 90 min every 
21 d (± 2 d). The initial dose of trastuzumab deruxtecan will be infused for approximately 
90 min. If there is no infusion related reaction, after the initial dose, the next doses of 
trastuzumab deruxtecan 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 trastuzumab deruxtecan. 
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. 
5.2.5. 
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 
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If storage conditions are not maintained per specified requirements, the Sponsor or contract 
research organization (CRO) should be contacted. 
For storage of the infusion solutions, see pharmacy instructions. 
5.2.6. 
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 the 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/investigator’s choice). 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 to the supply depot 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 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. 
5.3. 
Control Treatment (Investigator’s Choice) 
Subjects randomized to the investigator’s choice will be treated according to 1 of the following 
regimens: 
 Capecitabine in combination with trastuzumab for IV infusion: 
 Trastuzumab 8 mg/kg IV loading dose on the first day of treatment followed by 
6 mg/kg every 21 d (± 2 d) 
 Capecitabine 1250 mg/m2 administered PO twice daily approximately 12 h apart 
(equivalent to 2500 mg/m2 total daily dose) on Days 1 to 14 of a 21-d (± 2 d) 
schedule 
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 On the basis of the investigator’s judgment, subjects may discontinue 
capecitabine and remain on trastuzumab alone, and subjects may also discontinue 
trastuzumab and remain on capecitabine alone. If both trastuzumab and 
capecitabine are delayed longer than 28 d from the planned date of administration, 
the subject will permanently discontinue study treatment and will be followed for 
survival (Section 5.4.1). 
 Capecitabine in combination with lapatinib: 
 Lapatinib 1250 mg PO daily on Days 1 to 21 of a 21-d (± 2 d) schedule 
 Capecitabine 1000 mg/m2 PO twice daily approximately 12 h apart (equivalent to 
2000 mg/m2 total daily dose) on Days 1 to 14 of a 21-d (± 2 d) schedule 
 On the basis of the investigator’s judgment, subjects may discontinue 
capecitabine and remain on lapatinib alone, and subjects may also discontinue 
lapatinib and remain on capecitabine alone. If both lapatinib and capecitabine are 
delayed longer than 28 d from the planned date of administration, the subject will 
permanently discontinue study treatment and will be followed for survival 
(Section 5.4.1). 
Accountability for the investigator’s choice medications will follow the trastuzumab deruxtecan 
procedures (Section 5.2.6). Administration and storage for all medications must follow the 
locally approved label. 
Trastuzumab IV is the only acceptable formulation for this study. Trastuzumab subcutaneous or 
biosimilar may not be used. 
5.4. 
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 
investigator’s choice medications should be made in accordance with the locally approved label 
for that medication. 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. 
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Prophylactic or supportive treatment for expected toxicities, including management of study 
treatment-induced AEs will be as per treating physician discretion and institutional guidelines. 
5.4.1. 
Dose Reduction and Interruption Guidelines 
Trastuzumab deruxtecan: 
NOTE: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified below 
in Table 5.2. 
The starting dose of the trastuzumab deruxtecan Lyo-DP formulation will be 5.4 mg/kg. 
The trastuzumab deruxtecan dosage administered will be based upon the actual body weight 
calculated using the body surface area calculation method. 
Two dose reductions will be permitted. The adjustment for reduced dosing of trastuzumab 
deruxtecan depending on the initial starting dose is as shown in Table 5.1. 
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 
Once the dose of trastuzumab deruxtecan 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. Trastuzumab deruxtecan dose increases are not allowed in the study. 
Every effort should be made to limit study drug delay; however, in circumstances of AE 
management or medical intervention, the study drug can be held up to 18 weeks (126 days) from 
the last T-DXd dose. During this time, scheduled computed tomography (CT)/magnetic 
resonance imaging (MRI) scans should continue as per protocol, and subjects should fulfil all of 
the following criteria: 
 Study drug may be resumed with confirmation of continued benefit per 
RECIST version 1.1. Scans should be performed at the frequency defined per 
protocol while the study drug is being held. 
 At minimum, 1 restaging scan must be done within 6 weeks prior to restarting the 
study drug. 
 Investigational product(s) is/are restarted within the guidance of the Toxicity 
Management Guidelines for T-DXd and any combination agents, if appropriate. 
 No prohibited concomitant medications have been administered since the last dose of 
T-DXd. 
If a subject is assessed as requiring a dose delay of longer than 126 days, the subject will be 
withdrawn from the study drug and 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 
administration. 
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Investigators may contact the Sponsor Medical Monitor or designee to discuss questions 
regarding dose modification or discontinuation of study treatment. 
5.4.1.1. 
Dose Modifications 
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 5.2. 
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Table 5.2: 
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.  
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. 
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Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
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 h ± 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 h ± 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 
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 
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Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
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 
Anemia 
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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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 h ± 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 h ± 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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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 CT 
 
Pulmonologist consultation (infectious disease consultation as 
clinically indicated) 
 
Bronchoscopy and bronchoalveolar lavage if clinically indicated 
and feasible 
 
Pulmonary function tests (including forced vital capacity and 
carbon monoxide diffusing capacity) and pulse oximetry (SpO2) 
 
Other clinical laboratory tests (arterial blood gases if clinically 
indicated, blood culture, blood cell count, differential white blood 
cell count, and C-reactive protein) 
 
One blood sample collection for PK (central) analysis as soon as 
ILD/pneumonitis is suspected, if feasible 
Other tests could be considered as needed (eg, COVID-19) 
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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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 event 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 has not resolved within 18 
weeks (126 days) 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 
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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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 
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. 
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  
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Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
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 
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 
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Worst toxicity CTCAE 
version 5.0 Grade (unless 
otherwise specified) 
Management Guideline for trastuzumab deruxtecan 
Blood Alkaline Phosphatase Increased 
Grade 3(>5.0 to 20.0 × 
ULN if baseline was 
normal; >5.0 to 20.0 × 
baseline if baseline was 
abnormal) 
or 
Grade 4 (>20.0 × ULN if 
baseline was normal; >20.0 
× baseline if baseline was 
abnormal)) 
 
No modification unless determined by the investigator to be 
clinically significant or life-threatening 
Gastrointestinal 
Nausea 
Grade 3  
 
Delay dose 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 
Other Laboratory AEs 
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 AEs 
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 = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
ECG = electrocardiogram; FVC = forced vital capacity; 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. 
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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. 
Investigator’s Choice: 
Dose adjustments for investigator’s choice medications should be made in accordance with the 
locally approved label for that medication. Changes in medication dosage, timing, etc will be 
documented in the eCRF. Investigator’s choice medications can be interrupted for up to 28 d 
from the planned date of administration. If a subject requires 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. 
5.5. 
Method of Assessing Treatment Compliance 
Trastuzumab deruxtecan and investigator’s choice medication will be administered to subjects 
participating in the study and under the supervision of clinical study personnel at the site. Start 
and stop times of study drug infusion (trastuzumab and trastuzumab deruxtecan) and amount of 
drug administered are to be recorded by clinical study personnel. 
For lapatinib or capecitabine, treatment compliance will be reported by the subject or clinical 
study personnel. 
5.6. 
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 trastuzumab deruxtecan or control 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 week prior to Screening (see Section 4.1). 
Prophylactic or supportive treatment of study treatment-induced AEs will be as per investigator’s 
discretion and institutional guidelines. 
T-DXd is emetogenic, which includes delayed nausea and/or vomiting. Prior to each dose of 
T-DXd, subjects should be premedicated with a combination regimen of two or three medicinal 
products (eg, dexamethasone with either a 5-HT3 receptor antagonist and/or an NK1 receptor 
antagonist, as well as other medicinal products as indicated) for prevention of 
chemotherapy-induced nausea and vomiting. 
Concomitant use of dietary supplements, medications not prescribed by the investigator, and 
alternative/complementary treatments is discouraged, but not prohibited. Concomitant use of 
tobacco products, 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 
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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 HRT] is acceptable); 
 Use of bisphosphonates or receptor activator of nuclear factor kappa-Β ligand 
(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 PO) 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 investigator’s choice: 
 Refer to the approved local label for trastuzumab, lapatinib, or capecitabine for 
medications prohibited during treatment with the applicable product. 
5.7. 
Study Drug Discontinuation and Discontinuation from the Study 
5.7.1. 
Discontinuation of Study Drug 
Subjects may be withdrawn from study treatment for the following reasons: 
 PD per criteria set forth in RECIST version 1.1 (Section 17.4); 
 Clinical progression (definitive clinical signs of PD), but a recent radiographic 
assessment did not meet the criteria for PD according to RECIST 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 
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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 5.7.2) 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 continue 
regular assessment of tumor response by investigator until disease progression. 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. 
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) 
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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 or by any previously provided 
contact details 
 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). 
5.7.2. 
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. 
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 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, respectively). 
5.7.3. 
Subject Replacement 
Randomized subjects will not be replaced. 
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5.7.4. 
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 is confirmed HER2-positive 
expression as determined according to American Society of Clinical Oncology – College of 
American Pathologists guidelines26 evaluated at a central laboratory. 
Note: Subjects may continue on prior therapy while tissue 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: 
 Unless required by local regulations or IRB/EC, an HIV antigen/antibody test is not 
required prior to randomization/enrollment. 
 Perform a hepatitis B surface antigen/hepatitis C antibody test. Subjects who have a 
positive HCV antibody test will require a negative polymerase chain reaction for 
HCV RNA. 
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 Perform ophthalmologic assessments including visual acuity testing, slit lamp 
examination, and fundoscopy. 
 Perform an ECHO or MUGA (note: the same test must be used for the subject 
throughout the study). 
 Perform tumor assessment by CT or 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. 
 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 as 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 RECIST 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 9.2. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
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. 
 Note that subsequent ECGs will be performed in triplicate only if an abnormality 
is noted. 
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 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 
[Section 17.8]) 
 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 2:1 ratio into the treatment arms 
(trastuzumab deruxtecan versus investigator’s choice, which has 2 available treatment 
paradigms). 
Randomization will be stratified by hormone receptor status (positive, negative), prior treatment 
with pertuzumab (yes, no), and history of visceral disease (yes, no). 
Investigators will choose 1 of the 2 control treatments for every subject before randomization. 
A subject’s first dose/Cycle 1 Day 1 should occur within 7 d after 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 investigator’s choice are 
both 21 d in duration. 
6.4.1.1. 
Between -3 Days Through Immediately Before Dosing (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 at regular intervals and ECG, ECHO, or MUGA as clinically 
indicated. 
 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 dosing 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 Dosing (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 [Section 8.3.2] will be collected on Cycle 3 
Day 1 and at EOT. After implementation of protocol version 8, serum biomarker 
samples will not be taken except at EOT. 
 COVID-19 serology [Section 17.8]) assessment will be collected on Cycle 3 Day 
1. 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. 
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 Only subjects randomized to trastuzumab deruxtecan: 
 PK assessment before dosing (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); 
EOT; and at the 40-day follow-up only for those subjects randomized to 
trastuzumab deruxtecan. After implementation of protocol version 8, ADA 
samples will not be taken except at EOT and 40-day follow-up. 
 Obtain blood samples for exploratory biomarkers before treatment on Day 1 of 
Cycle 1 and every 3 cycles thereafter until protocol version 8 is approved and 
implemented. After approval and implementation of protocol version 8, collection of 
exploratory biomarkers will only occur at EOT. 
 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 trastuzumab deruxtecan 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. 
 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 the investigator’s choice 
treatment should occur per the locally approved label. An ECG and blood samples for 
PK analyses are not required at the end of infusion (EOI)/treatment for investigator’s 
choice treatment as part of this study protocol. 
 Record start and stop times of any study treatment and amount of drug administered 
(trastuzumab and trastuzumab deruxtecan). 
 Subjects randomized to investigator’s choice treatments should be treated and 
monitored per the approved product label. Subjects randomized to 
trastuzumab/capecitabine will receive trastuzumab by IV once every 21 d (± 2 d) and 
capecitabine PO twice daily approximately 12 h apart on Days 1 through 14 of the 
21 d (± 2 d) schedule. Subjects randomized to lapatinib/capecitabine will receive 
lapatinib PO daily on each day of a 21 d (± 2 d) schedule and capecitabine PO twice 
daily approximately 12 h apart on Days 1 through 14 of the 21 d (± 2 d) schedule.” 
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 Obtain vital signs after each infusion of trastuzumab or trastuzumab deruxtecan 
(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: 
 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 5.2. 
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 6 Weeks (12 weeks upon approval of version 8 ±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 weeks (±7 days) 
from randomization, until protocol version 8 is approved by the study site. After 
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approval and implementation of this protocol version, tumor assessments will be 
conducted every 12 weeks (±7 days), independent of treatment cycle. A CT and/or 
MRI (CT or MRI with ≤5 mm cuts) of the chest, abdomen, pelvis, and any other sites 
of disease 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 the Sponsor or its designee. Unscheduled tumor assessments may be 
performed if progression is suspected. 
 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 Table 17.2. 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. 
 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 clinically indicated. 
 ECHO or MUGA (note: the same test at screening must be used for the subject at 
EOT). 
 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; 
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 Serum biomarkers (eg, HER2ECD; Section 8.3.2, COVID-19 serology; 
Section 17.8); 
 Coagulation. 
 Blood sample for exploratory biomarkers 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 if PD is suspected (eg, MRI of the brain if brain metastases are 
suspected) should also be imaged, per RECIST version 1.1 (Section 17.4). After 
approval and implementation of this protocol version, tumor assessments will be 
conducted every 12 weeks (±7 days), independent of treatment cycle. If the previous 
scan was within the last 12 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 continue regular 
assessment of tumor response by the investigator until disease progression (see 
Section 5.7.1). 
 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. 
 An optional newly obtained tumor biopsy may be collected for those in the T-DXd 
group. See Section 8.3.3 for additional details. 
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 
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. 
 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. 
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 Obtain blood samples for ADA, only for subjects randomized to trastuzumab 
deruxtecan. 
 Serum or urine sample for pregnancy testing in women of childbearing potential. 
6.6.2. 
Long-term/Survival Follow-up 
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 the first 3 mo, which will be the last data 
collection point for these questionnaires); 
 Record subsequent anticancer treatments, their outcomes, and survival; 
 Further follow-up may be required for ongoing AEs (see Section 9.2). 
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 5.7.1 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 via 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). 
After the primary efficacy endpoint has been achieved, assessments by BICR (PFS, ORR, DoR, 
best overall response, best percent change in the sum of the diameter of measurable tumors, and 
CBR) will be discontinued. Subjects will continue with all other assessments as indicated in the 
Schedule of Events, including the assessment of tumor response and radiographic disease 
progression by investigators. 
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 or data cutoff date, whichever is earlier. Detailed censoring rules for OS will be specified in 
the SAP. 
7.1.3. 
Other Secondary Efficacy Endpoints 
Other secondary efficacy endpoints will be based on mRECIST version 1.1 (Section 17.4). Other 
secondary efficacy endpoints are: 
 ORR, defined as the proportion of subjects who achieve a best overall response of CR 
or PR. Assessments based on BICR and based on investigator assessment will be 
analyzed. 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 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 cases where there is no next-line therapy. In case a 2nd anticancer 
therapy is introduced prior to PFS2 event, then 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 as 
PFS2 event. 
 Any death following the next-line of therapy will be a PFS2 event if no 2nd new 
line of therapy is initiated. 
 PFS and PFS2 may be identical in case 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 anticancer 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),24 palbociclib (PALOMA studies),28,29 ribociclib 
(MONALEESA-2),30 and abemaciclib (MONARCH 2).31 Sample size has been calculated to 
ensure the study is adequately powered to detect a clinically meaningful OS benefit. 
Subjects 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). That is why it is particularly 
valuable to involve subjects in clinical studies by asking them to provide assessment of their 
health and QoL. In recent years a growing number of clinical studies in mBC have been 
reporting on health-related QoL, the most common patient-reported outcome (PRO) being used 
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is the EORTC QLQ-C30 with or without the breast cancer supplement EORTC QLQ-BR45, 
followed by FACT-B.32 
The index scores from the PROs will be used to show changes in overall health-related QoL and 
clinically meaningful changes in specific aspects of subject’s wellbeing over time. In addition, 
the outcomes will be used in further 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) 
EOIa 
5 h (± 2 h) after the start of drug administration  
Cycles 2, 3, 4, 6, 
and 8 
Day 1 
BI (within 8 h) 
EOIa 
BI = before infusion; EOI = end of infusion 
a The 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 the 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. 
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 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. 
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. 
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8.3.2. 
Blood Sampling 
The HER2ECD in serum may be measured by a central laboratory. Other exploratory biomarkers 
may be measured. 
8.3.3. 
Optional Newly Obtained Tumor Tissue Biopsy 
Additionally, an optional new tissue sample for exploratory biomarker analysis is requested after 
study treatment, if allowed by local laws and if consent is provided. This fresh biopsy sample can 
be obtained from subjects in the T-DXd group after the end of the study treatment, regardless of 
disease progression. Detailed instructions for the handling and shipping of tumor samples are 
included in the Study Laboratory Manual. It is recommended to obtain core needle biopsies. If a 
core needle biopsy is not feasible for safety reasons, a fine needle aspiration can be accepted. 
Bone biopsies will not be accepted for tissue samples. 
8.3.4. 
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. Biosamples and 
data may be used to design or improve methods for analyzing development of diagnostic agents, 
characteristics of cancer, and research related to other diseases that may lead to new treatments. 
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. 
8.3.5. 
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. 
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8.5. 
Pharmacogenetic Analysis 
8.5.1. 
Pharmacogenetic Analysis 
A single blood sample for pharmacogenetic 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. 
Pharmacogenetic samples may be analyzed for genes involved in the absorption, distribution, 
metabolism, elimination, and safety of trastuzumab deruxtecan. Additionally, samples may be 
analyzed for genes involved in trastuzumab deruxtecan-related signaling pathways or to examine 
diseases, physiologic processes, or safety related to trastuzumab deruxtecan, such as ILD. 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. 
8.5.2. 
Banking of Specimens 
If the subject agrees, the remaining samples (tumor, blood, or other specimen obtained in the 
study) may be stored for future research. The banked samples may be analyzed to design or 
improve methods for analyzing the development of diagnostic tests, for better understanding of 
the characteristics of cancer and, possibly, research-related other diseases that may lead to new 
treatments. This information may be useful in increasing the knowledge of differences among 
individuals in the way they respond to the study drug, as well as helping in the development of 
new drugs or improvement of existing drugs. 
Additionally, banked samples from this study may be shared globally in the future by the 
Sponsor, Sponsor’s commercial partners, Sponsor’s authorized representatives, Sponsor’s 
research partners, and/or Sponsor’s collaborators or shared with third parties, including other 
commercial entities and drug companies. 
8.5.2.1. 
Storage and Disposal of Specimens 
If the subject agrees, banked samples will be stored for a maximum of 15 years, or longer if 
required per local regulations, after the finalization of the clinical study report for this protocol. 
During the storage period, the samples will be coded with labels having no personal information 
and will not be immortalized or sold to anyone. Subjects will have the right to withdraw consent 
and have their sample destroyed at any time, with written request to the investigator. However, 
the data will not be discarded if analysis has been completed before the subject withdraws 
consent. 
8.5.2.2. 
Disclosure of the Results of Future Analysis 
Because the nature and value of future analysis cannot be known at this time, any results 
obtained from research involving the banked samples will not be disclosed to the subject or 
investigators now or in the future. 
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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, events associated with disease progression should be reported as an AE or an SAE. 
Death due to disease progression should be recorded on the Death eCRF. 
Any AESI or SAE that occurs beyond 47 days after the last treatment (Safety Follow-up Period) 
that the investigator assesses as related to study treatment should be reported to the Sponsor (see 
Section 9.5). 
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 LV dysfunction 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.12 
9.3.1.2. 
Management Guidance 
Interstitial lung disease/pneumonitis should be ruled out if a subject develops radiographic 
changes potentially consistent with ILD/pneumonitis or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnea, cough or fever. 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 5.4.1.1). 
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), bronchoscopy and 
bronchoalveolar lavage if clinically indicated and feasible, pulmonary function tests (including 
forced vital capacity [FVC] and carbon monoxide [CO] diffusing capacity) and pulse oximetry 
(SpO2), clinical laboratory tests (arterial blood gases if clinically indicated, blood culture, blood 
cell count, differential white blood cell count, and C-reactive protein), and one blood sample 
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collection for PK (central) analysis as soon as ILD/pneumonitis is suspected, if feasible. Other 
tests could be considered, as needed (eg, COVID-19 test). 
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 5.2). 
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 collections will cover a more in-depth relevant medical 
history (eg, smoking, radiation, COPD and other chronic lung conditions), diagnostic evaluation, 
treatment and outcome of the event. This data collection will be triggered for AEs reported for 
broad surveillance of ILD/pneumonitis based on a set of pre-defined preferred terms (PTs) 
eligible for adjudication as described in the Event Adjudication Site Manual. This list will be 
utilized for enhanced data collection. 
9.3.2. 
Left Ventricular Dysfunction 
9.3.2.1. 
Clinical Summary 
LV dysfunction in association with trastuzumab deruxtecan is 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.12 
For broad surveillance of LV dysfunction, standard cardiac function testing (ECHO or MUGA 
scanning) should be performed to assess LVEF prior to initiation of T-DXd, as clinically 
indicated, and at EOT. Perform ECHO or MUGA if clinically indicated; if abnormal, follow 
institutional guidelines. 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 
If clinically indicated, LVEF will be measured by either ECHO or MUGA scan. All 
ECHOs/MUGAs will be evaluated by the investigator or delegated physician for monitoring 
cardiac function. Troponin will be measured at Screening and as needed based on 
subject-reported cardiac signs and symptoms suggesting congestive heart failure, myocardial 
infarction, or other causes of cardiac myocyte necrosis. If ECG is abnormal, follow institutional 
guidelines. ECGs will be performed if clinically indicated, 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. 
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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, 
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).33 
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).33 
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. 
 Any AESI or SAE that occurs beyond 47 days after the last treatment (Safety 
Follow-up Period) that the investigator assesses as related to study treatment should 
be reported to the Sponsor (see Section 9.5). 
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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 
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). 
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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. 
 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. 
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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 LV dysfunction for 
the trastuzumab deruxtecan clinical program, regardless of seriousness, is to be collected through 
the targeted questionnaires built within the clinical study database. 
For broad surveillance of LV dysfunction, 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, a set of pre-defined list of PTs eligible for 
adjudication, as described in the Event Adjudication Site Manual, is utilized for enhanced data 
collection. 
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/pneumonitis cases should be reported within 24 hours; including 
both serious and non-serious potential ILD/pneumonitis cases (potential 
ILD/pneumonitis 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. Overdose will be 
reported via Serious Adverse Event Report (SAVER)/overdose form or eCRF. 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. 
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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 the EDC. 
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 
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 and follow-up information, such as those upgraded to fatal/life-threatening 
cases, must be followed up and addressed promptly. The investigator will submit any important 
and updated SAE data, as noted above, to the Sponsor within 24 hours of receipt of the 
information. Other 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 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. For investigator’s choice 
drugs, study sites should follow local or institutional guidelines. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome. If a pregnancy is reported, the investigator should inform the Sponsor 
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within 24 hours of learning of the pregnancy. 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. 
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 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 
dosing on Day 1 of each cycle, 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 
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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. 
9.10. 
Electrocardiograms 
Electrocardiograms will be taken in triplicate at Screening and if clinically indicated while on 
treatment. Singular ECGs will also be conducted at regular intervals during the study (see 
Table 17.2). If an abnormality is noted, follow institutional guidelines. Standard ECG parameters 
will be measured, including RR, PR, QT intervals, and QRS duration. All ECGs must be 
evaluated by the 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). LV 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 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 EORTC 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 EORTC 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. 
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 assessment. 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. Reporting will follow closely the 
Consolidated Standards of Reporting Trials (CONSORT) extension on reporting PROs.34 
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 EORTC QLQ-C30, deterioration is defined as an increase of 10 points or 
more on these symptom subscale scores and a decrease of 10 points or more for functional scale 
and global health status/QoL.36 
Further details on the scoring of these scales, including missing items, will be provided in the 
SAP. 
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10.1.2. 
EuroQoL Five Dimensions Five Levels Patient-Reported Outcome 
Questionnaire 
Study subjects will be asked to complete the EQ-5D-5L questionnaire (Section 17.7), 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.35 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. 
Reporting will follow closely the CONSORT extension on reporting PROs.34 
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 for the health-related QoL 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. 
 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 EORTC QLQ-C30, deterioration is defined as an 
increase of 10 points or more on these symptom subscale scores and a decrease of 
10 points or more for functional scale and global health status/QoL.36 
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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 Endpoints 
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 analysis for PFS will be performed when approximately 372 BICR-assessed PFS 
events are observed or 18 months from the last subject randomized, whichever comes first. 
Summary statistics will be presented by cohort/treatment group. Continuous variables will be 
summarized by the number of observations, mean, standard deviation, median, minimum, and 
maximum values. Categorical variables will be summarized using frequency counts and 
percentages. 
Assessment of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment 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). Some efficacy analyses 
such as PFS analysis will 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. 
11.2. 
Analysis Sets 
11.2.1. 
Full Analysis Set 
The FAS will include all subjects randomized into the study. The FAS will be the primary 
analysis set for all efficacy analysis. 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. 
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 in the FAS 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. 
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11.3. 
Study Population Data 
Subject disposition will be summarized for subjects in the FAS. The total number of subjects for 
each defined analysis set will also be tabulated. The demographic and baseline characteristics 
will be summarized descriptively for the FAS, and some baseline characteristics will also be 
summarized for PPS and Safety Analysis Set. 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 
The primary efficacy endpoint, PFS, and the key secondary efficacy endpoint, OS, will be tested 
hierarchically to maintain an overall type I error rate of 0.05 (2-sided) or less. 
11.4.1.1. Primary Efficacy Analyses 
The primary efficacy analyses will be performed based on data from the FAS. The primary 
efficacy endpoint is PFS based on BICR. 
PFS based on BICR will be compared between the treatment groups using stratified log-rank 
tests stratified by stratification factors per IXRS. 
PFS will be tested for statistical significance at an overall 2-sided alpha of 0.05. 
Kaplan-Meier estimates and survival curves will also be presented for each treatment group. The 
median survival time and 2-sided 95% CI for the median using Brookmeyer and Crowley 
methods will be provided for each treatment group. In addition, Kaplan-Meier estimates 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 hazard ratios (HRs) and their 2-sided 95% Cis will be estimated, using 
stratified Cox proportional hazards regression model stratified by the randomization stratification 
factors per IXRS. 
11.4.1.2. Secondary Efficacy Analyses 
The key secondary efficacy endpoint is OS, and other secondary efficacy endpoints include ORR 
based on BICR and investigator assessment, DoR based on BICR, and PFS based on investigator 
assessment. DoR will be measured for responding subjects (CR or PR) only. 
Progression-free survival based on investigator assessment will be analyzed in the same manner 
as the analysis of PFS based on BICR. Detailed censoring rules for PFS based on investigator 
assessment will be specified in the SAP. 
If the test of the primary endpoint, PFS based on BICR, is statistically significant, the key 
secondary endpoint, OS, will be tested. 
Group sequential testing with 2 OS interim analyses are planned. The first OS interim analysis is 
planned at time of the PFS analysis, and the second OS interim analysis will be performed when 
approximately 304 OS events have been observed (70% of the planned 434 OS events). 
Approximately 240 and 304 of the targeted 434 OS events will be documented (55% and 
70% information fractions) by time of the first and second OS interim analyses, respectively. The 
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second OS interim analysis will occur after all subjects have been randomized. The final OS 
analysis will occur after approximately 434 OS events have been documented. 
The OS interim analysis will allow the study to stop early for outstanding efficacy. Futility 
assessments will not be made at these interim analyses. Additional details of the interim analyses 
can be found in Section 11.5. 
Overall survival will be compared between the 2 treatment groups, using stratified log-rank test 
stratified by stratification factors per IXRS. Kaplan-Meier estimates and survival curves will also 
be presented for each treatment group. The median survival times and 2-sided 95% Cis for the 
medians will be provided using Brookmeyer and Crowley method for each treatment group. In 
addition, Kaplan-Meier estimates at fixed time points along with their 2-sided 95% Cis will be 
provided for each treatment group. The HR and its 95% CI will be estimated, using stratified 
Cox proportional hazards regression model stratified by the stratification factors per IXRS. 
Cochran-Mantel-Haenszel tests stratified by stratification factors per IXRS will be used to 
compare ORR (based on BICR and investigator assessment) between the treatment groups. ORR 
(based on BICR and investigator assessment) will be summarized by treatment group along with 
the 2-sided 95% Cis using Clopper-Pearson methods. In addition, ORR (based on BICR and 
investigator assessment) until fixed time points (eg, 3, 6, 9, 12 mo) along with the 2-sided 95% 
Cis will be provided by treatment group. 
Duration of response (based on BICR) will be summarized with median DoR and its 2-sided 
95% CI for the median 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 2-sided 95% CI using Brookmeyer and Crowley method will be provided for each 
treatment group. PFS 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 HR and its 2-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 2 treatment groups will be 
compared at a 2-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), OS, ORR (based on BICR), DoR (based on BICR), 
and CBR (based on BICR) 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) 
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 Prior treatment with pertuzumab (yes, no) 
 Lines of therapy prior to pertuzumab treatment (<3 line, ≥3 line) 
 Lines of therapy prior to T-DM1 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) 
 Best response to T-DM1 therapy (CR/PR/SD, PD) 
 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) 
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 
unstratified analysis and the same type of methodology as described for the overall analysis of 
the corresponding endpoint. These results will be considered exploratory because of smaller 
sample sizes and p-value will not be presented. Subgroup analyses of PFS will be performed 
only if at least 10 PFS 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, CBR based on BICR, and PFS2 based on investigator assessment will be 
evaluated and considered as exploratory efficacy endpoints. 
Descriptive statistics for percent change from baseline to the best (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 diameters 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 2-sided 95% Cis using 
Clopper-Pearson method. 
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 two-sided 95% CI using 
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 two-sided 95% Cis will be provided for each 
treatment group. The treatment effect HR and its two-sided 95% CI will be estimated using 
stratified Cox proportional hazards regression model with the treatment group as model factor 
and the randomization stratification factors from IXRS as strata variables. 
Exposure-response relationships will be explored. 
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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. A detailed analysis plan of QoL 
endpoints, including control of type I error regarding QoL analyses, could be provided in the 
SAP. Some descriptive analysis will be performed as follows. 
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-5D VAS by 
scheduled time of evaluation (including EOT) for all. 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 EORTC QLQ-C30, deterioration is defined as an increase of 10 points or 
more on these symptom subscale scores and a decrease of 10 points or more for functional scale 
and global health status/QoL. 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 subjects 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. 
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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. Descriptive statistics by 
region/country may also be provided for all serum concentration data 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/pharmacodynamics model may be developed to evaluate the relationship between 
exposure and efficacy and toxicity. The results of the nonlinear mixed effects 
pop-PK/pharmacodynamic models may be reported separately from the clinical study report. 
11.4.3.2. Pharmacodynamic Analyses 
Not applicable 
11.4.3.3. Biomarker Analyses 
Samples collected for biomarker analyses, such as tissue and blood, may be used for exploratory 
biomarker assessments. Biomarker data may be summarized by treatment group using 
descriptive statistics. 
11.4.4. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set for each cohort 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. 
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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 
post-treatment value, and minimum post-treatment 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 post-treatment 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. 
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 post-treatment 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 post-treatment 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 post-treatment, or who are ADA positive at baseline and 
post-treatment, but have an increase in ADA titer from baseline to post-treatment, or those who 
have missing ADA data at baseline but become ADA positive post-treatment. The number and 
percentage of subjects positive for neutralizing anti-drug antibody (NAB) of trastuzumab 
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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 
There is no planned interim analysis of the primary endpoint PFS. The primary PFS analysis will 
be performed when approximately 372 PFS events are observed or 18 months from the last 
subject randomized, whichever comes first. 
Overall survival endpoint will be tested only if the test of the primary efficacy endpoint PFS is 
statistically significant. Group sequential testing with 2 OS interim analyses are planned. The 
first OS interim analysis is planned at the time of the PFS analysis (approximately 240 OS events 
are anticipated), and the second OS interim analysis is planned when approximately 304 OS 
events (70% information fraction) have been observed. 
The OS interim analysis will allow the study to stop early for outstanding efficacy. Futility 
assessments will not be made at these interim analyses. 
A group sequential design utilizing 3-look Lan DeMets implementation of O’Brien-Fleming 
alpha spending function will be used to construct the efficacy stopping boundaries (significance 
levels) with an overall 2-sided type I error 0.05.37 
If the interim and final analyses are carried out with exactly 240, 304, and 434 OS events 
respectively, the efficacy boundaries expressed in 2-sided p-value scale (HR scale) at the interim 
and final analyses are presented in Table 11.1 below. The efficacy boundaries will be 
recalculated based on the actual number of observed events using the pre-specified alpha 
spending function if different from the specified number below. 
The final OS analysis will occur after approximately 434 OS events have been documented. 
See Table 11.1 for stopping boundaries for OS. 
Table 11.1: 
Efficacy Stopping Boundaries for OS 
Endpoint 
Median OS: 20 m for the T-DXd Arm,  
15 m for the Investigator’s Choice Arm; HR = 0.75 
OS 
Number of 
OS Events 
IF (%) 
Boundary 
2-sided p-value 
HR 
1st IA 
240 
55% 
0.0052 
0.682 
2nd IA 
304 
70% 
0.0132 
0.740 
Final 
434 
100% 
0.0452 
0.816 
IA = interim analysis; HR = hazard ratio; IF = information fraction; OS = overall survival. 
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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 
investigator’s choice, with a randomization ratio of 2:1. 
The hypothesized median PFS in the trastuzumab deruxtecan arm and the control arm were 
4.7 and 3.3 months (HR=0.7), respectively. If the true hazard ratio is 0.7 (under alternative 
hypothesis), a total of 372 PFS events are required to have 90% power at a 2-sided overall 5% 
level of significance to reject the null hypothesis (HR=1) using a log-rank test. PFS analysis will 
be performed when approximately 372 PFS events are observed or 18 months from the last 
subject randomized, whichever comes first. 
OS will be compared between the 2 treatment groups, provided that the test of the primary 
endpoint PFS is statistically significant. Based on available data from the TH3RESA study, the 
median OS in the investigator’s choice arm is expected to be 15 months.7 It is hypothesized that 
treatment with trastuzumab deruxtecan will result in a 25% reduction in the hazard rate of death 
(corresponding to an increase in median OS from 15 to 20 months under the exponential model 
assumption). If the true HR is 0.75 (under alternative hypothesis), a total of 434 OS events are 
needed to have 80% power at an overall 2-sided overall 5% level of significance to reject the null 
hypotheses (HR=1) using a log-rank test and a 3-look group sequential design. For details of the 
planned OS analyses, see Section 11.5. 
Approximately 600 subjects will be randomized (400 subjects to trastuzumab deruxtecan and 
200 subjects to investigator’s choice) in 30 months. 
The sample size computation is performed using EAST v6.4. 
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. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized before half enrollment. 
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, PUBLIC DISCLOSURE POLICY, AND DATA 
SHARING 
Daiichi Sankyo Inc. is committed to meeting the highest standards of publication and public 
disclosure of information arising from clinical studies sponsored by the company. We will 
comply with US, EU, and Japanese policies for public disclosure of the clinical study protocol 
and clinical study results, and for sharing of clinical study data. We follow the principles set 
forward in “Good Publication Practice for Communicating Company-Sponsored Medical 
Research (GPP3)”, and publications will adhere to the “Recommendations for the Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals” established by the 
International Council of Medical Journal Editors. 
In order to ensure that we are in compliance with the public disclosure policies and the 
International Council of Medical Journal Editors recommendations, and to protect proprietary 
information generated during the study, all publications (manuscripts, abstracts, or other public 
disclosure) based on data generated in this study must be accepted, reviewed, and approved in 
writing by the Sponsor prior to submission. 
The data from this study may be shared with or used by third parties, including commercial 
partners. 
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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: 
 Regulation (EU) No. 536/2014 of the European Parliament and of the Council of 
16 Apr 2014 on clinical trials on medicinal products for human use, and repealing 
Directive 2001/20/EC and/or 
 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 Mar 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. 
For EU study sites, the Sponsor will observe the rules laid down in the General Data Protection 
Regulation 2016/679/EU on the protection of individuals with regard to the processing of 
personal data and the free movement of such data. 
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 
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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 
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 only 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 noncompliance that the investigator becomes aware of. 
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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. 
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. 
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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. 
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 wellbeing 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 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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16. 
REFERENCES 
1. Fitzmaurice C, Allen C, Barber RM, et al. Global, Regional, and National Cancer 
Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-
Adjusted Life-years for 32 Cancer Groups, 1990 to 2015. JAMA Oncol. 2017;3(4):524-
48. 
2. Santa-Maria CA, Nye L, Mutonga MB, et al. Management of Metastatic HER2-Positive 
Breast Cancer: Where Are We and Where Do We Go From Here? Oncology. 2016 
Feb;30(2):148-55. 
3. National Comprehensive Cancer Network. Breast Cancer (Version 2.2016). 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. 25 Oct 2016. 
4. Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily 
pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. 
5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive 
advanced breast cancer. N. Engl. J. Med., 355 (2006), pp. 2733–43. 
6. Blackwell K, Burstein HJ, Storniolo AM et al. Randomized study of Lapatinib alone or in 
combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory 
metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. 
7. Krop IE, Kim SB, González-Martín A, et al. Trastuzumab emtansine versus treatment of 
physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a 
randomised, open-label, phase 3 trial. The Lancet Oncology. 2014; 15 (7): 689-99. 
8. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan 
and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic 
cancer. J. Clin Oncol. 2006;24(27):4441-7. 
9. Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-8951f) versus 
gemcitabine (Gem) in chemotherapy- naïve patients with advanced pancreatic cancer 
(APC). J Clin Oncol. 2004;22(14s):4005. 
10. De Jager R, Cheverton P, Tamanoi K, et al. DX-8951f: summary of phase I clinical trials. 
Ann N Y Acad Sci. 2000;922:260-73. 
11. Ogitani Y, Aida T, Hagihara K, et al. DS-8201a, A Novel HER2-Targeting ADC with a 
novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with 
differentiation from T-DM1. Clin Cancer Res. 2016; 22(20): 5097–108. 
12. DS-8201a Investigator’s Brochure, most current version. 
13. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated 
HER2-positive breast cancer. N Engl J Med. 2019 Dec 11. Doi: 
10.1056/NEJMoa1914510. (Epub ahead of print) 
14. Archer SG, Eliopoulos A, Spandidos D, et al. Expression of ras p21, p53 and c-erbB-2 in 
advanced breast cancer and response to first line hormonal therapy. Br J Cancer. 
1995;72(5):1259-66. 
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15. Esteva FJ, Guo H, Zhang S, et al. PTEN, PIK3CA, p-AKT, and p-p70S6K status: 
association with trastuzumab response and survival in patients with HER2-positive 
metastatic breast cancer. Am J Pathol. 2010;177(4):1647-56. 
16. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: 
ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 
2009;14(4):320-68. 
17. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric 
cancer: results from a validation study. Histopathology. 2008;52(7):797-805. 
18. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel 
therapeutic target. Ann Oncol. 2008;19(9):1523-9. 
19. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and 
capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J 
Cancer. 2012;106(6):1033-8. 
20. Yoshizawa A, Sumiyoshi S, Sonobe M, et al. HER2 status in lung adenocarcinoma: a 
comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-
ISH, and gene mutations. Lung Cancer. 2014;85(3):373-8. 
21. Blok EJ, Kuppen PJ, van Leeuwen JE, et al. Cytoplasmic overexpression of HER2: a key 
factor in colorectal cancer. Clin Med Insights Oncol. 2013;7:41-51. 
22. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in 
epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. 
Clinical study. Oncology. 2005; 68(2-3):154-61. 
23. Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in 
normal human adult and fetal tissues. Oncogene. 1990;5(7):953-62. 
24. Baselga J, Cortes J, Kim SB et al. Pertuzumab plus trastuzumab plus docetaxel for 
metastatic breast cancer. N Engl J Med. 2012; 366(2):109-19. 
25. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med. 2012;367(19):1783-91. 
26. Wolff A, Hammond M, Hicks D, Dowsett M, et al. Recommendations for human 
epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical 
Oncology/College of American Pathologists clinical practice guideline update. J Clin 
Oncol. 2013;31(31):3997-4013. 
27. Eisenhauer EA, Therasse P, Bogaerts J, et.al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-47. 
28. Finn RS, Crown JP, Lang I et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in 
combination with letrozole versus letrozole alone as first-line treatment of oestrogen 
receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a 
randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. 
29. Finn RS, Martin M, Rugo HS et al. Palbociclib and Letrozole in Advanced Breast 
Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-36. 
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30. Hortobagyi GN, Stemmer SM, Burris HA et al. Ribociclib as First-Line Therapy for HR-
Positive, Advanced Breast Cancer. N Engl J Med. 2016 Nov 3;375(18):1738-48. 
31. Sledge GW Jr, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in Combination With 
Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed 
While Receiving Endocrine Therapy. J Clin Oncol. 2017 Sep 1;35(25):2875-2884. 
32. Ghislain I, Zikos E, Coens C, et al. Health-related quality of life in locally advanced and 
metastatic breast cancer: methodological and clinical issues in randomised controlled 
trials. Lancet Oncol. 2016 Jul;17(7):e294-e304. 
33. International Conference on Harmonisation (ICH), ICH E2A Guideline. Clinical Safety 
Data Management: Definitions and Standards for Expedited Reporting, E2A. (27 
October, 1994). Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A
/Step4/E2A_Guideline.pdf 
34. Calvert M, Brundage M, Jacobsen PB, et al. The CONSORT Patient-Reported Outcome 
(PRO) extension: implications for clinical trials and practice. Health Qual Life Outcomes. 
2013 Oct 29;11:184. 
35. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 Dec;20(10):1727-36. 
36. Osoba D, Rodrigues G, Myles J, et al. Interpreting the significance of changes in health-
related quality-of-life scores. J Clin Oncol. 1998 Jan;16(1):139-44. 
37. Lan KKG and DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-63. 
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17. 
APPENDICES 
17.1. 
Schedule of Events 
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Table 17.1: 
Schedule of Events – Tissue Screening and Screening Period 
Visit/Cycle 
Tissue Screening 
Screening 
Window (Day) 
 
-28 to -1 
-14 to -1 
Procedures 
 
 
 
Tissue Screening Informed Consenta 
X 
 
 
Tumor Sample for HER2 Status  
Xb 
 
 
Main Informed Consenta 
 
X 
 
Optional Biomarker 
 
Xc 
 
Eligibility Assessment 
 
 
X 
Demographics 
 
 
X 
Medical and Surgical History (including target disease) 
 
 
X 
Physical Examination 
 
 
X 
Weight 
 
 
X 
Height 
 
 
X 
ECOG PS 
 
 
X 
Adverse Events  
Xd 
 
Xe 
Concomitant Medications 
 
 
Xe 
Hospitalization-related Records 
 
 
Xe 
Vital Signs 
 
 
X 
SpO2 
 
 
X 
12-lead ECG in Triplicatef 
 
 
X 
ECHO or MUGA (LVEF)g 
 
X 
 
Tumor Assessment (CT/MRI of the chest, abdomen, pelvis, and any other 
sites of disease) 
 
X 
 
CT/MRI of the Brain 
 
X 
 
Ophthalmologic Assessmentsh 
 
X 
 
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Visit/Cycle 
Tissue Screening 
Screening 
Window (Day) 
 
-28 to -1 
-14 to -1 
Hematology, Coagulation, Chemistry 
 
 
X 
Urinalysisi 
 
 
X 
Troponinj 
 
 
X 
Serum Biomarkers (eg, HER2ECD, COVID-19 serology) Sample 
 
 
X 
HIV Antibody Test (as required by local regulations or IRBs/ECs) 
 
X 
 
Hepatitis B/C Serology  
 
X 
 
Pregnancy Test (urine or serum)k 
 
 
X 
Assign SID 
X 
 
 
Randomization 
 
 
X 
Declaration of Investigator’s Choice Paradigm  
 
 
X 
COVID-19 = coronavirus disease 2019; CT = computed tomography; d = days; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern 
Cooperative Oncology Group performance status; HER2 = human epidermal growth factor receptor 2; HER2ECD = extracellular domain of HER2; 
HIV = human immunodeficiency virus; ICF = informed consent form; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
MUGA = multigated acquisition (scan); SAE = serious adverse event; SID = subject identification; SpO2 = peripheral oxygen saturation. 
a Tissue screening informed consent must be signed before tumor tissue screening assessments. The main informed consent form must be signed before initiating 
all other screening assessments. 
b Archived tissue appropriate for central laboratory HER2 testing. If archived tissue is not available, fresh biopsy is required. 
c Additional slides are requested for optional exploratory biomarker analysis. It is preferred if the slides are from the same block as the tissue sample sent for 
central laboratory HER2 testing. 
d For subjects who sign only the Tissue Screening Informed Consent Form, report only SAEs directly related to tissue screening procedure (ie, tumor biopsy) 
along with any associated treatment. Unless documentation of other adverse events is required by local law, only SAEs directly related to tumor biopsy will be 
recorded during tissue screening. 
e Collected after the Main ICF is signed. 
f ECG will be taken in triplicate at Screening. 
g ECHO or MUGA scan assessments will be performed at Screening. Note that the same test must be used for the subject throughout the study. 
h Ophthalmologic assessments including visual acuity testing, slit lamp examination, and fundoscopy will be performed at Screening and as clinically indicated. 
i Urinalysis test to be performed at baseline and as clinically indicated. 
j In addition to the troponin sample that is tested locally, a sample should also be submitted for central laboratory troponin-T testing. 
k For female subjects of childbearing potential. 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. 
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Table 17.2: 
Schedule of Events – Treatment and Follow-up Period (Continued) 
Visit/Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
and 
Subsequent 
Cycles 
Q6W 
EOTa 
Follow-up 
Study Day 
1 
8 
15 
1 ± 2 
1 ±2 
1 ± 2 
 
 
40-
dayb 
LT/Sc 
Window (Day) 
BId 
EOIe 
± 1 
± 1 
BI 
EOI 
BI 
EOI 
BI 
EOI 
±7 
 
+7 
± 14 
PK Blood (Serum) Sample 
Xm 
Xn,o 
 
 
Xm 
Xn 
Xm 
Xn 
Xm 
Xn 
 
 
 
 
ADA Blood Sample 
Xp 
 
 
 
Xp 
 
 
 
Xp 
 
 
Xp 
Xp 
 
Serum biomarkers (eg, HER2ECD, COVID-19 
serology) Sample 
 
 
 
 
 
 
Xq 
 
 
 
 
X 
 
 
Exploratory Biomarker Blood Samplesr 
Xr 
 
 
 
 
 
 
 
Xr 
 
 
Xr 
 
 
Pharmacogenetics Blood Sample 
Xs 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administer Study Treatment as appropriatet 
X 
 
 
X 
X 
X 
 
 
 
 
Tumor Assessment (CT/MRI of the chest, 
abdomen, pelvis, and any other sites of disease)u 
 
 
 
 
 
 
 
 
 
 
Xv,w 
Xv,w 
 
 
CT/MRI of the Brainx 
 
 
 
 
 
 
 
 
 
 
Xw 
Xw 
 
 
Newly obtained tumor tissue sample  
 
 
 
 
 
 
 
 
 
 
 
Xy 
 
 
Survival Follow-up  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ADA = anti-drug antibody; BI = before infusion/dosing; BICR = blinded independent central review; CO = carbon monoxide; COVID-19 = coronavirus disease 2019; 
CQ = chloroquine; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; d = days; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG PS = Eastern Cooperative Oncology Group performance status; EOI = end of infusion; EORTC QLQ = European Organization for Research and Treatment of Cancer 
quality of life questionnaire; EQ-5D-5L = EuroQoL-5 dimensions-5 levels of severity; EOT = end of treatment; FVC = forced vital capacity; HER2 = human epidermal growth 
factor receptor 2; HER2ECD = extracellular domain of HER2; HCQ = hydroxychloroquine; LT/S = Long-term/Survival; LVEF = left ventricular ejection fraction; 
MRI = magnetic resonance imaging; MUGA = multigated acquisition (scan); PK = pharmacokinetic; Q6W = every 6 wk; SpO2 = peripheral oxygen saturation. 
a All assessments required as part of EOT must occur within 7 days from the date the investigator decides to discontinue study treatment. If the EOT assessments have been 
performed within 30 d (±7 d) of subject’s last treatment, there is no need to repeat them. 
b 40 d (+7 d) after the last study treatment administration or before starting new anticancer treatment, whichever comes first. If EOT assessments occur > 40 d (+7 d) after last 
treatment, then the EOT assessments can also function as the 40-Day (+7 d) Follow-up assessments. 
c Long-term/Survival Follow-up visits will be performed every 3 mo (± 14 d) from the date of 40-Day Follow-up assessments until death, withdrawal of consent, loss to follow-up, 
or study closure, whichever occurs first. 
d First dose at Cycle 1 Day 1 should occur within 7 d after the date the subject is randomized. 
e EOI assessments are not required for subjects on lapatinib/capecitabine. 
f Done at Cycle 1, Cycle 2, and Cycle 3 and then every 2 cycles, (eg, Cycles 5, 7, 9, etc). Subject must complete the HEOR outcomes questionnaires before any other assessments 
or procedures are done that day. 
g Performed only 3 mo after the 40-Day (+7 d) Follow-up. 
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h Within 3 d BI. 
i Body surface area should be calculated for subjects treated with capecitabine. 
j At Cycle 1 Day 1 for trastuzumab deruxtecan subjects only, record ECG 5 hr (± 2 h) after start of drug administration. Perform ECG at regular intervals and ECG, ECHO, or 
MUGA if clinically indicated; if abnormal, follow institutional guidelines. 
k For female subjects of childbearing potential. During treatment, a positive urine pregnancy test result must be confirmed immediately using a serum test, with a confirmed 
negative result within 72 hours prior to drug administration. 
l Coagulation tests to be performed at EOT, at 40-Day (+7 d) Follow-up, and as clinically indicated. 
m PK samples should be obtained within 8 h BI on Day 1 of Cycles 1, 2, 3, 4, 6, and 8 for trastuzumab deruxtecan subjects only. ECGs should be performed before PK blood 
draws. 
n The sample should be collected as soon as possible after EOI and the actual time of sampling should be accurately recorded on Day 1 of Cycles 1, 2, 3, 4, 6 and 8, for 
trastuzumab deruxtecan subjects only. 
o 5 h (± 2 h) after the start of drug administration, for trastuzumab deruxtecan subjects only. 
p Obtained at Cycles 1, 2, and 4 then every 4 cycles; EOT; and at the 40-day follow-up only for subjects randomized to trastuzumab deruxtecan. After implementation of protocol 
version 8, ADA samples during treatment will not be taken except at EOT and 40-day follow-up. 
q Before administration at Cycle 3 Day 1for non-COVID-19 biomarkers. . After implementation of protocol version 8, these samples will not be taken except at EOT. 
r Collected at Cycle 1 and every 3 cycles until protocol version 8 is approved. After approval and implementation of this protocol version , collection of these samples will only 
occur at EOT. 
s Participation is optional for all subjects. 
t Trastuzumab deruxtecan should only be initiated by a physician or healthcare professional experienced in the administration of cytotoxic chemotherapy. For trastuzumab 
deruxtecan 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. Medicinal products to treat allergic/anaphylactic infusion reactions, as well as emergency equipment, should be 
available for immediate use. Treatment administration and monitoring of subjects randomized to the investigator’s choice treatment should occur per the locally approved label. 
u CT/MRI should be used unless another modality of disease assessment is necessary for the lesions. If a subject discontinues treatment for reasons other than disease progression 
or death, every attempt should be made to continue regular assessment of tumor response by investigator until disease progression. See Section 5.7.1. 
v This assessment frequency will be conducted every 6 weeks (±7 days) from randomization, until protocol version 8 is approved by the study site. After approval and 
implementation of this protocol version, tumor assessments will be conducted every 12 weeks (±7 days), independent of treatment cycle. 
w After the primary efficacy endpoint has been achieved, the assessment of the scans by BICR is no longer required. 
x CT or MRI of the brain is mandatory for all subjects included with baseline stable brain metastases. After protocol version 8 is approved and implemented, CT/MRI scans will 
occur every 12 weeks. Additional brain scans for all other subjects can be done if clinically indicated. 
y At the end of the study treatment, an optional newly obtained tumor tissue biopsy may be collected for those in the T-DXd group. 
Note: After study closure end date, subjects still benefiting from the study drug may be offered the opportunity to transition to a separate study to continue receiving trastuzumab 
deruxtecan, depending on country regulation. 
For suspected ILD/pneumonitis, treatment with study drug should be interrupted pending evaluation. 
Evaluations should include the following: 
 
High resolution CT 
 
Pulmonologist consultation (infectious disease consultation as clinically indicated) 
 
Bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
 
Pulmonary function tests (including FVC and CO diffusing capacity) and pulse oximetry (SpO2) 
 
Clinical laboratory tests (arterial blood gases if clinically indicated, blood culture, blood cell count, differential white blood cell count, and C-reactive protein) 
 
One blood sample collection for PK (central) analysis as soon as ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered, as needed (eg, COVID-19 test) 
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17.2. 
Cockcroft-Gault Equation 
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation based on actual weight (1 kilogram = 2.2 pounds): 
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140


  0.85 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140




  0.85 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16:31-41. 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140


0.0113
 
 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
  
years)]
(in 
 
age
 - 
[140




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17.3. 
Eastern Cooperative Oncology Group Performance Status 
Table 17.3: 
 Eastern Cooperative Oncology Group Performance Status Scale 
GRADE 
DESCRIPTION 
0 
Fully active, able to carry on all predisease performance without restriction 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities, up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-55 
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17.4. 
Response Evaluation Criteria in Solid Tumors, Version 1.1 
17.4.1. 
Measurability of Tumor at Baseline 
17.4.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
17.4.1.1.1. Measurable 
 Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter 
in the plane of measurement is to be recorded) with a minimum size of 10 mm by 
CT/MRI scan (CT scan slice thickness no greater than 5 mm) 
 Measurable malignant lymph nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm). At baseline 
(ie, Screening for this study) and in follow-up (ie, all on-study measurements), only 
the short axis will be followed. See also notes below on “Baseline documentation of 
target and non-target lesions” for information on lymph node measurement. 
17.4.1.1.2. Non-Measurable 
All other lesions, including small lesions (longest diameter < 10 mm or pathological lymph 
nodes with ≥10 to <15 mm short axis), as well as truly non-measurable lesions, are considered 
non-measurable. Lesions considered truly non-measurable include: leptomeningeal disease, 
ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of 
skin or lung, and abdominal masses/abdominal organomegaly identified by physical exam that is 
not measurable by reproducible imaging techniques. 
17.4.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
17.4.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions. However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
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17.4.1.1.3.2. Cystic Lesions 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 “Cystic lesions” thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
17.4.1.1.3.3. Lesions with Prior Local Treatment 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion. 
17.4.1.2. Specifications by Methods of Measurements 
17.4.1.2.1. Measurement of Lesions 
All measurements should be recorded in metric notation. All baseline evaluations should be 
performed as close as possible to the treatment start and NEVER more than 28 d before 
randomization 
17.4.1.2.2. Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (eg, for body scans). 
17.4.2. 
Tumor Response Evaluation 
17.4.2.1. Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
In this study, only subjects with measurable disease at baseline should be included. 
17.4.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs, with a maximum of 2 per organ) should be 
identified as target lesions and will be recorded and measured at baseline (this means in instances 
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where subjects have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions respectively 
will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline 
sum of lesion diameters. The short axis of the node is the diameter normally used by radiologists 
to judge if a node is involved by solid tumor. Nodal size is normally reported as 2 dimensions in 
the plane in which the image is obtained (for CT scan this is almost always the axial plane; for 
MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of these measures is 
the short axis. For example, an abdominal node which is reported as being 20 mm × 30 mm has a 
short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 20 mm 
should be recorded as the node measurement. Up to 2 nodal target lesions can be recorded. All 
other pathological nodes (those with short axis ≥10 mm but < 15 mm) should be considered 
non-target lesions. Nodes that have a short axis <10 mm are considered non-pathological and 
should not be recorded. 
A sum of the diameters (longest diameter for non-nodal lesions, short axis diameter for nodal 
lesions) for all target lesions will be calculated and reported as the baseline sum of diameters. If 
lymph nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum of diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.” In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case report form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
17.4.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
17.4.2.3.1. Evaluation of Target Lesions 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
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Progressive disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum of diameters must also 
demonstrate an absolute increase of at least 5 mm. (Note: the appearance of 1 or more new 
lesions is also considered progression). 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR (taking as reference the sum 
of diameters at baseline) nor sufficient increase to qualify for PD (taking as reference the 
smallest sum diameters while on study). 
17.4.2.3.2. Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study. This means that when lymph nodes are 
included as target lesions, the “sum” of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm. For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become “too small to measure”: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm). However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
“too small to measure.” When this occurs, it is important that a value be recorded on the eCRF. 
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned. (Note: It is less likely that this rule 
will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well). This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible, therefore providing this default value will prevent 
false responses or progressions based upon measurement error. To reiterate, however, if the 
radiologist is able to provide an actual measure, that should be recorded, even if it is below 
5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment,” the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the “coalesced lesion.” 
17.4.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they 
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need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10 mm short axis). 
Progressive disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions (Note: the appearance of 1 or more new lesions is also considered progression). 
Non-CR/Non-PD: Persistence of 1 or more non-target lesion(s). 
17.4.2.3.4. Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
When the subject also has measurable disease: In this setting, to achieve “unequivocal 
progression” on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
“increase” in the size of 1 or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status. The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be rare. 
When the subject has only non-measurable disease: The same general concepts apply here as 
noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly 
non-measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease (ie, an increase in tumor burden representing an additional 
73% increase in ‘volume’ [which is equivalent to a 20% increase diameter in a measurable 
lesion]). If ‘unequivocal progression’ is seen, the subject should be considered to have had 
overall PD at that time point. While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so; therefore, 
the increase must be substantial. 
17.4.2.3.5.  
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality or findings thought to represent something other than tumor (for example, some “new” 
bone lesions may be simply healing or flare of preexisting lesions). This is particularly important 
when the subject’s baseline lesions show PR or CR. For example, necrosis of a liver lesion may 
be reported on a CT scan report as a “new” cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. An example of this is 
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the subject who has visceral disease at baseline and while on study has a CT or MRI brain 
ordered which reveals metastases. The subject’s brain metastases are considered to be evidence 
of PD even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan. 
17.4.2.4. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the EOT. 
The subject’s best overall response assignment will depend on the findings of both target and 
non-target disease and will also take into consideration the appearance of new lesions. 
Confirmation of CR/PR is required for this study. 
17.4.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs. Table 17.4 
provides a summary of the overall response status calculation at each time point for subjects who 
have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, see Table 17.4. 
Table 17.4: 
Overall Response: Subjects with Target (+/–Non-target) Disease 
Target Lesions 
Non-target Lesions 
New Lesions 
Time Point 
Responsea 
CR 
CR 
No  
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PRb 
PR 
NE 
No 
PRb 
PR 
CR 
No 
PR 
PR 
Non-CR/Non-PD  
No  
PR 
SD 
NE 
No 
SDb 
SD 
CR 
No 
SD 
SD 
Non-CR/Non-PD  
No  
SD 
PD  
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
NE 
Non-PD 
No 
NE 
CR 
NAd 
No 
CR 
PR 
NAd 
No 
PR 
SD  
NAd  
No  
SD  
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Target Lesions 
Non-target Lesions 
New Lesions 
Time Point 
Responsea 
NAc  
Non-CR/Non-PD  
No  
Non-CR/Non-PD  
NAc  
CR  
No  
CR  
NAc  
NE 
No  
NE  
NAc  
NAd  
No  
NE  
CR = complete response; NA = not applicable; NE = not evaluable; PD = progressive disease; PR = partial response; 
SD = stable disease 
a Identification of new lesions at a post-Baseline time point will result in a time point response (TPR) of PD. If an 
identified new lesion subsequently becomes NE, the TPR will be recorded as PD unless the new lesion has proven 
to have resolved. Note: TPRs assessed after a progression event will not contribute to the determination of the Best 
Response. 
b If a non-target lesion is classified as NE, a designation of PR or SD may be assigned based on information from 
the target lesions. 
c No target lesions identified at Baseline. 
d No non-target lesions identified at Baseline. 
17.4.2.4.2. Missing Assessments and Non-evaluable Designation 
When no imaging/measurement is performed at all at a particular time point, the subject is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. For 
example, if a subject had a baseline sum of 50 mm with 3 measured lesions and at follow-up 
only 2 lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved PD 
status, regardless of the contribution of the missing lesion. 
17.4.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
The best overall response is the best response recorded from the start of the study treatment until 
the EOT. When SD is believed to be best response, it must also meet the protocol-specified 
minimum time of 5 wk from Cycle 1 Day 1. If the minimum time is not met when SD is 
otherwise the best time point response, the subject’s best response depends on the subsequent 
assessments. For example, a subject who has SD at first assessment, PD at second and does not 
meet minimum duration for SD, will have a best response of PD. The same subject lost to 
follow-up after the first SD assessment would be considered non-evaluable. 
17.4.2.4.4. Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes. As noted earlier, this means that subjects with CR may not 
have a total sum of diameters of “zero” on the eCRF. 
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For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
17.4.2.5. Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 wk (±7 d) while the subject remains 
on study until progression of disease, withdrawal of consent, death, or loss to follow-up. This 
assessment frequency will be conducted every 6 weeks (±7 days) from randomization, until 
protocol version 8 is approved by the study site. After approval and implementation of this 
protocol version, tumor assessments will be conducted every 12 weeks (±7 days), independent of 
treatment cycle. Scan dates should not be adjusted or rescheduled due to dose interruption of any 
type. 
Baseline tumor assessments must be performed within 28 d of randomization. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of chest, abdomen, and pelvis at 
screening period. A CT or MRI of the brain is mandatory for all subjects included with baseline 
stable brain metastases. Any additional suspected sites of disease should also be imaged. Every 
effort should be made to use the same assessment modality for all assessments for each subject. 
Follow-up evaluations should include all sites of disease identified at Screening and any other 
locations if PD is suspected (eg, MRI of the brain if brain metastases are suspected) should also 
be imaged. All evaluations should meet the standard of care for imaging of lesions in the 
respective organ(s) and should conform to the image acquisition guidelines according to 
institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 
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17.5. 
New York Heart Association Functional Classification 
Table 17.5: 
New York Heart Association Functional Classification 
Functional Capacity  
Objective Assessment  
Class I. Patients with cardiac disease but without resulting limitation of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
A. No objective evidence 
of cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical activity 
is undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
Source: American Heart Association, Inc. Classification of Functional Capacity and Objective Assessment. 
Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of-
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
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17.6. 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire C30 and BR45 
17.6.1. 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (version 3.0) 
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17.7. 
EuroQoL Five Dimensions Five Levels 
CCI
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17.8. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) 
Dose modification criteria for suspected or confirmed Severe Acute Respiratory Syndrome 
Coronavirus 2 infection 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Dose 
modifications will be based on the worst CTCAE grade. All interruptions or modifications must 
be recorded on the AE and drug administration eCRFs. Please use CTCAE v5.0 general 
grading criteria to evaluate COVID-19. 
Dose modification criteria 
If symptomatic or asymptomatic COVID-19 is suspected, interrupt trastuzumab deruxtecan and 
rule out COVID-19 per local guidance. 
 If COVID-19 is ruled out, follow dose modification and management guidance as 
outlined in Table 5.2. 
 If COVID-19 is confirmed or diagnosis is suspected after evaluation, follow dose 
modification as outlined below and manage COVID-19 per local guidance until 
recovery from COVID-19. COVID-19 recovery is defined as no respiratory 
signs/symptoms and completely or nearly resolved chest CT findings,* which are 
equivalent to CT Severity Score of 1 (CT Severity Score of 1 = Subtle Ground Glass 
Opacities) and very few findings. Then follow below dose modifications: 
 If Grade 1, after recovery, resume trastuzumab deruxtecan at the same dose. 
 If Grade 2, after recovery, 
o Maintain same dose if chest CT findings are completely resolved; 
o Reduce by 1 dose level if chest CT findings are nearly resolved (equivalent to 
CT Severity Score of 1). 
 If Grade 3, after recovery, 
o Reduce by 1 dose level if chest CT findings are completely resolved; 
o Discontinue study drug if chest CT findings are not completely resolved. 
 If Grade 4, discontinue study treatment. 
Closely monitor signs/symptoms after restarting trastuzumab deruxtecan, with a weekly phone 
call or site visit for 6 weeks. 
In addition to the recommendations outlined above, Investigators may consider dose 
modifications of the study drug according to the subject’s condition and after discussion with the 
study Medical Monitor or designee. If an event is suspected to be drug-related ILD, manage per 
protocol ILD management guideline. *Resolved or nearly resolved chest CT findings assume 
that COVID-19-associated findings were detected at the time of COVID-19 diagnosis or during 
the course of infection. 
Severe Acute Respiratory Syndrome Coronavirus 2 Infection Assessment(s) 
All confirmed or suspected COVID-19 events must be recorded in the eCRF. If a subject 
presents to the clinic with symptoms suggestive of COVID-19, infection should be confirmed via 
nucleic acid amplification test (such as real-time polymerase chain reaction) or rapid antigen 
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testing. Severe acute respiratory syndrome coronavirus 2 antigen testing can be used to confirm 
infection but not rule it out. 
Serum samples will be collected and may be used for COVID-19 testing from each subject who 
provides consent. Samples will be collected prior to the study drug infusion and will be shipped 
to a central laboratory and stored there until the testing is required. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
Serum sample collection, preparation, handling, storage, and shipping instructions are provided 
in the Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of COVID-19 
If deemed appropriate, analyses will be performed to explore the impact of COVID-19 on the 
safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of COVID-19 on study conduct, adjustments to the statistical analysis 
and interpretation will be made, if required. These will be described in the SAP. 
17.9. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product. Individuals who identify a potential 
product complaint situation should immediately report the event. Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative form the Sponsor. 
For product complaints, refer to the Pharmacy Manual for instructions and details. 
 
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Signature Page for VV-CLIN-104407
DS8201-A-U301: A Phase 3, Multicenter, Randomized, Open-Label, Active-Controlled
Signature Page for VV-CLIN-104407
Approval with eSign
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27-Apr-2023 23:13:17 GMT+0000
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