Clinical trial NCT04644237
Conditions: Non-Small Cell Lung Cancer
Keywords: Non-small Cell Lung Cancer Trastuzumab Deruxtecan
Sponsor: Daiichi Sankyo
Start date: 2021-03-19; Completion date: 2024-08-23
Enrollment: 152 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study was designed to evaluate the safety and efficacy of trastuzumab deruxtecan in HER2-mutated metastatic non-small cell lung cancer (NSCLC) participants who had disease recurrence or progression during/after at least one regimen of prior anticancer therapy (second line or later) that must have contained a platinum-based chemotherapy drug.

Detailed description:
This randomized, two-arm, phase 2, multicenter study will evaluate the safety and efficacy of 5.4 mg/kg and 6.4 mg/kg trastuzumab deruxtecan administered every 3 weeks (Q3W) in participants with HER2-mutated metastatic NSCLC. Each participant is expected to receive approximately 14 months of trastuzumab deruxtecan treatment. The primary endpoint of the study will be confirmed objective response rate (blinded independent central review). Secondary endpoints will include, but not limited to, disease control rate, duration of response, progression-free survival, objective response rate (investigator), overall survival, and safety.

Arms: arm 1: Participants will be randomized to receive trastuzumab deruxtecan 6.4 mg/kg administered by intravenous infusion every 3 weeks (Q3W). arm 2: Participants will be randomized to receive trastuzumab deruxtecan 5.4 mg/kg administered by intravenous infusion every 3 weeks (Q3W).
Interventions: intervention 1: Trastuzumab deruxtecan
Intervention descriptions: intervention 1: Trastuzumab deruxtecan 100 mg will be provided as a sterile lyophilized powder and reconstituted with 5 mL water for injection (final concentration 20 mg/mL \[ie, 100 mg/5 mL\]). The study drug will be administered as an intravenous (IV) infusion over 30 to 90 min Q3W ± 2 days. The initial dose of study drug will be infused for 90 ± 10 min.

Protocol documents:
Prot_SAP_000.pdf: 
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Page 1 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2, MULTICENTER, RANDOMIZED STUDY OF 
TRASTUZUMAB DERUXTECAN IN SUBJECTS WITH 
HER2-MUTATED METASTATIC NON-SMALL CELL 
LUNG CANCER (NSCLC) 
[DESTINY-LUNG02] 
 
(Trastuzumab deruxtecan for subjects with HER2-mutated 
metastatic NSCLC) 
 
PROTOCOL NUMBER: DS8201-A-U206 
IND NUMBER 137009 
 
VERSION 4.0, 09 November 2022 
 
DAIICHI SANKYO, INC. 
211 MT. AIRY ROAD 
BASKING RIDGE, NJ 07920-2311 
UNITED STATES 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc (DSI).  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 
DSI. 


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INVESTIGATOR AGREEMENT 
A Phase 2, multicenter, randomized study of trastuzumab deruxtecan in subjects with 
HER2-mutated metastatic Non-Small Cell Lung Cancer (NSCLC) 
[DESTINY-Lung02] 
This clinical study protocol has been reviewed and approved by the representative listed 
below. 
 
Print Name 
Signature 
Medical Monitor 
 
Title 
Date (DD MMM YYYY) 
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 International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) (ICH 
E6[R2]), which has its foundations in the Declaration of Helsinki, 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) 
PPD


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DOCUMENT HISTORY 
Version Number 
Version Date 
4.0 
09 Nov 2022 
3.0 
01 Dec 2021 
2.0 
22 Oct 2020 
1.0 
02 Jun 2020 
 


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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 4.0 (dated 09 Nov 2022) vs. 
protocol Version 3.0 (dated 01 Dec 2021) for actual changes in text.  The summary of changes 
below is a top-line summary of major changes in the current DS8201-A-U206 clinical study 
protocol (Version 4.0) by section. 
Amendment Rationale: 
Based on available data from the DS8201-A-U204 (DESTINY-Lung01) study, trastuzumab 
deruxtecan has shown the potential for responses in subjects to occur late, (beyond 9 months 
from enrollment).  The final analysis in this study is therefore being adjusted to allow for 
adequate follow-up of subjects treated with trastuzumab deruxtecan that were responders.  Thus, 
the primary scope of this protocol amendment is to update the timing of the final analysis until 
after all responders have been followed for at least 6 months from the date of initial response (or 
until disease progression, whichever comes first). 
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 this Summary of Changes document. 
Minor edits, such as update to language that does not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of 
abbreviations, moving verbiage within a section or table, change in style, or change in case, are 
not noted in the table below. 
Section  
Description of Change 
Brief Rationale 
Synopsis, Study 
Objectives 
Table 3.1, Description 
of Objectives, Outcome 
Measures and Endpoints 
Removed “approximately 31 months” where this 
refers to timing of final analysis.  Study duration 
(also “approximately 31 months”) remains 
unchanged 
To align with the timing for the 
final analysis. 
Synopsis, Secondary 
Objectives 
Table 3.1, Description 
of Objectives, Outcome 
Measures and Endpoints 
Added “definitive” to deterioration in EORTC 
QLQ-C30 
To align with statistical analysis 
plan. 
Table 1.1 Schedule of 
Events 
Ophthalmologic assessments removed at EOT 
To align with the latest safety 
information. 
Table 1.1 Schedule of 
Events 
Section 8.4.1.2 Adverse 
Events of Special 
Interest (AESIs) 
Section 8.7.4 
Immunogenicity 
Deleted ADA at Long Term Follow-up Visit 
Deleted troponin at EOT 
Currently, based on the totality of 
data collected from T-DXd 
clinical studies, immunogenicity 
profile of T-DXd has been well 
established. No further collection 
of blood samples for ADA 
analyses to understand 
immunogenicity is needed. 


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Section  
Description of Change 
Brief Rationale 
Table 1.1 Schedule of 
Events 
Section 7.1 
Discontinuation of 
Study Drug 
Added if EOT is > 40 days after last treatment, 
then the EOT assessments can also account for 
the 40-Day Follow-up visit 
Clarification and consistency with 
other studies in this program. 
Section 1.3 Schedule of 
Events 
Table 6.6 Management 
Guidelines for Other 
Non-Hematologic 
Toxicity 
Section 8.4.1.2 Adverse 
Events of Special 
Interest (AESIs), 
Management Guidance 
Modified management guidelines for suspected 
ILD/pneumonitis 
To align with the latest safety 
information by adding details 
regarding pulmonary function 
tests (including FVC and CO 
diffusing capacity), clinical 
laboratory tests including blood 
cell count, differential white 
blood cell count, C-reactive 
protein and reformatting the 
presentation of evaluations.  In 
addition, the duration of drug 
interruption for Grade 1 
ILD/pneumonitis has been 
updated from up to 49 days to up 
to 18 weeks (126 days). 
Section 2.1.5 Clinical 
Experience 
Removed whether study was completed or 
ongoing in each header 
Clarification. 
Section 6.5 Guidelines 
for Dose Modification 
Modified dose delay text  
To align with the latest safety 
information. 
Section 6.5 Guidelines 
for Dose Modification 
Changed dose delay requiring withdrawal from 
49 to 126 days 
To align with the latest safety 
information, which could be up to 
18 weeks. 
Table 6.6 Management 
Guidelines for Other 
Non-Hematologic 
Toxicity 
For Grade 1 ILD/pneumonitis, changed timing 
for resolution from within 49 days to within 
18 weeks (126 days) from the last infusion 
To align with the latest safety 
information, which could be up to 
18 weeks. 
Section 6.6 Prior and 
Concomitant 
Medications, subsection 
Prohibited 
Therapies/Products 
Added:  
7. 
Receipt of live, attenuated vaccine 
(mRNA and replication deficient adenoviral 
vaccines are not considered attenuated live 
vaccines) within 30 days prior to the first 
exposure to study intervention. Note: 
Participants, if enrolled, should not receive live 
vaccine during the study and up to 30 days after 
the last dose of study intervention. 
To align with the latest safety 
information to reflect the safety 
concerns for live, attenuated 
vaccine. 
Section 6.6 Prior and 
Concomitant 
Medications, subsection 
Permitted products 
Deleted previous text and changed #4 as follows: 
Trastuzumab deruxtecan is emetogenic, which 
includes delayed nausea and/or vomiting. Prior 
to each dose of trastuzumab deruxtecan, 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 
To align with the latest safety 
information to reflect the need of 
prophylaxis of nausea and 
vomiting. 


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Section  
Description of Change 
Brief Rationale 
prevention of chemotherapy-induced nausea and 
vomiting.   
Section 7.1 
Discontinuation of 
Study Drug 
Added: 
If there is evidence the subject is receiving 
benefit from treatment even though the subject 
has met criterion for discontinuation, the subject 
may remain on study treatment after discussion 
with approval from the Sponsor Medical Monitor 
or designee. 
Clarification and consistency with 
other studies in this program. 
Section 9.1 General 
Statistical 
Considerations 
Modified when the final analysis of the study 
will occur from when all subjects have 
discontinued to after all responders have been 
followed for at least 6 months from the date of 
initial response (or until disease progression, 
whichever comes first) 
Trastuzumab deruxtecan has 
shown the potential for responses 
in subjects to occur late, (beyond 
9 months from enrollment). The 
final analysis in this study is 
therefore being adjusted to allow 
for adequate follow-up of subjects 
treated with trastuzumab 
deruxtecan.  
Section 10.6, Appendix 
6 Instructions Related to 
Severe Acute 
Respiratory Syndrome 
Coronavirus 2 Infection 
Modified text as follows:  
Due to the potential impact of SARS-CoV-2 
infection, ie COVID-19, on subject safety, the 
Sponsor recommends the following SARS-Cov-
2 infection assessment and dose modification 
and management plan for subjects with 
confirmed or suspected SARS-CoV-2 infection 
while being treated with trastuzumab deruxtecan 
should be followed.   
Changed SARS-CoV-2 infection to COVID-19, 
where appropriate, throughout this section and in 
Table 10.7 
Added if COVID-19 diagnosed as well as 
confirmed to follow dose modification in 
Table 10.7 
Deleted the bullet regarding PCR testing 
Modified Table 10. 7  
To align with the latest safety 
information to reflect the updated 
instructions related to COVID-19. 
Section 12 List of 
Abbreviations 
The list was updated. 
As required 


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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
1. 
PROTOCOL SUMMARY ..............................................................................................14 
1.1. 
Protocol Synopsis ............................................................................................................14 
1.2. 
Study Schema ..................................................................................................................27 
1.3. 
Schedule of Events ..........................................................................................................28 
2. 
INTRODUCTION ...........................................................................................................44 
2.1. 
Background ......................................................................................................................44 
2.1.1. 
Description of Trastuzumab Deruxtecan .........................................................................44 
2.1.2. 
Intended Use Under Investigation ...................................................................................44 
2.1.3. 
Nonclinical Studies of Trastuzumab Deruxtecan ............................................................45 
2.1.4. 
Nonclinical Studies ..........................................................................................................45 
2.1.4.1. Pharmacology ..................................................................................................................45 
2.1.4.2. Safety Pharmacology .......................................................................................................45 
2.1.4.3. Pharmacokinetics and Drug Metabolism .........................................................................45 
2.1.4.4. Toxicology .......................................................................................................................46 
2.1.5. 
Clinical Experience .........................................................................................................47 
2.1.5.1. Efficacy: DS8201-A-J101 ...............................................................................................47 
2.1.5.2. Efficacy: DS8201-A-U204 ..............................................................................................49 
2.1.5.3. Safety: DS8201-A-J101 ...................................................................................................50 
2.1.5.4. Safety: DS8201-A-U204 .................................................................................................53 
2.1.6. 
Summary of Clinical Pharmacokinetics ..........................................................................55 
2.2. 
Study Rationale ...............................................................................................................55 
2.3. 
Benefit and Risk Assessment ..........................................................................................56 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ....................................58 
3.1. 
Rationale for Selection of Primary and Secondary Endpoints ........................................61 
4. 
STUDY DESIGN ............................................................................................................62 
4.1. 
Overall Design .................................................................................................................62 
4.1.1. 
Design Overview .............................................................................................................62 
4.1.2. 
End of Study ....................................................................................................................63 


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4.1.3. 
Dose Regimen .................................................................................................................63 
4.1.4. 
Duration ...........................................................................................................................63 
4.2. 
Rationale for Study Design .............................................................................................64 
4.3. 
Justification for Dose .......................................................................................................64 
5. 
STUDY POPULATION ..................................................................................................66 
5.1. 
Inclusion Criteria .............................................................................................................66 
5.2. 
Exclusion Criteria ............................................................................................................69 
5.3. 
Screening Failures, Re-screening, and Subject Replacement .........................................71 
6. 
STUDY TREATMENT(S) ..............................................................................................72 
6.1. 
Study Drug(s) Description ...............................................................................................72 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) ..........................72 
6.3. 
Measure to Minimize Bias: Randomization and Blinding ..............................................74 
6.4. 
Treatment Compliance ....................................................................................................74 
6.5. 
Guidelines for Dose Modification ...................................................................................74 
6.5.1. 
Dose Modifications .........................................................................................................76 
6.5.1.1. Cardiac Toxicities ............................................................................................................76 
6.5.1.2. Hematologic Toxicity ......................................................................................................77 
6.5.1.3. Non-Hematologic/non-cardiac Toxicity ..........................................................................77 
6.5.1.4. Other Non-Hematologic/Cardiac Toxicity ......................................................................80 
6.6. 
Prior and Concomitant Medications ................................................................................83 
7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION FROM 
THE STUDY ...................................................................................................................85 
7.1. 
Discontinuation of Study Drug ........................................................................................85 
7.2. 
Subject Withdrawal/Discontinuation from the Study ......................................................86 
7.3. 
Lost to Follow-up ............................................................................................................87 
8. 
STUDY PROCEDURES .................................................................................................89 
8.1. 
Eligibility Assessment .....................................................................................................89 
8.2. 
Randomization in a 2:1 Ratio ..........................................................................................90 
8.3. 
Efficacy Assessments ......................................................................................................90 
8.3.1. 
Primary Efficacy Endpoint ..............................................................................................90 
8.3.2. 
Secondary Efficacy Endpoints ........................................................................................90 
8.3.3. 
Exploratory Efficacy Endpoints (ORR and QoL) ...........................................................91 
8.4. 
Safety Assessments .........................................................................................................93 


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8.4.1. 
Adverse Event .................................................................................................................93 
8.4.1.1. Serious Adverse Events Reporting ..................................................................................94 
8.4.1.2. Adverse Events of Special Interest (AESIs) ....................................................................96 
8.4.2. 
Pregnancy ........................................................................................................................98 
8.4.3. 
Clinical Laboratory Evaluations ......................................................................................98 
8.4.4. 
Other Safety .....................................................................................................................99 
8.5. 
Health Economics and Outcomes Research ..................................................................100 
8.6. 
Pharmacokinetic (PK) Assessment ................................................................................101 
8.7. 
Pharmacodynamic Assessment(s) .................................................................................103 
8.7.1. 
Pharmacodynamic Biomarker Analysis ........................................................................103 
8.7.2. 
Pharmacogenomic (Inherited Genetic) Analysis (Optional) .........................................103 
8.7.3. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis .........................................................................................................................103 
8.7.4. 
Immunogenicity .............................................................................................................104 
9. 
STATISTICAL CONSIDERATIONS ..........................................................................105 
9.1. 
General Statistical Considerations .................................................................................105 
9.2. 
Statistical Hypothesis ....................................................................................................105 
9.3. 
Sample Size Determination ...........................................................................................105 
9.4. 
Population for Analysis Sets .........................................................................................107 
9.5. 
Statistical Analysis ........................................................................................................107 
9.5.1. 
Efficacy Analyses ..........................................................................................................107 
9.5.1.1. Primary Efficacy Analyses ............................................................................................107 
9.5.1.2. Secondary Efficacy Analyses ........................................................................................108 
9.5.1.3. Exploratory Analyses ....................................................................................................108 
9.5.1.4. Multiplicity Adjustment ................................................................................................108 
9.5.2. 
Safety Analyses .............................................................................................................108 
9.5.3. 
HEOR Analysis .............................................................................................................110 
9.5.4. 
Other Analyses ..............................................................................................................110 
9.6. 
Interim Analyses ............................................................................................................111 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ....................................................................................................113 
10.1. 
Appendix 1 Regulatory and Ethical Considerations .....................................................113 
10.1.1. Regulatory Compliance .................................................................................................113 


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10.1.2. Informed Consent ..........................................................................................................114 
10.1.3. Subject Confidentiality ..................................................................................................115 
10.1.4. Data Integrity and Quality Assurance ...........................................................................115 
10.1.5. Study Documentation and Storage ................................................................................117 
10.1.6. Finances .........................................................................................................................118 
10.1.7. Publication, Public Disclosure Policy, and Data Sharing ..............................................118 
10.1.8. Protocol Deviations .......................................................................................................119 
10.1.9. Study and Site Closure ..................................................................................................119 
10.1.10. Product Complaints .......................................................................................................119 
10.2. 
Appendix 2: Local Laboratory ......................................................................................120 
10.3. 
Appendix 3: Reference Standards .................................................................................122 
10.3.1. Cockcroft-Gault Equation .............................................................................................122 
10.3.2. Corrected Calcium Formula for Eligibility ...................................................................122 
10.3.3. New York Heart Association (NYHA) .........................................................................122 
10.3.4. Eastern Cooperative Oncology Group Performance Status ..........................................123 
10.3.5. Highly Effective Contraception .....................................................................................124 
10.3.6. Calculation of Body Surface Area .................................................................................124 
10.4. 
Appendix 4: Response Criteria ......................................................................................124 
10.5. 
Appendix 5: General Information - Adverse Events .....................................................132 
10.5.1. Definition of Adverse Event ..........................................................................................132 
10.5.2. Grade Assessment .........................................................................................................134 
10.5.3. Causality Assessment ....................................................................................................135 
10.5.4. Action Taken Regarding Study Drug(s) ........................................................................135 
10.5.5. Other Action Taken for Event .......................................................................................135 
10.5.6. Adverse Event Outcome ................................................................................................136 
10.6. 
Appendix 6: Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) Infection .......................................................................136 
11. 
REFERENCES ..............................................................................................................139 
12. 
LIST OF ABBREVIATIONS .......................................................................................141 
 


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LIST OF TABLES 
Table 1.1: Schedule of Events .....................................................................................................28 
Table 2.1: Efficacy Results in NSCLC Cancers in Study DS8201-A-J101 
(Enrolled Analysis Set) ...............................................................................................48 
Table 2.2: Efficacy Results for DS8201-A-U204 Cohort 2 by ICR ............................................50 
Table 2.3: Summary of Treatment-Emergent Adverse Events (≥20% of Subjects) in 
Study DS8201-A-J101 ................................................................................................52 
Table 2.4: Summary of Treatment-Emergent Adverse Events (TEAEs) (>10 % [Based 
on Cohort 2 by Descending Order]) from DS8201-A-U204, Cohort 2 and 
Overall ........................................................................................................................53 
Table 2.5: Summary of Grade ≥ 3 TEAEs (>5% - [Based on Cohort 2 by Descending 
Order]) from DS8201-A-U204 Cohort 2 and Overall ................................................54 
Table 2.6: Mean Pharmacokinetic Parameters of Trastuzumab Deruxtecan, Total 
Anti-HER2 Antibody and MAAA-1181a Following Cycle 1 (± Standard 
Deviation) in subjects with NSCLC at 6.4 mg/kg dose ..............................................55 
Table 3.1: Description of Objectives, Outcome Measures, and Endpoints .................................58 
Table 6.1: Study Drug Dosing Information .................................................................................72 
Table 6.2: Sample Dose Reduction Levels of Trastuzumab Deruxtecan ....................................75 
Table 6.3: Management Guidelines for Cardiac Toxicities .........................................................76 
Table 6.4: Management Guidelines for Hematologic Toxicities .................................................77 
Table 6.5: Management Guidelines for Hepatic Toxicities .........................................................78 
Table 6.6: Management Guidelines for Other Non-Hematologic Toxicity .................................80 
Table 8.1: Schedule of PK Sample Collection...........................................................................102 
Table 8.2: Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment ................................................................................102 
Table 9.1: The Probability That the Resulting Clopper-Pearson 95% Confidence 
Interval (CI) Will Exclude the Benchmark of 26.4% ORR ......................................106 
Table 9.2: Confidence Interval with 50 and 100 Subjects Under Scenarios of Observed 
ORR ..........................................................................................................................106 
Table 10.1: Clinical Laboratory Tests .........................................................................................120 
Table 10.2: List of HER2 (ERBB2) Mutations ...........................................................................121 
Table 10.3: New York Heart Association Classifications ...........................................................123 
Table 10.4: Eastern Cooperative Oncology Group Performance Status ......................................123 
Table 10.5: Time Point Response: Subjects With Target (±Non-Target) Disease ......................130 
Table 10.6: Best Overall Response When Confirmation of CR and PR Required ......................131 


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Table 10.7: COVID-19 Dose Modification Criteria ....................................................................137 
 


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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................27 
 






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Time frame:  
At least 9 months after 
the last subject is 
randomized  
 
Note: PFS and OS will 
be updated at the final 
database lock. 
 
• 
PFS, defined as the 
time from date of 
randomization until 
first objective 
radiographic tumor 
progression or death 
from any cause, based 
on BICR and 
investigator 
assessment 
• 
OS, defined as the 
time from date of 
randomization until 
death from any cause. 
To evaluate safety 
of trastuzumab 
deruxtecan at 5.4 
and 6.4 mg/kg 
doses. 
Title: Safety 
Description:  
The number and 
percentage of 
treatment-emergent 
adverse events 
(TEAEs) collected 
between first dose and 
database lock points 
 
Time frame: At least 9 
months after the last 
subject is randomized  
 
Note: Safety will be 
updated at the final 
database lock  
 
• 
Adverse Events 
(AEs) including 
TEAEs, serious 
adverse events 
(SAEs) and adverse 
events of special 
interest (AESIs) that 
will be graded 
according to the 
Common 
Terminology Criteria 
for Adverse Events 
(CTCAE) Version 5.0 
 
• 
Physical examination 
findings that may 
include Eastern 
Cooperative 
Oncology Group 
(ECOG) Performance 
Status (PS), vital sign 
measurements, 
ophthalmologic 
findings, standard 
clinical laboratory 
parameters, 
electrocardiogram 
(ECG) parameters, 
echocardiogram 
(ECHO)/multi-gated 
acquisition (MUGA) 
findings, and 
radiologic findings. 
Safety 
To evaluate 
pharmacokinetics 
(PK) and 
immunogenicity of 
trastuzumab 
deruxtecan at 5.4 
Title: Evaluation of PK 
and immunogenicity 
 
Description:  
• 
The PK endpoints 
include serum 
concentrations of 
trastuzumab 
deruxtecan, total anti-
Clinical Pharmacology 


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and 6.4 mg/kg 
doses. 
Evaluation of PK of 
trastuzumab 
deruxtecan, total anti-
HER2 antibody, and 
MAAA 1181a 
 
Determine the 
incidence of anti-drug 
antibodies (ADAs). 
 
Time frame: At least 9 
months after the last 
subject is randomized  
Note: PK and 
immunogenicity will be 
updated at the final 
database lock  
HER2 antibody, and 
MAAA 1181a.  
 
• 
The immunogenicity 
endpoint includes 
incidence of ADA. 
To assess 
symptoms, 
functioning and 
Health-related 
Quality of life 
(HRQoL) in 
subjects treated 
with trastuzumab 
deruxtecan at 5.4 
and 6.4 mg/kg 
doses. 
Title: HRQoL 
 
Description:  
Assessment of 
symptom functioning 
and HRQoL in subjects 
treated with 
trastuzumab 
deruxtecan. 
 
Time frame: 9 months 
after the last subject is 
randomized  
Note: HRQoL will be 
updated at the final 
database lock  
 
 
 
 
 
 
 
 
 
 
 
 
The (patient-reported 
outcomes) PROs include: 
• 
Change from baseline 
in European 
Organization for 
Research and 
Treatment of Cancer 
(EORTC) core 
quality of life 
questionnaire (QLQ-
C30) and EORTC 
quality of life 
questionnaire for lung 
cancer trials (QLQ-
LC13) scale scores 
• 
Time to definitive 
deterioration in 
EORTC QLQ-C30 
scores 
Health economics and 
outcomes research 
(HEOR) 








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Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count  
 100 000/mm3 (Platelet transfusion is not allowed within 1 
week prior to screening assessment) 
Hemoglobin  
≥ 9.0 g/dL (Red blood cell transfusion is not allowed within 1 
week prior to screening assessment) 
Absolute neutrophil count (ANC) 
 1500/mm3  
(Granulocyte-colony stimulating factor [G-CSF]) 
administration is not allowed within 1 week prior to screening 
assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥ 30 mL/min as calculated using the 
Cockcroft-Gault equation*  
Adequate hepatic function 
Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) 
 ≤ 5  upper limit of normal (ULN) 
Total bilirubin 
≤ 1.5 x ULN if no liver metastases or < 3 x ULN in the 
presence of documented Gilbert’s Syndrome (unconjugated 
hyperbilirubinemia) or liver metastases at baseline. 
Serum Albumin 
≥ 2.5 g/dL  
Adequate blood clotting function 
International normalized ratio 
(INR) / activated partial 
thromboplastin time (aPTT) 
≤ 1.5 × ULN 
 
*Cockcroft-Gault equation:  
CLcr (mL/min) =  
[140 - age (years)] × weight (kg)
[72 × serum creatinine (mg/dL)]  {× 0.85 for females} 
 
10. Has adequate treatment washout period before randomization defined as:  
Treatment 
Washout Period 
Major surgery 
≥ 4 weeks 
Radiation therapy including palliative stereotactic 
radiation to chest 
≥ 4 weeks  
Palliative stereotactic radiation therapy to other 
anatomic areas 
≥ 2 weeks 
Anticancer chemotherapy (Immunotherapy [non-
antibody-based therapy]), retinoid therapy 
≥ 3 weeks  
Targeted agents and small molecules (eg, 
5-fluorouracil-based agents, paclitaxel) 
≥ 2 weeks or 5 half-lives, whichever is longer 
Nitrosureas or mitomycin C 
≥ 6 weeks 


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Tyrosine kinase inhibitors (TKIs) approved for the 
treatment of non-small cell lung cancer (NSCLC)- 
baseline computerized tomography (CT) scan must 
be completed after discontinuation of TKI 
≥ 1 week 
Antibody-based anticancer therapy 
≥ 4 weeks 
Chloroquine /Hydroxychloroquine 
> 14 days 
Cell-free and concentrated ascites reinfusion 
therapy peritoneal shunt or drainage of pleural 
effusion, ascites, or pericardial effusion. 
≥ 2 weeks prior to screening assessment 
11. Male and 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 months for females and 4 months for males, after the last dose of study drug. 
Methods considered as highly effective methods of contraception are described in Section 5.1.  
12. Male subjects must not freeze or donate sperm starting at randomization and throughout the 
study period, and at least 4 months after the final study drug administration. Preservation of 
sperm should be considered prior to randomization in this study. 
13. Female subjects must not donate, or retrieve for their own use, ova from the time of 
randomization and throughout the study treatment period, and for at least 7 months after the 
final study drug administration.  Female subjects must refrain from breastfeeding throughout 
this time.  Preservation of ova may be considered prior to randomization in this study. 
14. Life expectancy of 3 months or more. 
Exclusion Criteria: 
Subjects meeting any exclusion criteria for this study will be excluded.  Below is a list limited to the key 
exclusion criteria: 
1. Has a known driver mutation in the epidermal growth factor receptor (EGFR), BRAF, or 
MET exon 14 gene or a known anaplastic lymphoma kinase (ALK), ROS1, RET, or NTRK 
fusion. 
2. Medical history of myocardial infarction within 6 months before randomization, symptomatic 
congestive heart failure (CHF) (New York Heart Association Class II to IV.  Subjects with 
troponin levels above ULN at screening (as defined by the manufacturer), and without any MI 
related symptoms should have a cardiologic consultation before randomization to rule out MI. 
3. Has a corrected QT interval (QTcF) prolongation > 470 msec (females) or >450 msec (males) 
based on average of triplicate12-lead ECG at screening. 
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening. 
5. Has spinal cord compression or clinically active central nervous system metastases, defined as 
untreated and 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 brain radiotherapy and study randomization. 
6. Has multiple primary malignancies within 3 years, except adequately resected non-melanoma 
skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated. 
7. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
8. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.  






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Population PK analysis may also be conducted by combining data from this study 
with other clinical studies of trastuzumab deruxtecan. In addition, exposure-
response (ER) analysis for key efficacy and safety endpoints may be conducted. 
The results of population PK and ER analyses will be provided in a separate report 
outside the clinical study report (CSR) for this study. 
Immunogenicity will be assessed through characterization of incidence and titer of 
the ADA.  The number and percentage of subjects will be reported for the presence 
or absence of development of ADA after the start of administration of study 
treatment, defining subjects who are negative for ADA at all-time points as 
negative and subjects who are positive for ADA at least one time point post-study 
drug treatment as positive. The ADA titer values will be summarized by time point 
and dose level using descriptive statistics.  The treatment-emerging ADA 
incidence will be calculated.  Treatment-emergent ADA positive subject will be 
defined as subjects who are ADA negative at baseline and become ADA positive 
posttreatment, or who are ADA positive at baseline and posttreatment, but have an 
increase in ADA titer from baseline to posttreatment, or those who have missing 
ADA data at baseline but become ADA positive post-treatment.  The number and 
percentage of subjects positive for NAb of trastuzumab deruxtecan may also be 
determined. 
Health Economic & 
Outcomes Research 
Analyses (optional) 
Descriptive statistics will be calculated to summarize change from the baseline in 
symptoms, physical functioning and general HRQoL scales in the C30 and LC13 
study questionnaires at each scheduled assessment time point by dose level.  The 
number of subjects completing each patient questionnaire and the number of 
missing or incomplete assessments will be provided for each scheduled assessment 
time point by dose level. 
Analysis Population  
 
 
Full Analysis Set 
The Full Analysis Set will include all subjects for whom study treatment has 
been assigned by randomization. 
 
Response Evaluable Set (RES)  
The Response Evaluable Set (RES) will include all subjects in FAS who 
received at least one dose of study treatment and had measurable target 
lesions as assessed by BICR at baseline. 
 
Safety Analysis Set 
The Safety Analysis Set will include all subjects who received at least one 
dose of study treatment. 
 
PK Analysis Set 
The PK Analysis Set will include all randomized subjects who received at 
least one dose of study drug and had measurable serum concentrations of 
trastuzumab deruxtecan. 
Data Cut-off 
 
The primary analysis data cut-off (DCO) will occur when all subjects completed at 
least 9 months of follow-up after the last subject has been randomized or has 
discontinued treatment. 
Adjustments for 
Multiplicity  
Not applicable.   
Interim Analyses (IA) 
Two interim analyses (IAs) are planned for this study.  If the planned DCO of the 
second IA is anticipated to fall within 3 months of the primary analysis DCO, 
when the data are sufficiently mature, then the second IA may not be performed. 
The first IA will occur when a total of at least 75 subjects have been randomized to 
receive a dose of trastuzumab deruxtecan (5.4 mg/kg or 6.4 mg/kg) and have had 




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1.2. 
Study Schema 
This is a randomized, 2 arm, Phase 2, multicenter study to evaluate the safety and efficacy of 
trastuzumab deruxtecan at 5.4 or 6.4 mg/kg in HER2-mutated non-small cell lung cancer 
(NSCLC) subjects who had disease recurrence or progression during/after at least one regimen of 
prior anticancer therapy (second-line or later, 2L+) that must have contained a platinum-based 
chemotherapy drug. 
A total of 150 subjects will be randomized in a 2:1 ratio to receive trastuzumab deruxtecan at 
the 5.4 mg/kg or 6.4 mg/kg dose cohort, respectively. 
Figure 1.1: 
Study Level Flow Diagram 
 
Randomization will be stratified by subjects who (i) received prior anti-PD-1 and/or anti-PD-L1 
treatment and (ii) those who received neither. 
HER2 = human epidermal growth factor receptor 2; NSCLC = non-small cell lung cancer;  PD-1 = programmed cell 
death receptor-1; PD-L1 = programmed cell death ligand 1 
































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x If a patient discontinues study treatment for reasons other than RECIST 1.1 progression, the Hospital Admission (HOSPAD) form should continue to be administered until 
progression has been confirmed. 
y The electronic patient-reported outcome (ePRO) device should be charged and fully functional prior to the patient’s arrival at the site for Cycle 1 Day 1 (-3 d) to ensure that the 
PROs can be completed at the start of the visit. 
z The patient should be trained on the use of the device, including the importance of completing the PRO questionnaires throughout the study in accordance with the completion 
schedule. 
 
Notes “d” to “m” and “p” to “w” are located in the “Comment” column of the SoE. 
For suspected interstitial lung disease (ILD)/pneumonitis, treatment with study drug should be interrupted pending evaluation. 
Evaluations should include: 
 High resolution computed tomography (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, C-reactive protein 
 One blood sample collection for pharmacokinetic (PK) as soon as ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered as needed (eg, COVID-19 test).  


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2. 
INTRODUCTION 
2.1. 
Background 
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality 
worldwide; accounting for approximately 18% of all cancer deaths.1  For years, platinum-based 
chemotherapy has been the cornerstone of treatment for NSCLC in the first line.  However, the 
5-year survival with conventional chemotherapy regimens is around only 5%.2   
In recent years, several targeted therapies have been approved and recommended for use in 
patients with advanced/metastatic NSCLC.  In particular, the advent of targeted therapies for 
specific driver mutations such as epidermal growth factor receptor (EGFR) as well as immune 
checkpoint inhibitors have significantly changed the outlook for this disease.  Despite recent 
advances, however, a significant number of advanced/metastatic NSCLC patients eventually 
progress on these treatments, and hence an unmet medical need exists for these patients.   
Human epidermal growth factor receptor 2 (HER2) activating mutations have been reported in 
approximately 2% to 3% of all NSCLC adenocarcinoma patients.3, 4,5,6,7,8  Whilst in an afatinib 
Phase 3 trial, 4.9% (12 of 245) of the squamous NSCLC patients also had the HER2 mutation.9  
Results from clinical studies suggest a potential role of an HER2-targeting antibody-drug 
conjugate (ADC) in NSCLC. A trastuzumab emtansine (T-DM1) study reported an objective 
response rate (ORR) of 44% in patients with HER2-mutated NSCLC.10 HER2 mutation is also 
considered a distinct molecular target, however, no HER2-targeted therapies are approved in 
NSCLC.  
2.1.1. 
Description of Trastuzumab Deruxtecan 
Trastuzumab deruxtecan is an ADC targeting HER2.  It 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 monoclonal 
antibody with the same amino acid sequence as trastuzumab.  MAAA-1181a, an exatecan 
derivative, is a topoisomerase I inhibitor that is cell membrane permeable, and more potent than 
SN-38 (active metabolite of irinotecan).4  This ADC achieves a high drug-to-antibody ratio 
(DAR) (7 - 8:1) with homogeneous conjugation with MAAA-1181a.  Trastuzumab deruxtecan is 
cleaved by lysosomal enzymes and releases MAAA-1181a in the cytoplasm after it binds to the 
HER2 receptor, which gets internalized in tumor cells. 
The Lyo-DP form will be administered in this trial.  For details of other forms of trastuzumab 
deruxtecan, refer to the latest version of the Investigator’s Brochure (IB).11  
2.1.2. 
Intended Use Under Investigation 
This study will investigate the safety and efficacy of trastuzumab deruxtecan in HER2-mutated 
NSCLC subjects. 


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2.1.3. 
Nonclinical Studies of Trastuzumab Deruxtecan 
In nonclinical studies for MAAA-1181a (free form), MAAA 1181c (additive form 
[3/10  MeCN·2/5 MeOH·3/10 H2O]) or MAAA-1181d (monohydrate) were used.  The doses 
and concentrations of MAAA-1181c and MAAA-1181d are expressed as those of 
MAAA-1181a, the free form. 
2.1.4. 
Nonclinical Studies 
2.1.4.1. 
Pharmacology 
In studies on the mechanism of action of trastuzumab deruxtecan, trastuzumab deruxtecan was 
confirmed to have an HER2-mediated Akt phosphorylation inhibition and an antibody-dependent 
cellular cytotoxicity (ADCC) activity, and has also been confirmed to cause DNA damage and 
induce apoptosis, effects that are assumed to be the result of MAAA-1181c, which has 
topoisomerase I inhibitory activity. 
Therefore, trastuzumab deruxtecan is considered to exhibit HER2-specific cell growth inhibition 
and antitumor activity via a novel mechanism of action that combined the pharmacological 
activities of MAAL-9001, the antibody component, with those of MAAA-1181a, the drug 
component. 
2.1.4.2. 
Safety Pharmacology 
In a safety pharmacology study in monkeys treated with single IV doses of trastuzumab 
deruxtecan, no effects on the cardiovascular system, the respiratory system, or the central 
nervous system were observed under the study condition.  In addition, in human ether- a-go-go-
related gene (hERG) studies of MAAA-1181a, MAAA-1181a did not inhibit the hERG channel 
current. 
2.1.4.3. 
Pharmacokinetics and Drug Metabolism 
In vitro release rates of MAAA-1181a from trastuzumab deruxtecan in mouse, rat, monkey, and 
human plasma up to 3 weeks were 3.9% or less. Cytochrome P450 (CYP) 3A4 was the primary 
CYP enzyme involved in the metabolism of MAAA-1181a12.  No human-specific metabolites 
were detected in vitro; the plasma protein binding of MAAA-1181a is approximately 97% in 
humans.   
In monkeys, excretion of radioactivity from administered 14C-trastuzumab deruxtecan into feces 
was predominant.  In rats, excretion of radioactivity from administered 14C-labeled MAAA 
1181a (14C-MAAA-1181a) into feces via bile was predominant. 
MAAA-1181d did not show any inhibition potential to CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A (concentration producing 50% inhibition [IC50] >50 μmol/L).  
MAAA-1181d did not show any induction potential for CYP3A4, CYP1A2, and CYP2B6 up to 
30 μmol/L.  MAAA-1181d did not inhibit organic anion transporter (OAT) 3, organic cation 
transporter (OCT) 1, OCT2, organic anion- transporting polypeptide (OATB) 1B3, multidrug 
and toxin extrusion (MATE) 1, MATE2-K, P-glycoprotein, breast cancer resistance protein, and 
bile salt export pump (IC50 >30 μmol/L).  MAAA-1181d inhibited OAT1 and OATP1B1 with 
the IC50 values of 12.7 μmol/L and 14.4 μmol/L, respectively; however, the values were much 


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higher than the maximum concentration (Cmax) of MAAA-1181a in humans (9.25 ng/mL 
[0.019 μmol/L] at 8.0 mg/kg of trastuzumab deruxtecan).  In addition, OATPs were considered 
to contribute to the human hepatic uptake of MAAA-1181a.  A summary of clinical 
pharmacokinetic (PK) data following administration of trastuzumab deruxtecan is provided in 
Section 2.1.6. 
2.1.4.4. 
Toxicology 
In a study of intermittent IV dosing of trastuzumab deruxtecan in rats (every 3 weeks, Q3W × 2), 
no deaths or moribund animals were found at dose levels up to 197 mg/kg, the maximum dose.  
The major observed findings included testicular and intestinal toxicity at dose levels of 20 mg/kg 
and greater, and lymphatic/hematopoietic, skin, incisor tooth, and renal toxicity at dose levels of 
60 mg/kg and greater.  Except for the testicular and incisor tooth changes, these changes were all 
found to recover.  
In an intermittent IV dosing study of trastuzumab deruxtecan in cynomolgus monkeys 
(Q3W × 2), one female was sacrificed moribund at 78.8 mg/kg, the highest dose level.  The 
major toxicity findings in this moribund animal were observed in the intestine, hematopoietic 
system, skin, and kidney.  The cause of the moribundity appeared to be the deteriorated condition 
of the animal from decreased body weight and food consumption, as well as bone marrow 
toxicity and intestinal toxicity.  The major findings of toxicity in the surviving animals were 
observed in the intestine at dose levels of 10 mg/kg and greater, and in the lung, testes, and skin 
at dose levels of 30 mg/kg and greater.  In addition, hematopoietic system toxicity, renal toxicity, 
and electrocardiogram (ECG) abnormalities (shortened PR interval and corrected QT interval 
[QTc] prolongation) were found at 78.8 mg/kg.  Except for the pulmonary and skin toxicity 
(pigmentation), these findings tended to recover.  
Thus, as described above, the severely toxic dose in 10% of the animals in a rat intermittent IV 
dosing study of trastuzumab deruxtecan was found to be greater than 197 mg/kg.  In the monkey 
study, due to observed moribundity at 78.8 mg/kg and evidence of critical pulmonary toxicity 
(eg, interstitial inflammation and/or alveolar edema) in the surviving animals, it was concluded 
that the highest non-severely toxic dose is 30 mg/kg.  
In an intermittent IV dose toxicity study of MAAA-1181a (morning dosing for 4 weeks), 
findings in the lymphatic/hematopoietic system, intestinal tract, and the cornea of the eye were 
observed at 3 mg/kg and greater in rats and there was no death or moribundity at up to 30 mg/kg.  
Findings similar to those in rats were observed in cynomolgus monkeys at dose levels of 1 mg/kg 
and greater.  In addition, one female monkey died and one male monkey was sacrificed 
moribund at 12 mg/kg.  Although effects on the heart (focal myocardial cell 
degeneration/necrosis) were found in the moribund male along with the above-mentioned 
toxicities, there were no abnormal heart findings in the female that died, even though both 
animals exhibited worsening clinical conditions associated with sustained decreases in food 
consumption, bone marrow toxicity, and intestinal toxicity.  These changes were considered to 
be the cause of the death and moribundity.  The common adverse findings in both trastuzumab 
deruxtecan and MAAA 1181a studies were intestinal and lymphatic/hematopoietic system 
toxicities.  For trastuzumab deruxtecan treatment, pulmonary, testicular, skin, and renal toxicities 
were observed while heart, liver, and corneal toxicities were found only when MAAA-1181a 
was administered.  


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In a human cross-reactivity study of trastuzumab deruxtecan with a panel of human tissues, 
trastuzumab deruxtecan-related cell membrane staining was found only in the placenta.  In a 
cross-reactivity study of trastuzumab deruxtecan with selected cynomolgus monkey tissues 
(eg, brain, liver, kidney, lung, heart, intestines, lymphoid organs, testes, and skin), neither 
membranous nor cytoplasmic staining was noted in any tissues.  
In an in vitro 3T3 NRU phototoxicity study, MAAA-1181a was found to be phototoxic to Balb/c 
3T3 mouse fibroblasts.  However, in an in vivo single dose phototoxicity study of MAAA-1181d 
in pigmented rats, no phototoxic reaction was noted at 3 mg/kg, the highest dose tested.  For 
additional nonclinical data supporting trastuzumab deruxtecan use in nonclinical studies, please 
refer to the Investigator’s Brochure (IB). 
2.1.5. 
Clinical Experience 
As of 08 Jun 2019, trastuzumab deruxtecan has been evaluated in 12 company-sponsored clinical 
studies (11 monotherapy studies and 1 combination therapy study) in multiple oncology 
indications, with an estimated 1036 subjects exposed to at least 1 dose. 
Study DS8201-A-J101 is a first-in-human, open-label, dose finding study to assess the safety and 
tolerability of trastuzumab deruxtecan in subjects with advanced solid tumors.  Part 1 (dose 
escalation) enrolled subjects with either advanced breast cancer or gastric/gastroesophageal 
junction adenocarcinoma.  Part 2 is the expansion phase and focuses on HER2-expressing breast 
and gastric/gastroesophageal junction adenocarcinoma, HER2-low-expressing breast cancer, as 
well as other HER2-expressing or -mutated solid cancers including NSCLC. 
2.1.5.1. 
Efficacy: DS8201-A-J101  
Efficacy results11 as of 01 Feb 2019 showed confirmed ORR by blinded independent central 
review (BICR) of 52.5% (95% confidence interval [CI]: 43.1 to 61.8) among the 118 subjects 
with HER2-positive breast cancer, with confirmed ORR of 51.0% (95% CI: 36.6 to 65.2) for the 
51 subjects in the 5.4 mg/kg dose group and confirmed ORR of 53.7% (95% CI: 41.1 to 66.0) for 
the 67 subjects in the 6.4 mg/kg dose group.  The median confirmed duration of response (DoR) 
by BICR was 13.3 months, 12.7 months, and 13.6 months for the pooled, 5.4 mg/kg, and 
6.4 mg/kg dose groups, respectively.  The median progression-free survival (PFS) by BICR was 
13.7 months, 13.7 months, and 14.1 months for the pooled, 5.4 mg/kg, and 6.4-mg/kg dose 
groups, respectively.  Median overall survival (OS) was not reached as of the data cut-off 
(DCO). 
As of the DCO date of 01 Feb 2019, efficacy results for all subjects with NSCLC in the Study 
DS8201-A-J101 study are summarized in Table 2.1.  All NSCLC subjects received a 6.4 mg/kg 
dose of trastuzumab deruxtecan.  
In the Enrolled Analysis Set, a confirmed ORR was observed in 55.6% (95% CI: 30.8 to 78.5) of 
NSCLC subjects (N = 18) and 73% among HER-2 mutant NSCLC subjects (N =11).  The 
median confirmed DoR (calculated using the Kaplan-Meier method) was 10.7 months and the 
median PFS was 11.3 months (95% CI: 7.2 to 14.3) in NSCLC subjects. 


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Table 2.1: 
Efficacy Results in NSCLC Cancers in Study DS8201-A-J101 
(Enrolled Analysis Set) 
Efficacy Variable 
NSCLC 
(N = 18) 
Confirmed ORR, n (%) (95% CIa) See Table 5.14 IB) 
 
ORR by BICR 
10 (55.6) 
(30.8, 78.5) 
ORR by investigator 
10 (55.6) 
(30.8, 78.5) 
ORR by BICR in response evaluable set (RES), n/N 
10/17 (58.8) 
(32.9, 81.6) 
- 
CR 
0 
- 
PR 
10 (55.6) 
- 
Stable disease 
5 (27.8) 
- 
PD 
2 (11.1) 
- 
NE 
1 (5.6) 
Confirmed best overall response by investigator, n (%) 
 
CR 
0 
PR 
10 (55.6) 
Stable disease 
4 (22.2) 
PD 
3 (16.7) 
Non-Evaluable (NE) 
1 (5.6) 
Confirmed DoR, median (95% CI) (months) 
 
DoR by BICR 
10.7 
(6.9, 11.5) 
DoR by investigator 
9.9 
(6.9, 11.5) 
Confirmed DCR,c n (%) (95% CIa) 
 
DCR by BICR 
15 (83.3) 
(58.6, 96.4) 
DCR by investigator 
14 (77.8)  
(52.4, 93.6) 
Time to confirmed response by BICR, medianb (95% CI) (months) 
1.4 
(1.2, 2.8) 
Duration of confirmed stable disease by BICR, medianb (95% CI) (months) 
- 
(2.1, -) 
PFS by BICR 
 


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Efficacy Variable 
NSCLC 
(N = 18) 
Events, n (%) 
9 (50.0) 
Medianb (95% CI) (months) 
11.3 
(7.2, 14.3) 
PFS by investigator 
 
Events, n (%) 
11 (61.1) 
Medianb (95% CI) (months) 
11.3 
(5.5, 14.1) 
Events, n (%) 
4 (22.2) 
Medianb (95% CI) (months) 
Not reached 
(17.3, -) 
Survival at 6 months, % (95% CId) 
88.9 
(62.4, 97.1) 
Survival at 12 months, % (95% CId) 
83.3 
(56.8, 94.3) 
Survival at 18 months, % (95% CId) 
66.7 
(26.2, 88.4) 
Survival at 24 months, % (95% CId) 
- 
(-, -) 
BICR = blinded independent central review; CI = confidence interval; CR = complete response; DCR = disease 
control rate; DoR = duration of response; HER2 = human epidermal growth factor receptor 2; IB = Investigator’s 
Brochure; NE = non-evaluable; NSCLC = non-small cell lung cancer; ORR = objective response rate; PD = 
progressive disease; PFS = progression-free survival; PR = partial response  
a 95% exact binomial CI. 
b Median was from Kaplan-Meier estimate.  CI for median as computed using the Brookmeyer-Crowley method. 
c DCR was calculated as the proportion of subjects demonstrating CR, PR, or stable disease for a minimum of 
6 weeks (±1 week) from the first dosing date. 
d CI for the rate at a fixed time point was computed by applying asymptotic normality to the log-log transformation 
of the rate. 
Dashes (-) represent data that are not estimable 
The range includes the censored observations where using “+” after the value indicates censoring.  Months were 
calculated as days × 12/365.25. 
Part 2 subjects are included. 
Data cut-off date: 01 Feb 2019.  Source: Trastuzumab deruxtecan IB, 09 Sep 2019. 
2.1.5.2. 
Efficacy: DS8201-A-U204  
A DCO was performed on 25 November 2019 to undertake an analysis of the initial 42 HER2 
mutant NSCLC subjects enrolled in Cohort 2, prior to the expansion of this cohort. As of 25 Nov 
2019, the median duration of follow-up was 8.0 months (range: 1.4-14.2). Treatment in 19 
subjects (45.2%) was ongoing at the time of data cut-off (DCO). The median treatment duration 
was 7.75 months (range: 0.7-14.3).  
Of the 42 subjects, the median age was 63.0 years (range: 34-83), 64.3% were female, 45.2% had 
central nervous system (CNS) metastases, and Eastern Cooperative Oncology Group (ECOG) 


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performance status (PS) was 0 in 23.8% and 1 in 76.2% of subjects. HER2 mutations were 
predominantly in the kinase domain (90.5%).  
Forty-one (97.6%) of the 42 subjects reported at least one prior systemic cancer therapy, and the 
median number of prior systemic cancer therapies was 2 [range: 1 to 6]. Thirty-eight subjects 
(90.5%) received prior platinum-based therapy, 20 (47.6%) and 6 (14.3%) received prior 
anti-programmed cell death receptor-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) 
treatment, respectively.  
Confirmed ORR by independent committee review (ICR) among the 42 subjects was 61.9% 
(95% CI: 45.6 to 76.4). Median DoR was not reached; 16 of 26 responders remained on 
treatment at DCO. Table 2.2 provides the efficacy results from the analysis by ICR. 
Table 2.2: 
Efficacy Results for DS8201-A-U204 Cohort 2 by ICR 
Efficacy variable 
HER2-mutant NSCLC  
Cohort 2 (N=42) 
Best Overall Response (Confirmed) 
n (%) 
  Complete Response (CR) 
1 (2.4) 
  Partial Response (PR) 
25 (59.5) 
  Stable Disease (SD) 
12 (28.6) 
  Progressive Disease (PD) 
2 (4.8) 
  Non-Evaluable (NE) 
2 (4.8) 
Confirmed ORR  
  95% CIa 
26 (61.9) 
(45.6, 76.4) 
DoR, median (months) (95% CI)b  
NE (5.3, NE) 
PFS, median (months) (95% CI)b  
14.0 (6.4, 14.0) 
DoR = duration of response; NE = not estimable; ORR = overall response rate; PFS = progression-free survival. 
Overall Response is determined by independent central review assessment based on RECIST criteria, Version 1.1. 
a The 2-sided 95% confidence intervals are based on the exact (Clopper-Pearson) binomial distribution. 
b 95% CI for median is computed using the Brookmeyer-Crowley method. 
2.1.5.3. 
Safety: DS8201-A-J101  
As of 01 Feb 2019, a total of 288 (99.7%) subjects experienced at least 1 treatment-emergent 
adverse event (TEAE), with most of the common TEAEs being gastrointestinal or hematological 
in nature.   
No dose-limiting toxicities (DLTs) were reported, and the maximum tolerated dose (MTD) was 
not reached in the Dose Escalation Phase. 
 Gastrointestinal: Nausea was most frequently reported, was predominantly Grade 1 or 
Grade 2, occurred early in the treatment (the majority occurring in the first 1 to 3 
cycles), and was manageable under routine clinical practice.   


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 Hematological: Events were predominantly Grade 1 or Grade 2, occurred early in 
treatment (the majority occurring in the first 1 to 3 cycles), and were manageable 
under routine clinical practice.  Platelet count decrease (grouped term for preferred 
terms [PTs] platelet count decreased and thrombocytopenia) was commonly seen.  
Treatment-emergent adverse events reported in ≥20% of total subjects (N = 289) by PT and 
grouped term, tumor type, and dose are provided in Table 2.3. 
The TEAEs of Grade ≥3 were reported in 168 (58.1%) subjects.  The most frequently (≥5% of 
subjects) reported TEAEs of Grade ≥3 in any tumor type and dose by PT were anaemia 
(60 [20.8%] subjects), neutrophil count decreased (53 [18.3%] subjects), white blood cell (WBC) 
count decreased (37 [12.8%] subjects), platelet count decreased (33 [11.4%] subjects), and 
hypokalaemia (18 [6.2%] subjects). 
Across all tumor types, a numerically higher proportion of subjects in the 6.4-mg/kg dose group 
than in the 5.4-mg/kg group experienced AEs of Grade ≥3 (overall and causally related), serious 
adverse events (SAEs) (including causally related), AEs leading to drug withdrawal (overall and 
causally related), and AEs leading to dose reduction (overall and causally related). 


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Table 2.3: 
Summary of Treatment-Emergent Adverse Events (≥20% of Subjects) in Study DS8201-A-J101 
MedDRA Preferred Term 
Number (%) of Subjectsa 
HER2-Positive 
Breast Cancer 
HER2-Low 
Breast Cancer 
HER2-Positive 
Gastric/GEJ Cancer 
Other 
Cancersb 
Total 
(N = 274) 
Total 
(N = 289) 
5.4 mg/kg 
(N = 50) 
6.4 mg/kg 
(N = 66) 
5.4 mg/kg 
(N = 21) 
6.4 mg/kg 
(N = 33) 
5.4mg/kg 
(N = 19) 
6.4 mg/kg 
(N = 25) 
6.4 mg/kg 
(N = 59) 
5.4 mg/kg 
(N = 91) 
6.4 mg/kg 
(N = 183) 
All Doses 
Subjects with any TEAEs 
50 (100.0) 
66 (100.0) 
20 (95.2) 
33 (100.0) 
19 (100.0) 
25 (100.0) 
59 (100.0) 
90 (98.9) 
183 (100.0) 
288 (99.7) 
Nausea 
43 (86.0) 
52 (78.8) 
15 (71.4) 
26 (78.8) 
12 (63.2) 
19 (76.0) 
44 (74.6) 
71 (78.0) 
141 (77.0) 
222 (76.8) 
Decreased appetite 
23 (46.0) 
47 (71.2) 
7 (33.3) 
20 (60.6) 
8 (42.1) 
22 (88.0) 
35 (59.3) 
38 (41.8) 
124 (67.8) 
168 (58.1) 
Vomiting 
28 (56.0) 
35 (53.0) 
10 (47.6) 
14 (42.4) 
3 (15.8) 
8 (32.0) 
31 (52.5) 
41 (45.1) 
88 (48.1) 
133 (46.0) 
Alopecia 
19 (38.0) 
45 (68.2) 
6 (28.6) 
18 (54.5) 
4 (21.1) 
4 (16.0) 
20 (33.9) 
29 (31.9) 
87 (47.5) 
120 (41.5) 
Anaemiac 
24 (48.0) 
30 (45.5) 
7 (33.3) 
14 (42.4) 
4 (21.1) 
14 (56.0) 
23 (39.0) 
35 (38.5) 
81 (44.3) 
118 (40.8) 
Fatigue 
24 (48.0) 
32 (48.5) 
11 (52.4) 
9 (27.3) 
4 (21.1) 
3 (12.0) 
21 (35.6) 
39 (42.9) 
65 (35.5) 
111 (38.4) 
Diarrhoea 
18 (36.0) 
28 (42.4) 
9 (42.9) 
16 (48.5) 
3 (15.8) 
5 (20.0) 
19 (32.2) 
30 (33.0) 
68 (37.2) 
102 (35.3) 
Constipation 
18 (36.0) 
30 (45.5) 
7 (33.3) 
14 (42.4) 
5 (26.3) 
7 (28.0) 
16 (27.1) 
31 (34.1) 
67 (36.6) 
100 (34.6) 
Platelet count decreased 
15 (30.0) 
24 (36.4) 
3 (14.3) 
14 (42.4) 
5 (26.3) 
12 (48.0) 
22 (37.3) 
24 (26.4) 
72 (39.3) 
100 (34.6) 
Neutrophil count decreasee 
12 (24.0) 
25 (37.9) 
3 (14.3) 
13 (39.4) 
2 (10.5) 
12 (48.0) 
21 (35.6) 
18 (19.8) 
71 (38.8) 
91 (31.5) 
White blood cell count 
decreasef 
9 (18.0) 
22 (33.3) 
4 (19.0) 
13 (39.4) 
3 (15.8) 
11 (44.0) 
17 (28.8) 
17 (18.7) 
63 (34.4) 
82 (28.4) 
Aspartate aminotransferase 
increased 
9 (18.0) 
23 (34.8) 
3 (14.3) 
10 (30.3) 
1 (5.3) 
3 (12.0) 
12 (20.3) 
13 (14.3) 
48 (26.2) 
63 (21.8) 
Malaise 
6 (12.0) 
19 (28.8) 
2 (9.5) 
13 (39.4) 
3 (15.8) 
5 (20.0) 
13 (22.0) 
11 (12.1) 
50 (27.3) 
62 (21.5) 
Pyrexia 
10 (20.0) 
18 (27.3) 
1 (4.8) 
9 (27.3) 
3 (15.8) 
8 (32.0) 
9 (15.3) 
14 (15.4) 
44 (24.0) 
60 (20.8) 
Stomatitisg 
7 (14.0) 
18 (27.3) 
4 (19.0) 
13 (39.4) 
1 (5.3) 
4 (16.0) 
10 (16.9) 
12 (13.2) 
45 (24.6) 
58 (20.1) 
GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; 
TEAE = treatment-emergent adverse event  
a Part 1 and Part 2 subjects are included.  Percentage was calculated using the number of subjects in the column heading as the denominator. 
b Does not include 1 subject with HER2-low gastric cancer who received trastuzumab deruxtecan at 5.4 mg/kg. 
c Grouped term that includes PTs anaemia, hemoglobin count decreased, and red blood cell count decreased. 
d Grouped term that includes PTs platelet count decreased and thrombocytopenia. 
e Grouped term that includes PTs neutrophil count decreased and neutropenia. 
f Grouped term that includes PTs white blood count decreased and leukopenia. 
g Grouped term that includes PTs stomatitis, aphthous stomatitis, mouth ulceration, oral mucosa erosion, and oral mucosal blistering. 
Adverse events were coded using MedDRA Version 20.1. 
Table is presented by decreasing order of preferred terms within the Total (N = 289) All Doses column. Numbers of subjects with TEAEs are expressed as n (%) 
Data cut-off date: 01 Feb 2019. 
Source: DS8201-A-J101 CSR, Table 10.6.  


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2.1.5.4. 
Safety: DS8201-A-U204  
As of 25 Nov 2019, 42 subjects received at least one dose of trastuzumab deruxtecan in Cohort 
2. The median treatment duration was 7.75 months (range: 0.7-14.3). Of the 42 HER2 mutated 
NSCLC subjects (all dosed at 6.4 mg/kg), treatment was ongoing in 19 (45.2%) subjects at the 
time of DCO. 
All subjects experienced a TEAE in Cohort 2. A summary of TEAEs (>10% based on Cohort 2) 
of any Grades for Cohort 2 is shown in Table 2.4. In descending order of frequency, TEAEs with 
a frequency of at least 30% in Cohort 2 were nausea, alopecia, anaemia, decreased appetite, 
neutrophil count decreased, vomiting, diarrhoea, and weight decreased. 
Table 2.4: 
Summary of Treatment-Emergent Adverse Events (TEAEs) (>10 % [Based 
on Cohort 2 by Descending Order]) from DS8201-A-U204, Cohort 2 and 
Overall 
Preferred Term 
HER2-mutant NSCLC  
 
Cohort 2 
(N=42) 
n (%) 
Overall (HER2-expressing and 
HER2-mutant NSCLC)* 
Cohort 1 and Cohort 2 
(N=84)a 
n (%) 
Subjects with Any TEAE 
42 (100.0) 
83 (98.8) 
Nausea 
32 (76.2) 
53 (63.1) 
Alopecia 
20 (47.6) 
26 (31.0) 
Anaemia 
18 (42.9) 
28 (33.3) 
Decreased Appetite 
18 (42.9) 
31 (36.9) 
Neutrophil Count Decreased 
18 (42.9) 
25 (29.8) 
Vomiting 
17 (40.5) 
27 (32.1) 
Diarrhoea 
15 (35.7) 
24 (28.6) 
Weight Decreased 
13 (31.0) 
21 (25.0) 
Constipation 
11 (26.2) 
22 (26.2) 
Fatigue 
11 (26.2) 
25 (29.8) 
White Blood Cell Count Decreased 
11 (26.2) 
14 (16.7) 
Aspartate Aminotransferase Increased 
9 (21.4) 
11 (13.1) 
Malaise 
8 (19.0) 
13 (15.5) 
Lung Infection 
7 (16.7) 
8 (9.5) 
Pyrexia 
7 (16.7) 
7 (8.3) 
Asthenia 
6 (14.3) 
11 (13.1) 
Urinary Tract Infection 
6 (14.3) 
8 (9.5) 
Alanine Aminotransferase Increased 
5 (11.9) 
7 (8.3) 
Dry Skin 
5 (11.9) 
6 (7.1) 
Dyspnoea 
5 (11.9) 
14 (16.7) 
Pneumonitis 
5 (11.9) 
10 (11.9) 
*Due to the dynamic nature of the safety dataset, the numbers might be subject to change. 
a N=84 comes from Cohort 1 N=42 and Cohort 2 N=42 as of 25 Nov 2019 data cut-off. 


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Of the 42 subjects in Cohort 2, 27 (64.3%) subjects experienced at least one Grade ≥ 3 TEAE. A 
summary of Grade ≥ 3 TEAEs (>5% based on Cohort 2) is shown in Table 2.5. In descending 
order of frequency, Grade ≥ 3 TEAEs with a frequency of at least 5% in Cohort 2 were 
neutrophil count decreased, anaemia, fatigue, and nausea. 
Table 2.5: 
Summary of Grade ≥ 3 TEAEs (>5% - [Based on Cohort 2 by Descending 
Order]) from DS8201-A-U204 Cohort 2 and Overall 
Preferred Term 
Cohort 2 
(N=42) 
n (%) 
Overall* 
Cohort 1 and Cohort 2 
(N=84)a 
n (%) 
Subjects with Any Grade ≥ 3 TEAE 
27 (64.3) 
54 (64.3) 
Neutrophil Count Decreased 
11 (26.2) 
18 (21.4) 
Anaemia 
7 (16.7) 
12 (14.3) 
Fatigue 
3 (7.1) 
7(8.3) 
Nausea 
3 (7.1) 
5 (6.0) 
*Due to the dynamic nature of the safety dataset, the numbers might be subject to change. 
a N=84 comes from Cohort 1 N=42 and Cohort 2 N=42 as of 25 Nov 2019 data cut-off. 
Of the 42 subjects in Cohort 2: 
 9 (21.4%) subjects had a TEAE associated with death. The TEAE associated with 
death reported in more than one subject was disease progression (5).  
 25 (59.5%) subjects had a dose interruption due to TEAEs. The TEAEs leading to 
dose interruption reported in more than one subject included neutrophil count 
decreased (8), lung infection (3), keratitis (2), and malaise (2).  
 16 (38.1%) subjects had dose reductions due to TEAEs. The TEAEs leading to dose 
reduction reported in more than one subject included fatigue (5), nausea (4), febrile 
neutropenia (2), and malaise (2).  
 10 (23.8%) discontinued study treatment due to TEAEs. The TEAE leading to 
treatment discontinuation reported in more than one subject was pneumonitis (4).  
Adverse events of special interest (AESIs) include interstitial lung disease (ILD)/pneumonitis 
and left ventricular ejection fraction (LVEF) decrease. An independent ILD adjudication 
committee has been established to adjudicate all potential ILD/pneumonitis cases on an ongoing 
basis.  A set of pre-defined list of PTs eligible for adjudication as described in the Event 
Adjudication Site Manual, will be utilized for enhanced data collection.  As of 25 Nov 2019, in 
Cohort 2, 5 subjects experienced drug-related Grade 2 ILD as adjudicated by the independent 
ILD AC; there was no Grade 5 ILD observed. As per protocol, all these subjects discontinued 
study therapy due to the diagnosis of ILD. In Cohort 1, 4 subjects experienced drug-related ILD 
(2 Grade 1, 1 Grade 2, and 1 Grade 5).  
As of 25 November 2019, 1 subject had two events of ejection fraction decreased (Grade 2). Of 
the 2 events, 1 event was reported as recovered and 1 event is recovering. Dose was interrupted 
for 1 event and drug discontinued for 1 event.  


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2.1.6. 
Summary of Clinical Pharmacokinetics 
Following a single IV administration of trastuzumab deruxtecan, the systemic exposure of 
trastuzumab deruxtecan increased approximately proportional to dose across the dose range of 
0.8 to 8.0 mg/kg.  The mean terminal elimination half-life (t1/2) of trastuzumab deruxtecan was 
approximately 6.0 to 7.0 days.  The t1/2 of MAAA-1181a was similar to that of trastuzumab 
deruxtecan. The PK parameters of total antibody were close to that of trastuzumab deruxtecan. 
The trastuzumab deruxtecan, total anti-HER2 antibody and MAAA-1181a PK parameters at 
6.4 mg/kg dose in Cycle 1 in NSCLC subjects are shown in Table 2.6. 
The Cmax of trastuzumab deruxtecan was achieved with a median time to Cmax (Tmax) 
approximately 2.5 h.  The Cmax and area under the curve (AUC) from time 0 to 21 days 
(AUC0-21 days), at 6.4 mg/kg were 162 μg/mL and 675 μg•d/mL, respectively.  The Cmax and 
AUC of MAAA-1181a for the dosing interval were quite low compared to the corresponding 
values for trastuzumab deruxtecan. 
Table 2.6: 
Mean Pharmacokinetic Parameters of Trastuzumab Deruxtecan, Total 
Anti-HER2 Antibody and MAAA-1181a Following Cycle 1 (± Standard 
Deviation) in subjects with NSCLC at 6.4 mg/kg dose 
 
Cmax 
(g/mL)a  
or (ng/mL)b 
Tmax 
(h) 
Median (range) 
AUC0-21d 
(μgd/mL) a 
or (ngd/mL) b 
 
Trastuzumab deruxtecan 
162.1± 36.1  
2.57 (1.50, 6.83) 
675.0 ± 212.20 
 
 
 
 
Total Anti-HER2 Antibody  
147.7 ± 33.8 
2.41 (1.50, 6.83) 
772.5 ± 293.2 
MAAA-1181a 
11.5 ± 3.7 
6.75 (3.83, 7.08) 
40.38 ±12.8 
AUC = area under the concentration time curve; AUC0-21d = AUC from the time 0 to 21 d; Cmax = maximum 
serum concentration; d = day, N = number of evaluable subjects; Tmax = time to Cmax  
a Trastuzumab deruxtecan or total anti-HER2 antibody 
b MAAA-1181a 
2.2. 
Study Rationale 
Targeted therapies (eg, EGFR, anaplastic lymphoma kinase [ALK], proto-oncogene 1 [ROS1] 
tyrosine kinase inhibitor [TKI]) are recommended as systemic treatment for a subset of NSCLC 
patients who have those driver mutations/rearrangements. HER2 mutation is also considered a 
distinct molecular target, however, no HER2-targeted therapies are approved in NSCLC. Several 
pan-class HER family TKIs were investigated in HER2-mutated NSCLC; however, clinical 
activity of those treatments was very limited, with ORR range of 0 to 19%.13,14,15,16  Platinum- or 
taxane-based chemotherapy or immune checkpoint inhibitor remain the treatment options for no 
known mutation or after disease progression against molecular targeted therapy. 
Results from clinical studies suggest a potential role of HER2-targeting ADC in NSCLC. A 
single-center, investigator-sponsored, phase II basket trial of T-DM1 study reported an ORR of 
44% (n=8/18; 95% CI: 22 to 69) in patients with HER2-mutant NSCLC.10  While there are no 


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direct HER2-targeted therapies approved for NSCLC, further investigation of HER2 targeting 
strategies are warranted in this patient population. 
Trastuzumab deruxtecan is a HER2-targeting ADC with a high DAR, and a novel topoisomerase 
I inhibitor.  Trastuzumab deruxtecan is expected to inhibit tumor growth on the basis of the 
following reasons: it exhibits ADCC activities and Akt phosphorylation inhibition similar to 
those of trastuzumab 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 Part 1 of Study DS8201-A-J101, there have been no reported DLTs, the MTD was not reached 
in the 0.8 to 8.0 mg/kg Q3W, and 5.4 mg/kg or 6.4 mg/kg were considered as the recommended 
Phase 2 doses.  Efficacy results as of 01 Feb 2019 showed confirmed ORR by BICR of 52.5% 
(95% CI: 43.1 to 61.8) among the 118 subjects with HER2-positive breast cancer, with 
confirmed ORR of 51.0% (95% CI: 36.6 to 65.2) for the 51 subjects in the 5.4 mg/kg dose group 
and confirmed ORR of 53.7% (95% CI: 41.1 to 66.0) for the 67 subjects in the 6.4 mg/kg dose 
group.  Trastuzumab deruxtecan dose of 6.4 mg/kg has shown promising efficacy in 
HER2-expressing and HER2-mutant NSCLC subjects in the Study DS8201-A-J101.  The 
confirmed ORR was 55.6% across all NSCLC subjects (N =18) and 73% among HER2 mutant 
NSCLC subjects (N =11).  See Section 2.1.5.1.  Moreover, as of the DCO date, 25 Nov 2019, a 
data snapshot for Study DS8201-A-U204 (ORR: 61.9% [n=26/42]; 95% CI: 26.8 to 69.4) has 
shown clinical efficacy in HER2-mutated NSCLC subjects at the 6.4 mg/kg dose.  Preliminary 
evidence suggests that the response rate with trastuzumab deruxtecan is substantially higher than 
the standards of care for second-line or later, namely nivolumab, docetaxel, or docetaxel and 
ramucirumab. 
Both 5.4 and 6.4 mg/kg doses of trastuzumab deruxtecan have shown clinical efficacy in 
multiple cancer indications.  However, the 5.4 mg/kg dose was not tested in HER2 mutated 
NSCLC subjects but is being tested in HER2-expressing NSCLC subjects.  
This Phase 2, randomized study will evaluate the efficacy and safety of the 5.4 mg/kg dose in 
HER2-mutated NSCLC subjects for the first time.  It will also be used to confirm the efficacy of 
the 6.4 mg/kg dose thereby fully characterizing the benefit-risk profile of trastuzumab 
deruxtecan in this population.   
2.3. 
Benefit and Risk Assessment 
Preliminary clinical evidence for trastuzumab deruxtecan in HER2-mutated NSCLC comes from 
Study DS8201-A-U204 and is supported by the results from Study DS8201-A-J101.  In Study 
DS8201-A-U204, confirmed ORR (DCO date: 25 Nov 2019) was 61.9% (95% CI: 45.6 to 76.4) 
and the median DoR was not reached (95% CI: 6.2 months to NE) in HER2-mutated NSCLC 
subjects. 
As of 08 Jun 2020, based on the cumulative review of the safety data, including available 
nonclinical, clinical, and epidemiologic information and scientific literature (published and 
unpublished) and taking into consideration biological plausibility, ILD/pneumonitis and 
neutropenia including febrile neutropenia are classified as important identified risks.  Left 
ventricular (LV) dysfunction and embryo-fetal toxicity are classified as important potential risks.   


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ILD/pneumonitis is a known serious risk of trastuzumab deruxtecan, and cases with fatal 
outcomes have been reported.  Most events were Grade 1 or Grade 2 and were manageable by 
dose modification and following clinical treatment guidelines for drug-induced ILD/pneumonitis. 
Specific recommendations included close monitoring of signs/symptoms of ILD/pneumonitis 
(eg, cough, fever, and dyspnea) to identify potential ILD/pneumonitis and proactively managing 
ILD/pneumonitis with dose modification and treatment (eg, steroids).  ILD/pneumonitis requires 
proper monitoring, dose modification, and supportive care instituted in a timely fashion.   
Other identified risks of trastuzumab deruxtecan were generally manageable through dose 
modification and routine clinical practice. 
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. 
Trastuzumab deruxtecan has demonstrated an overall acceptable safety profile in the treated 
populations to date.   
In conclusion, given the data available on the efficacy and safety of trastuzumab deruxtecan, the 
overall benefit-risk profile remains favorable for clinical development. 
For current details on safety and tolerability profile of trastuzumab deruxtecan and assessments 
of risks and benefits to subjects, please refer to the current IB. 










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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, 2 arm, Phase 2, multicenter global study to evaluate the safety and efficacy 
of trastuzumab deruxtecan at 5.4 or 6.4 mg/kg in HER2-mutated NSCLC subjects who had 
disease recurrence or progression during/after at least one regimen of prior anticancer therapy 
(2L+) in the metastatic/locally advanced setting, including platinum therapy. 
The number of the sites is approximately 45, including but not limited to, North America, 
Europe, and Asia-Pacific.  The subject population is described in Section 5. 
4.1.1. 
Design Overview 
This study will enroll approximately 150 NSCLC subjects with documented HER2 mutant status 
who had disease recurrence or progression during/after at least one regimen of prior anticancer 
therapy (2L+), including platinum therapy.  Randomization will be stratified by (i) subjects who 
received prior anti-PD-1 and/or anti-PD-L1 treatment and (ii) those who received neither, in a 
2:1 ratio to receive trastuzumab deruxtecan at a dose of 5.4 mg/kg or 6.4 mg/kg, respectively.  
See Section 2.3. 
 Two dose arms:  
 5.4 mg/kg Q3W (N = 100) 
 6.4 mg/kg Q3W (N = 50) 
The treatment assignment will remain blinded to study subjects, Investigators, study site 
personnel (except the unblinded pharmacist and other unblinded staff members as deemed 
necessary for site operations to maintain the blind), central imaging readers and ILD 
Adjudication Committee.  The Sponsor and the Contract Research Organization (CRO) are not 
blinded to the treatment assignment of the subjects.  The study start date is the date when the first 
subject has signed ICF.  A subject is randomized when the Investigator or designee has obtained 
written consent, has confirmed all eligibility criteria have been met and all screening procedures 
have been completed.   
During the Treatment Period, subjects will receive the assigned dose of study drug Q3W until 
progression of disease or until the subject meets one of the discontinuation criteria (Section 7.1).  
Subjects who discontinue study drug for any reason other than PD, death or loss to follow-up 
will be followed every 6 weeks (Q6W) until radiological disease progression or start of new 
therapy. 
After study treatment is discontinued, subjects will be followed for 40 days for safety.  Subjects 
will then enter long-term follow-up for collection of information on subsequent anticancer 
treatment and survival including the cause and date of death.   
Two interim analyses (IAs) are planned for this study.  The first IA will be performed when a 
total of at least 75 subjects have been randomized to receive a dose and had at least 4.5 months 
of follow-up before the DCO or have discontinued treatment.  The DCO of the second IA will be 
approximately 6 months after the DCO of the first IA.  If the planned DCO of the second IA is 
anticipated to fall within 3 months of the primary analysis DCO, when the data are sufficiently 


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mature, then the second IA may not be performed.  The main purpose of these IAs is to evaluate 
the safety and efficacy of each dose without the intent to modify the study design and study 
conduct.  There is no plan for stopping the trial for efficacy.  The evaluation of the study results 
will be based primarily on point estimation and 95% CI.  Hence, futility and efficacy stopping 
boundaries are not defined for both IAs.  A PK assessment will also be performed.  Additionally, 
exposure-response analyses for key efficacy and safety endpoints may be performed at the time 
of these IAs. 
The subject population is described in Section 5.  A flow diagram of study activities is presented 
in Figure 1.1. 
4.1.2. 
End of Study 
The primary completion date is the date when the last randomized subject has completed at 
least 9 months of follow-up treatment or when all subjects have been discontinued from the 
study, whichever is earlier.  This date is used as the cut-off date for the analysis of the primary 
efficacy endpoint. All subjects still on treatment and continuing to derive benefit from 
trastuzumab deruxtecan at the primary completion date will continue to follow the study 
schedule of events (SoE) (Table 1.1) until the overall EOS is reached. 
EOS will occur when the last subject’s last visit has occurred, all subjects have discontinued 
from the study or have died, an alternative study has become available where trastuzumab 
deruxtecan is offered to subjects continuing to derive benefit from such treatment, or the study is 
discontinued by the Sponsor for other reasons. 
The subject’s EOS is the date of their last study visit/contact. 
4.1.3. 
Dose Regimen 
Trastuzumab deruxtecan will be administered at doses of either 5.4 mg/kg or 6.4 mg/kg 
respectively, as an IV infusion over 90 min (± 10 min) Q3W ±2 d.   
Subjects will continue to receive trastuzumab deruxtecan if they continue to experience clinical 
benefit or until unacceptable toxicity/symptomatic deterioration attributed to PD (ie, pain 
secondary to disease or unmanageable ascites, etc), after an integrated assessment of both 
radiographic data and clinical status by the Investigator.  See Table 6.1 for complete details on 
dose regimen. 
4.1.4. 
Duration 
Study duration is inclusive of 3 periods: Screening Period, Treatment Period and Follow-up 
Period (which includes the long-term survival follow-up) as shown in the SoE, Table 1.1. 
Duration of Treatment and Subject Participation 
Each subject is expected to receive approximately 14 months of treatment with trastuzumab 
deruxtecan.  It is expected that a subject’s total duration of participation in the study will be 
approximately 16 months: 4 weeks in the Screening Period, 14 months in the Treatment Period, 
and 40 days of Follow-up. All subjects who discontinue study drug will be followed for survival 
assessment every 3 months. 


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Overall Study Duration 
Enrollment is planned to occur over approximately 16 months.  The anticipated total duration of 
the study is expected to be 31 months.  See Section 4.1 for the definition of study start and 
Section 4.1.2 for the definition of the overall EOS.  
Study Drug Continuation After the End of Study 
Not applicable. 
4.2. 
Rationale for Study Design 
This Phase 2 study design is based on data from the Study DS8201-A-J101 and the preliminary 
data from the Study DS8201-A-U204 demonstrating the clinical efficacy of trastuzumab 
deruxtecan in HER2-mutated NSCLC subjects at the 6.4 mg/kg dose.  
Both 5.4 and 6.4 mg/kg doses of trastuzumab deruxtecan have shown clinical efficacy in 
multiple cancer indications.  However, the 5.4 mg/kg dose has not been tested in HER2-mutated 
subjects although it is being tested in HER2 expressing subjects.  It is important to more fully 
characterize the benefit-risk profile for the two doses in this study.  
The study design will implement both blinding (with respect to study subjects and investigators) 
and randomization to minimize bias in the trial conduct and to allow unbiased assessment of 5.4 
and 6.4 mg/kg doses.  Moreover, randomization will be stratified by important and potential 
prognostic/predictive factor of whether the subject had prior therapy of anti-PD-1 or anti-PD-L1 
antibody, in order to reduce the risk of prognostic imbalance between treatment groups. 
4.3. 
Justification for Dose 
The dose selection of 5.4 mg/kg and 6.4 mg/kg in this study was based on the efficacy, safety, 
tolerability and PK data of trastuzumab deruxtecan from prior clinical studies in subjects with 
breast cancer, NSCLC and other solid tumors.   
In the dose escalation portion (Part 1) of the first-in-human Study DS8201-A-J101, no DLTs 
were observed, and the MTD was not reached in the evaluated dose range of 0.8 to 8.0 mg/kg. 
Based on the efficacy and safety data in Part 1, the 5.4 mg/kg and 6.4 mg/kg doses exhibited 
clinical activity with a qualitatively similar safety profile, and therefore were selected for the 
dose expansion portion (Part 2) of Study DS8201-A-J101 in subjects with NSCLC and other 
solid tumors; subjects with NSCLC received only 6.4 mg/kg dose of trastuzumab deruxtecan.  
Trastuzumab deruxtecan dose of 6.4 mg/kg is also being evaluated in Cohort 2 of the ongoing 
Phase 2 Study DS8201-A-U204.   
Trastuzumab deruxtecan dose of 6.4 mg/kg has shown promising efficacy in HER2-expressing 
and HER2-mutant NSCLC subjects in Study DS8201-A-J101. The confirmed ORR was 55.6% 
across all NSCLC subjects (N =18) and 73% among HER-2 mutant NSCLC subjects (N =11). 
See Section 2.1.5.1.  
A trastuzumab deruxtecan dose of 6.4 mg/kg is also being evaluated in the ongoing Phase 2 
Study DS8201-A-U204 in subjects with HER2-mutated NSCLC and the 5.4 mg/kg and 6.4 
mg/kg doses in subjects with HER2-expressing NSCLC.  Promising efficacy was also observed 
based on analysis (DCO date: 25 Nov 2019) using data from the ongoing Study DS8201-A-U204 


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(Section 2.1.5.2).  In subjects with HER2-mutated NSCLC following treatment with trastuzumab 
deruxtecan dose of 6.4 mg/kg, confirmed ORR by ICR was 61.9% (26/42; 95% CI: 45.6 to 76.4) 
with median DoR not reached (95% CI: 5.3 months to NE) and the median PFS was 14.0 months 
(95% CI: 6.4 months to 14.0 months).  From a safety perspective, trastuzumab deruxtecan dose 
of 6.4 mg/kg was generally tolerated with an acceptable and manageable safety profile consistent 
with the safety profile observed in other solid tumors.  These results support evaluation of a 
trastuzumab deruxtecan dose of 6.4 mg/kg in subjects with HER2-mutated NSCLC in Study 
DS8201-A-U206.   
A trastuzumab deruxtecan dose of 5.4 mg/kg has been evaluated in the DS8201-A-J101 study 
and a Phase 2 study (DS8201-A-U201) in subjects with HER2-positive, unresectable and/or 
metastatic breast cancer.  The dose of 5.4 mg/kg has shown robust efficacy with confirmed ORR 
of 60.9% (111/184; 95% CI: 53.4 to 68.0).  From a safety perspective, a numeric trend for better 
safety profile was seen at the 5.4 mg/kg dose compared to higher doses (≥ 6.4 mg/kg) in subjects 
with breast cancer.  The trastuzumab deruxtecan dose of 5.4 mg/kg is currently being evaluated 
in the ongoing Phase 3 studies in subjects with metastatic breast cancer and also in subjects with 
HER2 expressing NSCLC in the ongoing Study DS8201-A-U204. 
From the PK perspective, the systemic exposures parameters (Cmax, AUC0-21d [AUC over 
21 days of dosing cycle] and Ctrough in Cycle 1) of intact trastuzumab deruxtecan and 
MAAA-1181a were comparable across subjects with metastatic breast cancer and 
HER2-expressing or -mutated NSCLC at the 6.4 mg/kg dose.  Based on the exposure-response 
(ER) analyses for efficacy, the mean (90% CI) probability of ORR in subjects with metastatic 
breast cancer was predicted to be 63% (55%- 70%) and 68% (58% - 77%) for the 5.4 mg/kg and 
6.4 mg/kg dose groups, respectively.  Hence, the ER analyses support clinically meaningful 
efficacy for trastuzumab deruxtecan at both the 5.4 mg/kg and 6.4 mg/kg doses and a small 
improvement in ORR at 6.4 mg/kg compared to the 5.4 mg/kg dose level in subjects with 
metastatic breast cancer.   
The ER analyses for safety estimated a numerically higher incidence (approximately 1% to 7%) 
of the safety endpoints (AE related discontinuation, dose reduction or drug interruption), AEs 
≥ Grade 3, SAE, anaemia, neutropenia or thrombocytopenia and ILD (any grade and ≥ Grade 3), 
and decreased LVEF (≥ Grade 2) at 6.4 mg/kg dose compared to 5.4 mg/kg dose.  The details of 
these analyses were provided in a separate report (DS8201-PMx003), submitted to the Agency 
under BLA 761139 (SN. 0002) for the breast cancer indication.  Overall, these ER results for 
efficacy and safety indicate that while both 5.4 and 6.4 mg/kg doses showed a positive 
benefit-risk profile, the 6.4 mg/kg dose showed a numerical trend for an increase in the ORR as 
well as a numerical increase in the incidence of AEs compared to the 5.4 mg/kg dose.  These 
findings along with the observed efficacy and safety data in subjects with NSCLC in the Studies, 
DS8201-A-J101 and DS8201-A-U204 support the selection of 6.4 and 5.4 mg/kg doses in 
subjects with HER2-mutated NSCLC in the current study.   
Based on the efficacy, tolerability and PK profile of trastuzumab deruxtecan, the doses of 
5.4 mg/kg and 6.4 mg/kg were selected for evaluation in the Study DS8201-A-U206 to more 
fully characterize the benefit-risk profile in subjects with HER2-mutated NSCLC.   


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5. 
STUDY POPULATION 
Adult subjects with HER2-mutated metastatic NSCLC.   
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for randomization into the study: 
1. Must have provided informed consent for study participation (see Section 10.1.2) 
before performance of any study-specific procedure or test. 
2. Men or women ≥18 years old. (Please follow local regulatory requirements if the 
legal age of consent for study participation is >18 years old).   
3. Pathologically documented metastatic NSCLC with a known activating HER2 
mutation (please refer to the list of HER2 mutations, Table 10.2). The HER2 mutation 
must be documented from an archival or fresh tumor tissue sample analyzed by 
Clinical Laboratory Improvement Amendments (CLIA) certified laboratory or 
equivalent laboratory performing testing to Good Laboratory Practice (GLP) 
standard.   
Note: HER2 mutation documented only from a liquid biopsy sample cannot be used 
for enrollment. 
4. Subjects who had previous treatment including platinum therapy in the 
metastatic/locally advanced setting and not amenable to curative surgery or radiation.  
The subject must have progressed during or after the last treatment regimen or 
discontinued because of unacceptable toxicity. 
5. Presence of at least 1 measurable lesion confirmed by BICR based on RECIST 
version 1.1. 
6. Is willing and able to provide an adequate archival tumor tissue sample. A fresh 
biopsy is required if an archival tumor tissue sample cannot be supplied.  Resection 
and core needle biopsy are acceptable.  Other tissue samples, eg, fine needle aspirates 
or cell block are not acceptable.  For detailed instruction on tissue submission, please 
refer to the laboratory manual.   
7. Has ECOG PS of 0 to 1. 
8. Has LVEF ≥ 50% within 28 days before randomization. 
9. Has adequate organ function within 14 days before randomization, defined as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count  
 100 000/mm3 (Platelet transfusion is not allowed within 1 
week prior to screening assessment) 
Hemoglobin  
≥ 9.0 g/dL (Red blood cell transfusion is not allowed within 1 
week prior to screening assessment) 
Absolute neutrophil count (ANC) 
 
 1500/mm3  


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Parameter 
Laboratory value 
 
 
(granulocyte-colony stimulating factor [G-CSF] 
administration is not allowed within 1 week prior to screening 
assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥ 30 mL/min as calculated using the 
Cockcroft-Gault equation*  
Adequate hepatic function 
Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) 
 ≤ 5  ULN 
Total bilirubin 
≤ 1.5 x ULN if no liver metastases or < 3 x ULN in the 
presence of documented Gilbert’s Syndrome (unconjugated 
hyperbilirubinemia) or liver metastases at baseline. 
 
 
Serum Albumin 
≥ 2.5 g/dL  
Adequate blood clotting function 
International normalized ratio 
(INR) / activated partial 
thromboplastin time (aPTT) 
≤ 1.5 × ULN 
*Cockcroft-Gault equation:  
CLcr (mL/min) =  
[140 - age (years)] × weight (kg)
72 × serum creatinine (mg/dL)   {× 0.85 for females} 
10. Has adequate treatment washout period before randomization, defined as: 
Treatment 
Washout Period 
Major surgery 
≥ 4 weeks 
Radiation therapy including palliative 
stereotactic radiation to chest 
≥ 4 weeks  
Palliative stereotactic radiation therapy to 
other anatomic areas 
≥ 2 weeks 
Anticancer chemotherapy (Immunotherapy 
[non-antibody-based therapy]), retinoid 
therapy 
≥ 3 weeks  
Targeted agents and small molecules (eg, 
5-fluorouracil-based agents, paclitaxel) 
≥ 2 weeks or 5 half-lives, whichever is longer 
Nitrosureas or mitomycin C 
≥ 6 weeks 
Tyrosine kinase inhibitors (TKIs) approved 
for the treatment of non-small cell lung 
cancer (NSCLC) - baseline computerized 
tomography (CT) scan must be completed 
after discontinuation of TKI 
≥ 1 week 
 Antibody-based anticancer therapy 
≥ 4 weeks 
Chloroquine/Hydroxychloroquine 
>14 days 


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Treatment 
Washout Period 
Cell-free and concentrated ascites reinfusion 
therapy peritoneal shunt or drainage of 
pleural effusion, ascites, or pericardial 
effusion 
≥ 2 weeks prior to screening assessment 
11. Male and 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 months for females and for 4 months for 
males after the last dose of study drug. Methods considered as highly effective 
methods of contraception are listed below.  
 Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
o Progestogen-only hormonal contraception associated with inhibition of 
ovulation: 
o Oral 
o Injectable 
o 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 months for females and 4 months for males after 
the last dose of study drug. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods) is not an acceptable 
method of contraception. 
Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 
months of spontaneous amenorrhea (in questionable cases, a blood sample with 
simultaneous follicle-stimulating hormone [FSH] > 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 
one 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 
randomization. For most forms of HRT, at least 2-4 weeks will elapse between 
the cessation of therapy and the blood draw; this interval depends on the type and 


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dosage of HRT. Following confirmation of their postmenopausal status, they can 
resume use of HRT during the study without use of a contraceptive method. 
12. Male subjects must not freeze or donate sperm starting at randomization and 
throughout the study period, and at least 4 months after the final study drug 
administration. Preservation of sperm should be considered prior to 
randomization in this study. 
13. Female subjects must not donate, or retrieve for their own use, ova from the time 
of randomization and throughout the study treatment period, and for at least 7 
months after the final study drug administration.  Female subjects must refrain 
from breastfeeding throughout this time.  Preservation of ova may be considered 
prior to randomization in this study.  
14. Life expectancy of 3 months or more. 
5.2. 
Exclusion Criteria 
1. Has a known driver mutation in the EGFR, BRAF, or MET exon 14 gene or a known 
ALK, ROS1, RET, or NTRK fusion. 
2. Medical history of myocardial infarction within 6 months before randomization, 
symptomatic congestive heart failure (CHF) (New York Heart Association Class II to 
IV).  Subjects with troponin levels above ULN at screening (as defined by the 
manufacturer), and without any MI related symptoms should have a cardiologic 
consultation before randomization to rule out MI. 
3. Has a corrected QT interval (QTcF) prolongation > 470 msec (females) or >450 msec 
(males) based on average of the triplicate12-lead ECG at screening. 
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening. 
5. Has spinal cord compression or clinically active CNS metastases, defined as untreated 
and 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 brain radiotherapy and study 
randomization. 
6. Has multiple primary malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors 
curatively treated. 
7. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
8. Has a history of severe hypersensitivity reactions to other monoclonal antibodies.  


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9. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals. 
10. Has substance abuse or any other medical conditions such as clinically significant cardiac 
or psychological conditions, that may, in the opinion of the investigator, interfere with the 
subject’s participation in the clinical study or evaluation of the clinical study results.  
11. Known human immunodeficiency virus (HIV) infection.  Subjects should be tested for 
HIV prior to randomization if required by local regulations or institutional review board 
(IRB)/independent ethics committee (IEC). 
12. Known active clinically relevant liver disease (eg, active hepatitis B, or active hepatitis 
C), such as those with serologic evidence of viral infection within 28 days of Cycle 1, 
Day 1.  Subjects with past or resolved hepatitis B virus (HBV) infection are eligible, if 
negative for hepatitis B surface antigen (HBsAg[-]) and positive for hepatitis B core 
antibody (anti-HBc[+]).  Subjects positive for hepatitis C (HCV) antibody are eligible 
only if the polymerase chain reaction is negative for HCV RNA.   
13. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to Grade ≤ 1 or baseline.  Note: Subjects may be enrolled with 
chronic Grade 2 toxicities (defined as no worsening to > Grade 2 for at least 3 months 
prior to randomization and managed with standard of care treatment) which the 
investigator deems related to previous anticancer therapy, such as:  
a. Chemotherapy-induced neuropathy 
b. Fatigue 
c. Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies 
which may include: 
 Hypothyroidism/ hyperthyroidism 
 Type I diabetes 
 Hyperglycemia 
 Adrenal insufficiency 
 Adrenalitis 
 Skin hypopigmentation (vitiligo) 
14. Is pregnant, breastfeeding, or planning to become pregnant. 
15. Otherwise considered inappropriate for the study by the investigator. 
16. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any 
underlying pulmonary disorder (eg. pulmonary emboli within three months of the study 
randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion 
etc.). 
17. Any autoimmune, connective tissue or inflammatory disorders (eg, Rheumatoid arthritis, 
Sjӧgren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary 
involvement at the time of screening. Full details of the disorder should be recorded in 
the eCRF for patients who are included in the study.  


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18. Prior complete pneumonectomy. 
19. Had prior treatment with any agent, including an ADC, containing a chemotherapeutic 
agent targeting topoisomerase I. 
5.3. 
Screening Failures, Re-screening, and Subject Replacement 
For subjects who do not meet the criteria for participation in the study, the reason for screening 
failure must be recorded in the Screening Log. 
Subjects who have dropped out will not be replaced. 
Re-screening is permitted one time for any subject who failed to meet reversible or transient 
eligibility criteria upon initial screening. The screening period for subjects who are re-screened is 
28 d.  The subject identification number must remain the same at the time of re-screening. 


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6. 
STUDY TREATMENT(S) 
See Table 1.1 for treatment sequence. 
6.1. 
Study Drug(s) Description 
Table 6.1 describes the formulation, dose, regimen, duration, packaging, and labeling of 
trastuzumab deruxtecan for the 2 study arms: 5.4 mg/kg and 6.4 mg/kg. 
Table 6.1: 
Study Drug Dosing Information 
Study Drug Name 
Trastuzumab Deruxtecan 
Dosage Formulation 
Trastuzumab deruxtecan for injection 100 mg will be provided as a 
sterile lyophilized powder containing 100 mg of Trastuzumab 
deruxtecan in a glass vial (Lyo-DP). Each glass vial should be 
reconstituted with 5 mL water for injection to a concentration of 20 
mg/mL (ie, 100 mg/5 mL).  
Dosage Level(s) 
5.4 mg/kg 
6.4 mg/kg 
Route of Administration 
Trastuzumab deruxtecan will be administered with 5% dextrose as an IV 
infusion.   
Dosing [Instructions/Regimen] 
Each vial is designed for single use only and is not to be used to treat 
more than one subject.  Refer to Pharmacy Instructions. 
Duration 
The study drug will be administered as an IV infusion over 90 min (± 10 
min) Q3W ± 2 days.   
Packaging 
Trastuzumab deruxtecan for injection 100 mg will be labeled in 
compliance with regulatory requirements and packaged. 
Labeling 
The packaging will clearly display the name of the study drug, the lot 
number, storage condition, and other required information in accordance 
with local regulations. 
min = minutes; PO = oral 
Trastuzumab deruxtecan will be supplied to the clinical site by Daiichi Sankyo Inc. (DSI), unless 
this is prohibited by country or institutional regulations. 
Refer to Table 6.1 above for description on administration. 
6.2. 
Preparation, Handling, Storage, and Accountability for Study 
Drug(s) 
Preparation, Handling, and Disposal 
The study drug for IV infusion is prepared by dilution of the required volume of the study drug 
calculated based on the subject’s body weight, by the study site pharmacist.  Prepared study drug 
solutions should be used as directed in 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. 
The preparation of study drug will be conducted in accordance with the Pharmacy Manual 
provided by the Sponsor.   


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Administration 
The study drug will be administered as an IV infusion 90 min (± 10 min) Q3W ± 2 d.  If there is 
no infusion-related reaction (IRR), after the initial dose, the subsequent doses of trastuzumab 
deruxtecan will be infused over 30 ± 10 min.  The subject’s weight (at screening or Cycle 1 Day 
1 before infusion) will be used to calculate the initial dose.  If a subject experiences IRR, follow 
management guidelines for adverse events in Table 6.6 of this document. 
If during the course of treatment, the subject’s weight changes by ≥10% of the baseline weight, 
the subject’s dose will be recalculated based on the subject’s updated weight.  Refer to the 
pharmacy instructions for detailed information about administration of study drug. 
Storage 
Trastuzumab deruxtecan must be stored in a secure, limited access storage area under the storage 
conditions listed below: 
 Stored at 2°C to 8°C (protected from light) for lyophilized powder  
If storage conditions are not maintained per specified requirements, the Sponsor or CRO should 
be contacted. 
See pharmacy instructions for storage conditions of the infusion solution. 
Drug Accountability 
When a drug shipment is received, the investigator or designee will check the amount and 
condition of the drug, drug expiration date, and acknowledge receipt in interactive response 
technology (IRT).  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 drug (trastuzumab deruxtecan).  The 
record must be kept current and should contain the following: 
 Dates and quantities of drug received,  
 Subject Identification (SID) and/or initials or supply number (as applicable),  
 The date and quantity of study drug dispensed and remaining (if from individual 
subject drug units),  
 The initials or seal of the dispenser.  
At the end of the study, as per local laws and/or directed by the Sponsor, all unused study drug 
will be returned or destroyed as per local laws or site policy and only after the study monitor has 
completed a final inventory.  As applicable, the study site must file a copy of the appropriate 
institution policy within their investigator site file and provide a copy to the Sponsor.  See 
pharmacy instructions for details.  
At the end of the study, a final study drug reconciliation statement must be completed by the 
investigator or designee and provided to the Sponsor.  Unused drug supplies may be destroyed 
by the investigator when approved in writing by the Sponsor and the Sponsor has received copies 


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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 drug. 
All study drug forms must be made available for inspection by the Sponsor’s authorized 
representative or designee and regulatory agency inspectors. 
6.3. 
Measure to Minimize Bias: Randomization and Blinding 
Method of Treatment Allocation 
Once all screening procedures have been completed and study eligibility has been confirmed, 
subjects will be enrolled in the study and centrally randomized in a 2:1 ratio to receive 
trastuzumab deruxtecan 5.4 mg/kg or 6.4 mg/kg, respectively.  Randomization will be stratified 
by subjects who (i) received prior anti-PD-1 and/or anti-PD-L1 treatment and (ii) those who 
received neither.  The randomization schedule will be developed by a third-party vendor. 
After randomization, the first dose of study treatment should occur as soon as possible and no 
more than 7 days after the randomization date. 
Blinding 
The treatment assignment will remain blinded to study subjects, Investigators, study site 
personnel (except the unblinded pharmacist and other unblinded staff members as deemed 
necessary for site operations to maintain the blind), central imaging readers and the ILD 
Adjudication Committee.  The Sponsor and the CRO are not blinded to the treatment assignment 
of subjects.  
The randomization schedule will be kept securely. 
6.4. 
Treatment Compliance 
Trastuzumab deruxtecan will be administered IV only to subjects participating in the study and 
under the supervision of clinical study personnel at the study site.  Therefore, treatment 
compliance will be guaranteed as long as the subject attends each visit for administration of the 
study treatment.  Start and stop date/time of injection, amount of drug administered, and reason 
for change or interruption (if applicable) must be recorded in the medical record by clinical study 
personnel.  These data will be recorded in the electronic case report form (eCRF). 
6.5. 
Guidelines for Dose Modification 
The investigator will evaluate which toxicities are attributed to the study drug and adjust the dose 
of the drug as recommended below for study drug.  All dose modifications should be based on 
the worst preceding toxicity (Common Terminology Criteria for Adverse Events [CTCAE] 
version 5.0).  Specific criteria for interruption, re-initiation, dose reduction and/or 
discontinuation of trastuzumab deruxtecan are listed in table below, which is 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.   
If there is no toxicity, dose and schedule should be maintained.   


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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.  
More than 2 dose reductions are not allowed and the subject will be withdrawn from the study 
treatment if further toxicity meeting the requirement for dose reduction occurs.  The adjustments 
for reduced dosing of trastuzumab deruxtecan depending on the initial starting dose are shown in 
Table 6.2. 
Table 6.2: 
Sample Dose Reduction Levels of Trastuzumab Deruxtecan 
Starting Dose 
Dose Level -1 
Dose Level -2 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
Every effort should be made to limit study drug delay, however, in circumstances of adverse 
event management or medical intervention, the study drug can be held up to 18 weeks (126 days) 
from the last trastuzumab deruxtecan dose. During this time, scheduled CT/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 drug is being held. 
 At minimum 1 restaging scan must be done within 6 weeks prior to restarting the 
study drug. 
 Investigational product is restarted within the guidance of the Toxicity Management 
Guidelines for trastuzumab deruxtecan. 
 No prohibited concomitant medications have been administered since the last dose of 
trastuzumab deruxtecan.   
If a subject is assessed as requiring a dose delay of longer than 126 days, the subject will be 
withdrawn from the study. 
Treatment cycles for a subject for whom trastuzumab deruxtecan dosing is temporarily withheld 
for any reason may have future cycles scheduled based on the date of the last trastuzumab 
deruxtecan dose.  All confirmed or suspected severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection events must be recorded in the eCRF.  Please refer to Section 10.6 for 
additional information on dose modification.   
Investigators may consider dose reductions or discontinuations of the study drug according to the 
subject’s condition and after discussion with the Sponsor Medical Monitor. 
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) 
should be performed at intervals no greater than 7 days until AE is determined to be resolving or 
subject is discontinued at EOT. 
Prophylactic or supportive treatment for expected toxicities, including management of study 
drug-induced AEs will be as per treating physician discretion and institutional guidelines. 


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6.5.1. 
Dose Modifications 
6.5.1.1. 
Cardiac Toxicities 
Table 6.3: 
Management Guidelines for Cardiac Toxicities 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Cardiac Toxicities  
Symptomatic CHF 
Discontinue subject from study drug 
Decrease in LVEF 10 to 20% (absolute 
value), but LVEF > 45% 
Continue treatment with study drug 
LVEF 40% to ≤ 45% and decrease is < 
10% (absolute value) from baseline 
Continue treatment with study drug 
Repeat LVEF assessment within 3 weeks 
LVEF 40% to ≤ 45% and decrease is 
10-20% (absolute value) from baseline 
Interrupt study drug dosing 
Repeat LVEF assessment within 3 weeks 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue subject from study drug 
If LVEF recovers to within 10% from baseline, resume treatment 
with study drug 
LVEF < 40% or > 20% (absolute value) 
drop from baseline 
Interrupt study drug dosing 
Repeat LVEF assessment within 3 weeks. 
If LVEF < 40% or > 20% drop from baseline is confirmed, 
discontinue subject from study drug 
ECG 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 study drug, reduce by one 
dose level 
Grade 4 (Torsade de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Discontinue subject from study drug 
AMI = acute myocardial infarction; CHF = congestive heart failure; CTCAE = Common Terminology Criteria for 
Adverse Events; ECG = electrocardiogram; LVEF = left ventricular ejection fraction; NCI = National Cancer 
Institute; QTc = corrected QT interval; ULN = upper limit of normal 


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6.5.1.2. 
Hematologic Toxicity 
Table 6.4: 
Management Guidelines for Hematologic Toxicities 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3  
 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
 
Delay dose until resolved to ≤ Grade 2,  
Reduce by one dose level 
Febrile Neutropenia (absolute 
neutrophil count < 1 × 109/L, 
fever > 38.3°C or a sustained 
temperature of ≥ 38°C for more 
than one h) 
Delay dose until resolved,  
Reduce by one dose level 
Lymphocyte Count Decreased 
Grade 1 to Grade 3 
lymphopenia 
No dose modification 
Grade 4  
(< 0.2 × 109/L) 
Delay dose until resolved to ≤ Grade 2: 
If resolved in ≤ 14 d from day of onset, maintain dose 
If resolved in > 14 d from day of onset, reduce dose one level 
Anaemia 
Grade 3 (Hemoglobin 
<8.0 g/dL); transfusion 
indicated 
Transfuse.  Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 (Hemoglobin 
<8.0 g/dL) Life-threatening 
consequences; urgent 
intervention indicated 
Transfuse.  Delay dose until resolved to ≤ Grade 2, then reduce dose one level 
Platelet Count Decreased 
Grade 3 
(<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 one level 
Grade 4  
(< 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1, then reduce dose one level 
CTCAE = Common Terminology Criteria for Adverse Events 
6.5.1.3. 
Non-Hematologic/non-cardiac Toxicity 
6.5.1.3.1. Hepatic Toxicity 
Dose and schedule modifications for hepatic toxicities in subjects with normal hepatic function 
and mild/moderate hepatic impairment at baseline (ie, the last measurement prior to study drug 
administration on Cycle 1 Day 1) should be followed as outlined in Table 6.5. 


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Table 6.5: 
Management Guidelines for Hepatic Toxicities 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Aspartate aminotransferase (AST) or Alanine aminotransferase (ALT) with Simultaneous Total Bilirubin 
(TBL) 
AST/ALT ≥3.0 × ULN with 
simultaneous TBL ≥2.0 × ULN 
Delay study medication until drug-induced liver injury (DILI) can be ruled 
out.  
If DILI is ruled out, the subject should be treated accordingly, and resumption 
of study drug may occur after discussion between the Investigator and 
Sponsor.  
If DILI cannot be ruled out from diagnostic workup, permanently discontinue 
study treatment. 
Monitor AST/ALT and TBL twice weekly until resolution or return to 
baseline. 
AST or ALT 
Grade 2 (>3.0 - 5.0 × ULN if 
baseline was normal; >3.0 - 5.0 
× baseline if baseline was 
abnormal) 
No action for Grade 2 AST/ALT  
Grade 3 (>5.0 - 20.0 × ULN if 
baseline was normal; >5.0 - 
20.0 x 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 x 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 - 20.0 × ULN if 
baseline was normal; >8.0 - 
20.0 x 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 (>20.0 x ULN if 
baseline was normal; >20.0 × 
baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Total Bilirubin 
Grade 2 (>1.5 - 3.0 × ULN if 
baseline was normal; >1.5 - 3.0 
× baseline if baseline was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at baseline delay 
dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose 1 level 
 
If documented Gilbert’s syndrome or liver metastases at baseline, continue 
study treatment 


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CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Grade 3 (>3.0 - 10.0 × ULN if 
baseline was normal; >3.0 - 
10.0 × baseline if baseline was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at baseline, repeat 
testing within 3 d.  Delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, reduce dose 1 level 
If resolved in > 7 d from day of onset, discontinue trastuzumab deruxtecan  
 
If documented Gilbert’s syndrome or liver metastases at baseline, repeat 
testing within 3 d.  Delay dose until resolved to < Grade 2: 
If resolved in ≤ 7 d from day of onset, reduce dose 1 level 
If resolved in > 7 d from day of onset, discontinue trastuzumab deruxtecan 
Grade 4 (>10.0 × ULN if 
baseline was normal; >10.0 × 
baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Blood Alkaline Phosphatase Increased 
Grade 3 (>5.0 - 20.0 × ULN if 
baseline was normal; >5.0 - 
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. 
CTCAE = Common Terminology Criteria for Adverse Events; d = days; SAE = serious adverse event; ULN = upper 
limit of normal 


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6.5.1.4. 
Other Non-Hematologic/Cardiac Toxicity 
Table 6.6: 
Management Guidelines for Other Non-Hematologic Toxicity 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
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 study drug 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 restarted 
at a 50% reduced infusion rate. 
Subsequent administrations should be conducted at the reduced rate. 
Grade 3 or 4 (Prolonged or life-
threatening consequences, urgent 
intervention indicated) 
Administration of study drug should be discontinued immediately and 
permanently. 
Urgent intervention indicated.  Antihistamines, steroids, epinephrine, 
bronchodilators, vasopressors, IV fluid therapy, oxygen inhalation 
etc., should be administered. 
Pulmonary Toxicity 
 
 
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, 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 AEs” in the dose modification section of the 
study protocol.  
If the AE is suspected to be ILD/pneumonitis, treatment with study 
drug should be interrupted pending further evaluation.  
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 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, C-reactive protein 
• 
One blood sample collection for PK   
 
analyses as soon as ILD/pneumonitis is suspected, if feasible.   


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CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Other tests could be considered, as needed (eg, COVID-19 test). 
If the AE is confirmed to be ILD/pneumonitis, follow the 
ILD/pneumonitis management guidance as outlined below. 
All events of ILD/pneumonitis regardless of severity or seriousness 
will be followed until resolution including after drug discontinuation.  
Grade 1 
The administration of trastuzumab deruxtecan must be interrupted for 
any ILD/pneumonitis events regardless of grade.  
• 
Monitor and closely follow-up in 2 to 7 d 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 days from day of onset, maintain dose 
• 
If resolved in > 28 days from day of onset, reduce dose 1 level 
However, if the event grade 1 ILD/pneumonitis has not resolved 
within 18 weeks (126 days) from the last infusion, the study drug 
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 
1mg/kg/day prednisone or equivalent) for at least 14 d then 
followed by a gradual taper over at least 4 weeks. 
• 
Monitor symptoms closely. 
• 
Re-image as clinically indicated. 
• 
If worsening or no improvement in clinical or diagnostic 
observations in 5 days,  
Consider increasing dose of steroids (eg, 2 mg/kg/day prednisone or 
equivalent) and administration may be switched to intravenous (IV) 
(eg, methylprednisolone). 
Re-consider additional workup for alternative etiologies as described 
above. 
Escalate care as clinically indicated. 


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CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Grades 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 d), followed by at least 
1.0 mg/kg/day of prednisone (or equivalent) for at least 14 d 
followed by a gradual taper over at least 4 weeks  
• 
Re-image as clinically indicated. 
• 
If still no improvement within 3 to 5 d, re-consider additional 
workup 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 
one level 
Grade 4 (> 6.0 × ULN) 
Discontinue subject from study drug 
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 one level 
Diarrhoea/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 one level 
Grade 4 
Discontinue subject from study drug 
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 
AEs = adverse events; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
d = days; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; SAE = serious adverse event; 
ULN = upper limit of normal 


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In addition, Investigators may consider dose reductions or discontinuations of the study drug 
according to the subject’s condition and after discussion with the study Medical Monitor or 
designee. 
6.6. 
Prior and Concomitant Medications 
Medications used from the time the subject signs the ICF for study participation to the 40-D FUP 
(+7 d) visit after the last administration of trastuzumab deruxtecan will be recorded.  
Prophylactic treatment for the study treatment and all concomitant medications will be recorded 
in the eCRF.  
All therapies received by subjects within 28 days prior to randomization will be recorded.  
Concomitant therapies include all prescription, over-the-counter, and herbal remedies. 
Prohibited Therapies/Products 
The following medications and products will be prohibited during the treatment period.  The 
Sponsor must be notified if a subject receives any of these during the study. 
1. 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). 
2. Other investigational therapeutic agents. 
3. 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).  
4. Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing AEs (topical steroids, inhaled 
steroids, physiologic dose of steroids to prevent or treat adrenal insufficiency, 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.  
5. Radiotherapy to the thorax. 
6. Chloroquine or hydroxychloroquine  
 If treatment with chloroquine or hydroxychloroquine is required, trastuzumab 
deruxtecan must be interrupted and a washout period of >14 days is required 
before restarting trastuzumab deruxtecan. 
7. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines 
are not considered attenuated live vaccines) within 30 days prior to the first exposure to 
study intervention. Note: Participants, if enrolled, should not receive live vaccine during 
the study and up to 30 days after the last dose of study intervention. 


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Permitted products: 
1. Hematopoietic growth factor may be used for prophylaxis or treatment based on the 
clinical judgment of the investigator. 
2. Concomitant use of dietary supplements, medications not prescribed by the Investigator, 
and alternative/complementary treatments is discouraged, but not prohibited. 
3. Prophylactic or supportive treatment of study drug-induced AE will be otherwise 
permitted as per investigator’s discretion and the institutional guidelines. 
4. Trastuzumab deruxtecan is emetogenic, which includes delayed nausea and/or vomiting. 
Prior to each dose of trastuzumab deruxtecan, 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. 
Restricted products 
1. Use of tobacco products, e-cigarettes and vaping is strongly discouraged but not 
prohibited.   


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7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION 
FROM THE STUDY 
7.1. 
Discontinuation of Study Drug 
The primary reason for the permanent discontinuation of trastuzumab deruxtecan treatment 
administration must be recorded.  Reasons for treatment discontinuation include: 
 Death 
 Adverse Event 
 Progressive Disease 
 Clinical Progression 
 Withdrawal by Subject (to discontinue study drug) NOTE: in this section this is 
only withdrawal for treatment with study drug and is NOT the same thing as a 
complete withdrawal from the study.  Discuss with the subject that they will remain 
in the study (ie, continue with study visits and assessments, including survival 
follow-up). 
 Physician Decision 
 Lost to Follow-up (see Section 7.3 for details on when a subject is considered Lost to 
Follow-up) 
 Pregnancy 
 Protocol Deviation 
 Study Termination by Sponsor 
 Other 
If there is evidence the subject is receiving benefit from treatment even though the subject has 
met criterion for discontinuation, the subject may remain on study treatment after discussion with 
approval from the Sponsor Medical Monitor or designee. 
After study drug is permanently discontinued for any reason other than death or lost to 
follow-up, the subject will be treated as clinically indicated by the Investigator or referring 
physician. 
The Investigator must discuss with the subject that their decision to permanently discontinue the 
study drug means the subject still agrees to continue into the Follow-up Period for onsite or 
modified follow-up visits.  Subjects will be followed for disease progression, if applicable, and 
survival at regularly scheduled intervals (see Table 1.1). 
Procedures for Discontinuation from Study Drug 
The subject should be instructed to contact the Investigator or study site staff before or at the 
time study drug is discontinued.   
If a subject is discontinued from the study drug: 


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 The reason(s) for discontinuation and the last dose date should be documented in the 
subject’s medical record and eCRF; 
 Due to an AE, the Investigator will follow the subject until the AE has resolved or 
stabilized; 
 An end of treatment (EOT) evaluation should be performed as described in the SoE 
(Table 1.1); 
 A safety follow-up evaluation should be performed approximately 40 days after the 
last dose of study drug as described in the SoE (Table 1.1)  (If EOT is > 40 days after 
last treatment, then the EOT assessments can also function as the 40-Day Follow-up 
visit); 
 If subject has not discontinued for “Progressive Disease,” continue disease 
progression assessments until progression or start of new therapy, if applicable, and 
survival as described in the SoE (Table 1.1); 
 Long-term follow-up evaluations will be performed to assess survival as described in 
the SoE (Table 1.1). 
The Investigator will complete and report the observations as thoroughly as possible up to the 
date of discontinuation, including the date of last dose.  All procedures and tumor assessments 
specified for the EOT visit will be conducted.  See Table 1.1 for specific EOT procedures. 
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 (may be quarterly, bi-annually, 
annually, or only at EOS) 
 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 from 
alternative sources (eg, doctor’s notes, hospital records) 
Dates of the modified follow-up contact(s) should be recorded.  See Section 7.2 for definition of 
withdrawal by subject from the study (ie, withdrawal of consent). 
7.2. 
Subject Withdrawal/Discontinuation from the Study 
Subjects may discontinue from the study for any of the following reasons: 
 Death 
 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 


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 Lost to Follow-up (see Section 7.3 for details on when a subject is considered Lost to 
Follow-up) 
 Study Termination by Sponsor 
 Other 
If the reason for study discontinuation is the death of the subject, the options for categorizing the 
primary cause of death are PD or AE.  If reason of death is unknown every effort should be made 
to obtain the primary cause of death.  Only one AE will be recognized as the primary cause of 
death. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation (ie, from the interventional portion and follow-up): 
 Attendance at study visits per protocol 
 Study personnel contacting the subject by telephone 
 Study personnel contacting an alternative person 
 Study personnel accessing and reviewing the subject’s medical information from 
alternative sources 
If the subject refuses all of the above methods of follow-up, the 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 will 
document this as a withdrawal of consent (from the interventional portion and follow-up). 
Withdrawal Procedures 
If a subject is withdrawn from both the interventional and follow-up portions of 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 dose, date of last contact, and 
the reason for withdrawal; 
 And disclosure of future information is also withdrawn; the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent; 
 The subject may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records; 
 Study site personnel may use local, regional, and national public records (in 
accordance with local law) to monitor vital status. 
See SoE (Table 1.1) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 
7.3. 
Lost to Follow-up 
Subjects will be considered lost to follow-up if he/she fails to return for 2 consecutive scheduled 
visits and is unable to be contacted by the study site staff.  Before a subject is deemed lost to 
follow-up, the Investigator or designee will make every effort to regain contact with the subject 
(where possible, 3 telephone calls, texts, emails, and if necessary, a certified letter to the 
subject’s last known mailing address or local equivalent methods).  These contact attempts 
should be documented. 


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If direct contact with the subject is not possible the site must make every effort to collect survival 
status from public records (eg, obituaries, death certificates, etc) in accordance with local laws. 


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8. 
STUDY PROCEDURES 
See SoE, Table 1.1 for study procedures during the Screening period, Treatment, EOT, and 
Follow-up study procedures. 
8.1. 
Eligibility Assessment 
Review the subject's demographics, medical and target disease history, vitals, and results of tests 
(eg, physical examination, ECHO/multi-gated acquisition [MUGA], ECG, ECOG PS, 
ophthalmologic assessments, laboratory assessments, CT/MRI of the brain, tumor assessment 
and pulmonary imaging) and compare against the eligibility criteria (Section 5.1 and 
Section 5.2).  See Section 5.3 for information on re-screening.  For screening procedures, see 
SoE, Table 1.1. 
Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive responses 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.  See Section 10.1.2 for additional details. 
Tumor Tissue Specimen 
For the 2 study arms, archival tumor sample or fresh biopsy sample must be obtained.  It is not 
required to perform a pre-treatment biopsy if the subject already has an adequate archived tumor 
tissue sample that is available to be submitted.  Resection and core needle biopsy are acceptable.  
Other tissue samples, eg, fine needle aspirates or cell block are not acceptable.  For detailed 
instruction on tissue submission, please refer to the laboratory manual.   
Assessment of HER2 Mutation Status 
Archival tumor sample and fresh biopsy sample will be analyzed for HER2 mutant status as well 
as exploratory biomarkers. 
General Medical History and Baseline Conditions 
The subject’s medical history will be obtained by the Investigator or a qualified designee and 
will include his/her NSCLC history (eg, prior biomarker history) and smoking history. 
Untoward medical occurrences (including clinically relevant laboratory values that are not 
symptoms of NSCLC vital signs that are out of range) that were diagnosed or known to exist 
prior to the first dose of study medication/consent date will be recorded on the General Medical 
History and Baseline Conditions eCRF, not the Adverse Event eCRF.  Record the start date of 
any medical occurrence that started after the ICF was signed and is ongoing at the time of the 
first dose of trastuzumab deruxtecan on the General Medical History and Baseline Conditions 
eCRF. 


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Demographics 
Review the subject’s demographics against the eligibility criteria. 
Human Immunodeficiency Virus (HIV) Antibody Test 
Perform an HIV antibody test as required by local regulations or independent IRBs/ECs.   
Hepatitis Screening 
Perform hepatitis B and C screening (HBsAg, anti-HBc, anti-hepatitis B surface antigen 
[anti-HBS] and anti-HCV antibody). 
8.2. 
Randomization in a 2:1 Ratio 
After all screening procedures are performed, results of screening tests are available (ie, between 
the Screening visit and the Cycle 1 Day 1 visit), and subjects are confirmed to continue to meet 
all eligibility criteria, eligible subjects will be randomized to receive trastuzumab deruxtecan in 
1 of the 2 following treatment groups: 
 5.4 mg/kg Q3W (N = 100) 
 6.4 mg/kg Q3W (N = 50) 
The subject will be randomized in IRT to one of the dose levels listed above and an unblinded 
pharmacist will prepare the assigned dose.  Randomization will be stratified by subjects who 
(i) received prior anti-PD-1 and/or anti-PD-L1 treatment and (ii) those who received neither. 
If a subject does not meet the eligibility criteria on the scheduled day of randomization, 
Investigators must discuss with the Sponsor (Clinical Leader/Scientist).   
Subjects can receive trastuzumab deruxtecan on the same day as randomization.   
8.3. 
Efficacy Assessments 
8.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is confirmed ORR, defined as the sum of CR and PR rates, 
assessed by BICR based on RECIST version 1.1.  Efficacy assessments will be based on tumor 
assessments to be performed at screening and Q6W until PD or start of new therapy regardless of 
the posttreatment Follow-up period. 
8.3.2. 
Secondary Efficacy Endpoints 
Tumor assessments, based on sites of disease identified at Screening and any additional newly 
suspected sites of PD, will be conducted Q6W (±7 d) from Cycle 1 Day 1, independent of 
treatment cycle.  A CT and/or MRI (spiral CT or MRI with ≤ 5 mm cuts) of chest, abdomen, and 
pelvis should be used for tumor assessment unless another modality of disease assessment is 
necessary for the lesions.  The same assessment modality should be used throughout the study 
for all assessments for each subject unless prior approval is obtained from the Sponsor or its 
designee.  Unscheduled tumor assessments may be performed if progression is suspected.  


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A CT or MRI of the brain is mandatory for all subjects included with baseline stable brain 
metastases.  Subjects without brain metastases do not need additional brain scans for tumor 
assessment unless clinically indicated.   
Bone scan (bone scintigraphy) or 18F-fluorodeoxyglucose (18F-FDG)-positron emission 
tomography (PET)/CT is required at baseline and if bone metastases are present within 28 days 
before Cycle 1 Day 1, and Q12W (±7 d) from Cycle 1 Day 1.  Otherwise, bone imaging is 
required only if new bone metastases are suspected.  Bone imaging is also required at the time of 
confirmation of response for subjects who have bone metastases. 
Other secondary efficacy endpoints are DCR (the sum of CR, PR, and SD rates), PFS, and OS. 
These endpoints will be assessed by the investigator and/or BICR review will be based on 
RECIST version 1.1. (except OS) and include: 
 DoR, defined as time from the initial response (CR or PR) until documented tumor 
progression or death from any cause.  DoR is only defined for subjects who achieved 
confirmed CR or PR.  DCR is defined as the proportion of subjects who achieve CR, 
PR, or SD during study treatment.  
 PFS, defined as the time from date of randomization until first objective radiographic 
tumor progression or death from any cause, based on BICR and investigator 
assessment.  Detailed censoring rules will be provided in statistical analysis plan 
(SAP). 
 ORR, defined above, based on investigator assessment 
 OS, defined as the time from date of randomization until death from any cause (based 
on records in clinical database and public records where it is allowed by law).  
Subjects last known to be alive are censored at the date of last contact.  
Detailed censoring rules for secondary efficacy endpoints will be specified in the SAP. 
8.3.3. 
Exploratory Efficacy Endpoints (ORR and QoL) 
Exploratory efficacy endpoints include: 
 Best percent change from baseline in the sum of the diameters for all target lesions 
based on BICR and investigator assessment  
 Explore symptoms functioning and HRQoL with newly recommended NSCLC-SAQ 
 To explore the impact of treatment and disease state on health utility using the 
EQ-5D-5L 
 To assess patient-reported treatment tolerability 
 To assess the patient’s overall impression of the severity of their cancer symptoms, 
change in condition since starting the study 
 To explore the impact of treatment and disease on health care resource use 


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Radiographic Tumor Assessments 
Radiographic tumor assessments will include all known or suspected disease sites.  Imaging may 
include chest, abdomen and pelvis CT or MRI scans; brain CT or MRI scan at baseline 
(screening) for all subjects.   
The CT scans should be performed with contrast agents unless contraindicated for medical 
reasons, follow the local label/package insert/SMPC or institutional guidelines for allergic 
reactions to contrast agents.  Baseline tumor assessment should be performed within 28 days of 
expected Cycle 1 Day 1 (tumor assessment performed for the assessment of disease progression 
on the prior therapy will be acceptable as baseline if performed within 28 days of Cycle 1 Day 
1). A complete set of the scans is required in this study.  Perform radiographic tumor assessments 
using spiral CT or MRI with ≤5 mm cuts unless another modality of disease assessment is 
necessary for the lesions. 
Antitumor activity will be assessed at baseline (screening), at Q6W (±7 d) from Cycle 1 Day 1 
independent of treatment cycle until documented PD or start of new therapy, or death, or loss to 
follow-up, or withdrawal of consent (Table 1.1). Subjects who discontinue study treatment for 
other reasons than PD will continue to undergo tumor assessments Q6W during the Follow-up 
period until documented PD or start of new therapy.  Imaging timing should follow calendar 
days.  Imaging time points will be projected from Cycle 1 Day 1 date and should not be adjusted 
for delays in cycle starts.  In addition, radiographic tumor assessments will also be conducted 
whenever disease progression is suspected (eg, symptomatic deterioration) and at the time of 
withdrawal from the treatment (if not done in the previous 6 weeks).  Tumor measurements are 
performed as per RECIST version 1.1 criteria (Section 10.4).  See Table 1.1. 
The same imaging technique used to characterize each identified and reported lesion at baseline 
will be employed in the following tumor assessments. 
Bone scan (bone scintigraphy) or 18F-FDG-PET/CT is required within 28 days before Cycle 1 
Day 1 and if bone metastases are present at baseline, Q12W (±7 d) from Cycle 1 Day 1.  
Otherwise bone imaging is required only if new bone metastases are suspected.  Bone imaging is 
also required at the time of confirmation of response for subjects who have bone metastases. 
When tumor assessments at a visit are performed over multiple days, the date of response (CR, 
PR, SD, or not evaluable [NE]) should be recorded as the date of the last radiographic evaluation 
included in the series for that assessment and the date of PD should be recorded as the date of the 
earliest date of the scan which has documented progression if scans span multiple days.  
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions unless increase in size has been observed following completion of radiation 
therapy. 
Assessment of response will be made using RECIST version 1.1. 
Response Assessment 
Assess the subject based upon the local laboratory results using the Response Criteria22 
(Section 10.4). 


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Subsequent Anticancer Treatments 
Subsequent anticancer treatments taken since the EOT and their outcomes must be monitored 
and recorded in the eCRF until the end of the study. 
Disease Progression 
The date of disease progression on subsequent therapies will be recorded in the eCRF regardless 
of subsequent anticancer treatments.  
Survival Follow-up 
All subjects should be followed for survival at least every 3 months from EOT.  Survival 
monitoring will continue until the end of the study.  
8.4. 
Safety Assessments 
Safety endpoints will include: 
 AEs including TEAEs, SAEs and AESIs will be graded according to the CTCAE 
Version 5.0.  
 Physical examination findings (including ECOG PS), vital sign measurements, 
ophthalmologic findings, standard clinical laboratory parameters, ECG parameters, 
and ECHO/MUGA findings.   
8.4.1. 
Adverse Event  
Method to Detect Adverse Events 
The definitions of an AE or SAE can be found in Section 10.5.  Adverse Events may be directly 
observed, reported spontaneously by the subject or by questioning the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally authorized representative) 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.  The Investigator and any qualified designees are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE and 
remain responsible for following AEs that are serious, considered related to the study drug or 
study procedures, or that caused the subject to discontinue trastuzumab deruxtecan. 
All clinical 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 drug discontinuation, lead to dose reduction, require 
corrective treatment, or constitute an AE in the Investigator’s clinical judgment. 
Time Period for Collecting Adverse Events, including Adverse Events of Special Interest 
and Serious Adverse Events 
All SAEs occurring after the subject signs the ICF and up to 40 (+7) days after the last dose of 
study medication (ie, the Follow-up Period), whether observed by the Investigator or reported by 


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the subject, will be recorded on the Adverse Event eCRF.  SAEs with an onset or worsening 
subsequent to the Follow-up Period, if considered related to the study treatment by the 
Investigator, are also TEAEs.  They will also be recorded on the Adverse Event eCRF.  All SAEs 
will be followed until resolution, stabilization, the event is otherwise explained, or the subject is 
lost to follow-up. 
After the 40-day Safety Follow-up Visit, only SAEs considered to be related to study drug by the 
investigators should be reported. 
All non-serious AEs occurring after the subject has taken the first dose of trastuzumab 
deruxtecan until 40 days after the last dose of trastuzumab deruxtecan will be recorded on the 
Adverse Event eCRF. 
Exacerbation of a pre-existing medical condition and symptom after the first dose of trastuzumab 
deruxtecan including increase in severity of the symptom will be recorded as an AE on the 
Adverse Event eCRF, unless it is a condition of NSCLC. 
Reporting Procedure for Investigators 
All AEs (including AESIs and SAEs) will be reported in the Adverse Event eCRF.  All AEs 
(serious and non-serious) must be reported with the Investigator’s assessment of seriousness, 
severity, and causality to trastuzumab deruxtecan. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom 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, report them as individual entries of AE or SAE. 
Disease-Specific AEs and SAEs 
Disease progression/worsening of NSCLC will not be recorded as an AE on the Adverse Event 
eCRF.  However, events associated with disease progression, such as bronchitis, Pneumocystis 
jirovecci pneumonia, may be recorded as AEs. 
Death due to disease progression should be recorded on the Death eCRF. 
8.4.1.1. 
Serious Adverse Events Reporting 
The following types of events should be reported by the Investigator in the electronic data 
capture (EDC) within 24 h of awareness: 
 SAEs  
 All potential ILD/pneumonitis cases should be reported within 24 h; including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD is described 
by the Event Adjudication Site Manual).  
 Hepatic events (both serious and non-serious) which meet the potential Hy’s Law 
criteria defined as an elevated (ALT or AST) ≥ 3 x ULN and an elevated TBL 
≥ 2 x 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. 


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 Overdose, defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important. An “excessive and 
medically important” overdose includes any overdose in which either an SAE, a 
non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject.  
 Overdose is always serious. By definition an overdose is medically important, 
which meets the seriousness criterion of important medical event. An overdose 
can occur with or without an AE. AEs can either be serious or non-serious. 
Details of the overdose including trastuzumab deruxtecan dosage, clinical course, 
associated AEs, and outcome must be captured in the Narrative form of the Case 
Report Form (CRF) within EDC. 
Details summarizing the course of the SAE, including its evaluation, treatment, and outcome 
should be provided.  Specific or estimated dates of AE onset, treatment, and resolution should be 
included.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the SAE report.  For fatal events, the SAE report should 
state whether an autopsy was or will be performed and should 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. 
If using EDC for SAE reporting: Complete the eCRF within 24 h of awareness.  In the event that 
the eCRF is unavailable, report SAEs by faxing or emailing completed SAVER Form to Sponsor 
using the provided fax transmittal form and the appropriate fax number provided for your 
country or email address.  Once EDC becomes available, please enter SAEs reported on the 
SAVER Form into the eCRF as soon as possible.  Please refer to the eCRF Completion Guide for 
additional instructions. 
Call the local SAE Hotline (see Study Site Manual) or your study monitor for any questions on 
SAE reporting. 
See Section 8.4.1 for details on the time period for collecting SAEs. 
Reporting Requirement to Sites and Regulatory Authorities 
Daiichi Sankyo Inc., and/or CRO will inform Investigators and regulatory authorities of any 
suspected unexpected serious adverse reactions (SUSARs) occurring in study sites or other 
studies of trastuzumab deruxtecan, as appropriate per institutional and/or local reporting 
requirements. 
DS and/or CRO will comply with any additional local safety reporting requirements.  The 
Investigator will assess if an AE is to be considered “unexpected” based on the “Reference 
Safety Information” section in the current IB.11  
Follow-up for AEs and SAEs 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible.  This may include additional laboratory tests or 


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investigations, histopathological examinations, or consultation with other health care 
professionals. 
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 updated 
SAE data to the safety database within 24 hours of receipt of the information.  Other follow-up 
information and responses to non-urgent safety queries should be combined for reporting to 
provide the most complete data possible within each follow-up report. 
8.4.1.2. 
Adverse Events of Special Interest (AESIs) 
The AESIs include LV dysfunction and ILD/pneumonitis. Additional relevant information 
regarding the AESIs, ie, LV dysfunction and ILD/pneumonitis regardless of seriousness is to be 
collected through the targeted questionnaires (TQs) within the clinical study database. 
 For broad surveillance of LV dysfunction, relevant AEs under the MedDRA SMQs of 
Cardiac Failure are included for enhanced data collection; additional data for these 
AEs are collected via TQs of heart failure.  
 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.  
Left Ventricular (LV) Dysfunction: 
Clinical Summary: 
LV dysfunction in association with trastuzumab deruxtecan is considered to be an important 
potential risk based on the available pre-clinical data, literature and available safety information 
for drugs of similar class. Refer to the current IB for a summary of preliminary clinical trial data. 
Management Guidance:  
LVEF will be measured by either ECHO or MUGA scan.  All ECHOs/MUGAs will be evaluated 
by the Investigator or delegated physician for monitoring cardiac function. 
Troponin will be measured locally at screening, and as needed based on subject reported cardiac 
signs or symptoms suggesting CHF, myocardial infarction, or other causes of cardiac myocyte 
necrosis.  If ECG is abnormal, follow institutional guidelines. 
ECGs will be performed, and standard ECG parameters will be measured, including RR, PR, QT 
intervals, and QRS duration.  All ECGs must be evaluated by Investigator or delegated physician 
for the presence of abnormalities.  Whether or not measurement is performed, date performed, 
results, and findings for each parameter is to be recorded in the eCRF 
Interstitial Lung Disease/Pneumonitis: 
Clinical Summary:  
ILD/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 Adjudication 
Committee, available data from recent epidemiology/literature, biological plausibility, and safety 


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information from drugs of similar class. Refer to the current IB for a summary of preliminary 
clinical study data. 
ILD/pneumonitis Monitoring: 
Non-symptomatic grade 1 ILD/pneumonitis has been detected in clinical studies of trastuzumab 
deruxtecan in metastatic NSCLC during the regularly scheduled chest CT imaging performed 
Q3W as part of tumor assessment.  
Management Guidance:  
ILD/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 AEs” dose modification section of the study protocol.  
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 should be considered, 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, C-reactive protein), and one blood sample collection for PK 
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.  
All events of ILD/pneumonitis regardless of severity or seriousness will be followed until 
resolution including after drug discontinuation. 
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.  This additional data collection will cover a more in-depth and relevant medical 
history (eg, smoking, radiation, chronic obstructive pulmonary disease, and other chronic lung 
conditions), diagnostic evaluation, treatment, and outcome of the event.  This data collection will 
be based on a set of pre-defined list of PTs eligible for adjudication as described in the Event 
Adjudication Site Manual. 
Combined Elevations of Aminotransferases and Bilirubin 
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law criteria defined 
as an elevated (ALT and/or AST) ≥3 × ULN and an elevated TBL ≥2 × ULN, regardless if it is 
due to disease progression per Investigator assessment, that may occur at different time points 
during the study conduct, should always be reported to the Sponsor.18  These events must be 
reported either by eCRF, with the Investigator’s assessment of seriousness, severity, causality, 


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and a detailed narrative.  These events should be reported within 24 hours of Investigator’s 
awareness of the event regardless of seriousness.  A targeted questionnaire will be available as an 
eCRF to collect relevant additional information for these potential cases. 
If the subject discontinues study drug due to liver enzyme abnormalities, the subject will have 
additional clinical and laboratory evaluations as described in Section 8.4.3 in order to determine 
the nature and severity of the potential liver injury. 
8.4.2. 
Pregnancy 
Sponsor must be notified of any female subject who becomes pregnant while receiving or within 
7 months of discontinuing the trastuzumab deruxtecan.  Similarly, the Sponsor must also be 
notified if a female partner of a male subject becomes pregnant while receiving or within 4 
months of discontinuing trastuzumab deruxtecan. 
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 
within 24 h 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 or 
partner of a male 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.  The 
Investigator should make every effort to follow the female subject or partner of a male subject 
(upon obtaining written consent from partner) until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  Any adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, post-partum complications, spontaneous 
or induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted 
fetus), the Investigator should follow the procedures for reporting SAEs. 
Infants born to female subjects or partners of male subjects who were exposed to trastuzumab 
deruxtecan should have follow-up safety information collected 40 (+7) days after the birth for 
immediate safety follow-up, focusing especially on any presumable congenital birth defect. 
Any presumable congenital birth defects, regardless of the time of the diagnosis, should also be 
reported to the Sponsor. 
Pregnancy Test 
For women of childbearing potential (as defined in Section 5.1), document the results of a 
negative serum or urine pregnancy test.  A positive urine pregnancy test must immediately be 
confirmed using a serum test.  Repeat pregnancy test (urine or serum per institutional guidelines) 
must be performed 72 h before infusion at each cycle and at EOT visit (see SoE, Table 1.1). 
8.4.3. 
Clinical Laboratory Evaluations 
The clinical laboratory tests including hematology, blood chemistry, and pregnancy will be 
performed as per the SoE by the local laboratory (Table 1.1).  Coagulation testing and urinalysis 


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will be performed at screening only.  Refer to Section 10.2 for the complete list of laboratory 
parameters. 
All laboratory values must be appraised by the investigator as to clinical significance and used to 
take appropriate clinical management measures. All abnormal laboratory values considered 
clinically significant by the investigator should be recorded on the AE page of the eCRF.  If the 
abnormal laboratory value constitutes an SAE, the SAE should be reported in the CRF and other 
relevant procedures must be followed (See Section 8.4.1.1). 
Abnormal laboratory values (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 relevant.  New or worsened clinically relevant abnormalities should be recorded as 
AEs on the Adverse Event eCRF. 
8.4.4. 
Other Safety 
Physical Examinations 
Physical examinations should be performed as per the SoE (Table 1.1).  A complete physical 
examination should include a weight measurement and an evaluation of the head, eyes, ears, 
nose, and throat and the cardiovascular, dermatological, musculoskeletal, respiratory, 
gastrointestinal, genitourinary, and neurological systems.  Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.  At 
subsequent visits (or as clinically indicated), limited, symptom-directed physical examinations 
should be performed.  Changes from baseline abnormalities should be collected in the subject’s 
study record.  New or worsened clinically relevant abnormalities should be recorded as AEs on 
the Adverse Event eCRF. 
Vital Signs 
Vital signs will be measured and recorded as per the SoE (Table 1.1).  They include the 
measurements of respiratory rate, heart rate, systolic and diastolic blood pressures, temperature, 
pulse oximetry, SpO2, height (obtained once, prior to dosing) and body weight.  Blood pressure 
and pulse rate will be measured after the subject has rested for 5 minutes or more and prior to 
laboratory draws, if both are done sequentially.  The same procedure for measuring the subject’s 
blood pressure and pulse rate should be used throughout the study. 
Electrocardiograms 
Twelve lead-ECGs will be performed and recorded for every subject (SoE, Table 1.1). The ECG 
will be measured after the subject has rested in a supine/recumbent position for 5 minutes or 
more.  The baseline ECG must be performed within 14 days prior to randomization.  Triplicate 
ECGs are required at screening or if an abnormality is detected.  The three individual ECG 
tracings should be obtained as closely as possible in succession, approximately 3 minutes apart.  
ECGs should be performed before PK blood draws.  At any visit during which a subject exhibits 
a heart rate ≤50 bpm or other clinical indications for ECG, the ECG will be repeated.  Abnormal, 
clinically relevant findings occurring postbaseline will be reported as AEs.  Regardless of 
whether the measurement is performed, the date on which the standard ECG parameters were 


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scheduled to be measured (including RR, PR, QT intervals, and QRS duration and results), will 
be recorded in the eCRF. 
Multi-gated Acquisition Scan or Echocardiogram 
MUGA/ECHO must be performed as per the SoE (Table 1.1) and within 28 days of 
randomization.  Subjects must have LVEF ≥50% to be eligible for the study.  If the planned date 
of study drug administration is delayed after examination of ECHO or MUGA, and there are no 
abnormal findings on the examination, it is up to the Investigator’s judgment as to whether 
ECHO or MUGA need to be repeated. 
ECOG Performance Status 
Assess and record the subject’s ECOG PS (Table 1.1). 
Ophthalmologic Assessments 
The ophthalmologic assessment must be performed as per the SoE (Table 1.1) and must include 
a visual acuity testing, slit lamp examination, and fundoscopy.  If the planned date of study drug 
administration is delayed after examination of ophthalmologic assessments, and there are no 
abnormal findings on the examination, it is up to the investigator’s judgment as to whether 
ophthalmologic assessments need to be repeated. 
Pulmonary Assessments 
Computed tomography or MRI of the chest will be performed per the SoE (Table 1.1).  
Additionally, SpO2 will be measured as part of Vital Signs as mentioned above. 
An ILD AC will review all cases of (potential) ILD on an ongoing basis.  Description of the ILD 
AC is available in Section 8.4.1.2. 
Pulmonary Function Test 
Pulmonary function will be performed as per the SoE (Table 1.1), and should include basic 
spirometry with optional additional components as follows: 
Required spirometry components 
Optional components 
Forced vital capacity (FVC) (L) 
Peak expiratory flow (PEF) 
FVC % predicted 
Diffusion capacity of the lungs for carbon monoxide (DLCO) 
Forced expiratory volume – 1 second (FEV1) (L)  
(Forced expiratory volume – 6 seconds) FEV6 
FEV1 % predicted 
Total lung capacity (TLC) 
FEV1/FVC  
 
See Table 6.6 for tests required if ILD/pneumonitis is suspected. 
8.5. 
Health Economics and Outcomes Research 
Patient-Reported Outcomes 
PROs provide an understanding of the impact a treatment has on a subject.  The EORTC 
QLQ-C30 is a validated and reliable self-report measure and has been widely used in assessing 
quality of life (QoL) in subjects with NSCLC.7,8,9 The core instrument assesses global health 


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status/QoL, functions (physical, role, emotional, cognitive, and social), and general cancer 
symptoms.  It consists of 30 questions assessing global health−related QoL, five aspects of 
subject functioning (physical, emotional, role, cognitive, and social), three symptom scales 
(fatigue, nausea and vomiting, and pain), and six single-items (dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).  Scale scores can be obtained for the multi-item 
scales. 
The EQ-5D-(5L) is a generic preference-based HRQoL questionnaire that provides a single 
index value for health status (see Section 9.5.3) and is used to inform pharmacoeconomic 
evaluations.  The EQ-5D-(5L) consists of two parts; the first part, health state classification, 
contains five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression.  From these five items, a utility measure is obtained for each subject.  The 
second part, consisting of a visual analog scale, will not be used in this study. 
A paper instrument or electronic patient-reported outcome (ePRO) data collection modality may 
be employed.  The PRO questionnaires, translated as required in the local language, will be 
distributed by the Investigator’s staff and completed in their entirety by the subject.  To ensure 
instrument validity and that data standards meet health authority requirements, PRO 
questionnaires should be self-administered at the investigational site prior to the completion of 
other study assessments and the administration of trastuzumab deruxtecan.  Study personnel 
should review all questionnaires for completeness before the subject leaves the study site.  Hard 
copy originals of the questionnaires must be maintained as part of the subject’s medical record at 
the site for source data verification.  These originals should have the subject’s initials on each 
page in compliance with good clinical practices (GCP). 
The PRO questionnaires (EORTC QLQ-C30 and EQ-5D-[5L]) will be completed as per the SoE 
Table 1.1. 
Healthcare Resource Utilization 
The following variables will be collected and recorded to assess healthcare resource utilization 
during the Treatment Period: 
 Hospitalizations 
 Emergency room visits 
 Skilled nursing facility care 
 Unscheduled clinic visits 
 Hospice care 
 Concomitant medications and procedures. 
8.6. 
Pharmacokinetic (PK) Assessment 
The PK endpoints include serum concentrations of trastuzumab deruxtecan, total anti-HER2 
antibody, and MAAA 1181a.  PK parameters will include AUC, Cmax and Ctrough. 
Blood samples for PK analyses will be obtained at the time points shown in Table 8.1.  ECGs 
should be performed before PK blood draws.  


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Table 8.1: 
Schedule of PK Sample Collection 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (– 8 to 0 h)  
EOI: Within 15 min after EOI 
5 h after the start of drug administration (±2 h) 
Cycle 1 
Day 8 
7 d after the start of drug administration (±1 d) 
Cycle 1 
Day 15 
14 d after the start of drug administration (±1 d) 
Cycle 1 
Day 22 
If treatment of next cycle is delayed by 3 days or more, or subject is 
discontinued, collect PK blood sample on C1, D22 (±2 days). 
Cycle 2 
Day 1 
BI (– 8 to 0 h) 
EOI: Within 15 min after EOI 
Cycle 3 
Day 1 
BI (– 8 to 0 h) 
EOI: Within 15 min after EOI 
Cycle 4 
Day 1 
BI (– 8 to 0 h) 
Cycle 6 
Day 1 
BI (– 8 to 0 h) 
BI = before infusion; C = cycle; d = day; EOI = end of infusion; h = hour; min = minutes 
Note: Obtain one blood sample collection for PK as soon as ILD/pneumonitis is suspected, if feasible 
In case of chloroquine or hydroxychloroquine administration, additional PK samples should be 
collected at the following time points (Table 8.2). 
Table 8.2: 
Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment 
Day of Chloroquine or Hydroxychloroquine 
Administration 
Sampling Time Point 
Day 1 
Prior to chloroquine or hydroxychloroquine dose 
Day 3 or 4 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 h)  
EOT with chloroquine or hydroxychloroquine 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 h) 
Prior to re-initiation of trastuzumab deruxtecan 
BI (within 8 h) 
BI = before infusion; EOT = end of treatment; h = hours 
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 drug administration and the 
exact time of blood sampling for PK analysis must be recorded on the eCRF, including those 
samples collected in case of chloroquine or hydroxychloroquine administration.  
Details for blood sampling, processing, storage, and shipment 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. 


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8.7. 
Pharmacodynamic Assessment(s) 
8.7.1. 
Pharmacodynamic Biomarker Analysis 
Biomarker analyses will be used to investigate the effect of trastuzumab deruxtecan at the 
molecular and cellular level as well as to determine how changes in the markers may relate to 
exposure and clinical outcomes.  Blood plasma samples will be collected for circulating tumor 
DNA analysis BI on Day 1 of Cycles 1 to 4 and then starting from Cycle 7, every 4 cycles, and at 
EOT.  See the SoE (Table 1.1). 
8.7.2. 
Pharmacogenomic (Inherited Genetic) Analysis (Optional) 
A single blood sample for pharmacogenomic analysis will be collected from each subject who 
provides consent, where allowed per local regulations.  This optional pharmacogenomic blood 
sample will be scheduled for Cycle 1 Day 1 predose.  Detailed instructions for the collection, 
handling, and shipping of samples are outlined in the Study Laboratory Manual. 
Pharmacogenomic samples may be analyzed for genes involved in absorption, distribution, 
metabolism, elimination, safety, and efficacy of trastuzumab deruxtecan.  Additionally, samples 
may be analyzed for genes involved in trastuzumab deruxtecan-related signaling pathways, or to 
examine diseases or physiological pathways or safety related to trastuzumab deruxtecan, such as 
ILD. 
Genetic analyses will not be performed on blood samples collected for PK or safety assessments. 
Subject confidentiality will be maintained.  If subjects agree, the remaining DNA will be stored, 
as outlined in Section 8.7.3, for performing future pharmacogenomic analysis. Otherwise, all 
remaining DNA samples will be destroyed.  
8.7.3. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained for a maximum of 15 years after the finalization of the clinical study 
report for this study.  
These specimens will be kept for pharmacogenomic analysis in case new genomic or genetic 
information is obtained in the future regarding the response (PK or pharmacodynamic) to 
trastuzumab deruxtecan, or in case serious adverse drug reactions are noted in a clinical study 
and pharmacogenomic analysis is to be conducted for investigation into the cause. 
During the period of storage, 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.  However, the data will not be 
discarded if the analysis has been completed before the subject withdraws consent. 
Disclosure of the Results of Future Pharmacogenetic Analysis 
Because the nature and value of future pharmacogenomic analysis cannot be known at this time, 
any results obtained from research involving pharmacogenomic samples will not be disclosed to 
the subject or Investigators now or in the future. 


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8.7.4. 
Immunogenicity 
Blood samples for ADA analyses will be collected prior to dosing in Cycles 1, 2, 4, and 
thereafter every 4 cycles, and 40-D FUP (+7 d) visit.   
Immunogenicity will be assessed through characterization of incidence and titer of ADA.  
Details for ADA serum sampling, processing, storage, and shipment for immunogenicity samples 
will be provided in the Study Laboratory Manual.  Serum concentrations of trastuzumab 
deruxtecan and/or total anti-HER2 antibody may be measured using the same immunogenicity 
samples as used for ADA assessment. 
The ADA testing will be performed using validated ADA assay following tiered assay steps 
including screening, confirmatory as well as titer determination.  Only samples confirmed 
positive for ADA may be analyzed for the presence of neutralizing ADA. 


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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
General Statistical Considerations 
The DCO date for the primary analysis will occur when all subjects have completed at least 9 
months of follow-up after the last subject has been randomized or have discontinued treatment.  
All data collected up to the DCO date will be included in the primary analyses. Data from all 
sites will be pooled for analyses.  
The final analysis of the study will occur after all responders have been followed for at least 6 
months from the date of initial response (or until disease progression, whichever comes first).  
Data collected beyond the primary analysis DCO will be presented as appropriate in a clinical 
study report (CSR) addendum if deemed necessary. 
Descriptive statistics on continuous variables will include the number of observations, mean, 
standard deviation, median, and minimum and maximum values (as well as geometric mean and 
geometric coefficient of variation for PK variables, if applicable).  Categorical variables will be 
summarized using frequency counts and percentages.  Graphical representation of data will be 
employed when appropriate. 
In general, the baseline value for an efficacy variable is the last non-missing value before 
randomization. The baseline value for a safety variable is the last non-missing value before the 
first dose of study treatment.  Summary for change from baseline and percent change from 
baseline will include only subjects with both baseline and postbaseline assessments.  Missing 
data will not be imputed for data analysis, unless specifically noted otherwise. 
9.2. 
Statistical Hypothesis 
The primary objective of this study is to evaluate confirmed ORR of trastuzumab deruxtecan in 
HER2-mutated NSCLC subjects treated at 5.4 and 6.4 mg/kg doses.  For each single arm, the 
evaluation of the study results will be based primarily on point estimation and 95% CI.  For both 
IAs described in Section 9.6, no statistical hypothesis testing is planned. However, for the 
primary analysis referenced in Section 9.1, statistical hypothesis against the null of 26.4% will be 
performed by comparing the lower bound of the 95% Clopper-Pearson CI of confirmed ORR 
with the benchmark value of 26.4%.  
9.3. 
Sample Size Determination 
The sample size in this study is determined on the basis of the probability evaluation that the 
95% Clopper-Pearson CI exceeds and excludes the ORR benchmark of 26.4%. 
Consistent with the primary objective, for each of the two single arm treatment groups, the 
probability that the resulting Clopper-Pearson 95% CI will exclude the ORR benchmark of 
26.4% will be evaluated.  This benchmark is the upper bound of the 95% CI (ORR 22.9; 95% CI: 
19.7 to 26.4) in ramucirumab plus docetaxel arm in the REVEL trial that was investigated as a 
second-line treatment for patients with stage IV NSCLC after platinum-based therapy.28  
One hundred and fifty subjects will be randomized in a 2:1 ratio to receive trastuzumab 
deruxtecan at the 5.4 mg/kg or 6.4 mg/kg dose level, respectively.   
With 100 subjects to receive trastuzumab deruxtecan at 5.4 mg/kg, the probability to exclude the 
ORR benchmark of 26.4% is at least 80% when the true ORR is 40%.  Assuming 50 subjects 


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will be randomized in the 6.4 mg/kg concurrent arm, the probability to exclude the ORR 
benchmark of 26.4% is at least 80% when the true ORR is 45%.  Details of the probability 
evaluation under different true ORR values are shown in Table 9.1. 
The resulting 95% CIs using exact (Clopper-Pearson) method under several scenarios of 
observed ORR are provided in Table 9.2, indicating that with 50 subjects and 42% observed 
ORR, the 95% CI excludes the benchmark of 26.4% ORR.  With 100 subjects and 36% observed 
ORR, the 95% CI excludes the benchmark of 26.4% ORR. 
With 100 subjects at 5.4 mg/kg and 50 subjects at the 6.4 mg/kg dose level, if the higher dose 
true ORR is at least 12.3% higher than that of the lower dose, the probability of observing the 
ORR difference between dose levels being 5% or more is at least 80%. 
Assuming 100 subjects at 5.4 mg/kg and 50 subjects at the 6.4 mg/kg dose level, the 95% CI of 
the ORR difference between dose levels is expected to extend approximately 16% from the 
observed difference in proportions to either confidence limit. 
Table 9.1: 
The Probability That the Resulting Clopper-Pearson 95% Confidence 
Interval (CI) Will Exclude the Benchmark of 26.4% ORR 
True ORR (%) 
Probability evaluated for N=100 (%) 
Probability evaluated for N=50 (%) 
36 
53.8 
32.6 
37 
61.9 
38.1 
38 
69.4 
43.8 
39 
76.2 
49.6 
40 
82.1 
55.4 
45 
97.3 
80.3 
50 
99.8 
94.1 
55 
99.9 
98.8 
CI = confidence interval; ORR = objective response rate 
Calculations were made using R package of binom. 
Table 9.2: 
Confidence Interval with 50 and 100 Subjects Under Scenarios of Observed 
ORR 
N=100 
N=50 
Observed ORR (%) 
95% CI using exact method (%) 
Observed ORR 
(%) 
95% CI using exact method 
(%) 
35 
(25.7, 45.2) 
36 
(22.9, 50.8) 
36 
(26.6, 46.2) 
42 
(28.2, 56.8) 
45 
(35.0, 55.3) 
44 
(30.0, 58.7) 
50 
(39.8, 60.2) 
54 
(39.3, 68.2) 
55 
(44.7, 64.9) 
58 
(43.2, 71.8) 
60 
(49.7, 69.7) 
60 
(45.2, 73.6) 
65 
(54.8, 74.3) 
64 
(49.2, 77.1) 
CI = confidence interval; ORR = objective response rate 
Calculations were made using R package of binom. 


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9.4. 
Population for Analysis Sets 
Analysis Sets 
 The Full Analysis Set (FAS) will include all subjects for whom study treatment has 
been assigned by randomization.  Following the Intent-to-Treat principle, subjects 
will be analyzed according to the treatment and strata they have been assigned to 
during the randomization process. 
 The Safety Analysis Set (SAS) will include all subjects who received at least one 
dose of study treatment.  Subjects will be analyzed according to the study treatment 
received, where treatment received is the randomized study drug if the subject took at 
least one dose of the randomized study drug; otherwise the first treatment received 
will be used. 
 The Response Evaluable Set (RES) will include all subjects in FAS who received at 
least one dose of study treatment and had measurable target lesions as assessed by 
BICR at baseline. 
 The PK Analysis Set will include all randomized subjects who received at least one 
dose of study drug and had measurable serum concentrations of trastuzumab 
deruxtecan. 
9.5. 
Statistical Analysis 
The SAP will be developed and finalized before database lock and will describe the details of the 
planned statistical analyses.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 
9.5.1. 
Efficacy Analyses 
Efficacy analyses will be performed for the FAS and RES.  Point estimates will be accompanied 
with 2-sided 95% CIs, unless specified otherwise. 
Table 3.1 lists the primary and secondary endpoints and their corresponding definitions of all 
endpoints.  Additional details for the analysis and censoring rules are noted in the following 
sections.  Detailed censoring rules for the applicable secondary efficacy endpoints will be 
specified in the SAP. 
9.5.1.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is confirmed ORR, defined as the sum of CR and PR rate, 
assessed by the BICR based on RECIST version 1.1 
The primary analysis of ORR will be performed for FAS.  The ORR for each dose level will be 
estimated along with the two-sided Clopper-Pearson 95% CIs.  In addition, if the lower limit of 
the 95% CI in a dose level is greater than 26.4%, the ORR in the dose level will be concluded to 
have exceeded 26.4%. 
In addition, the ORR difference between dose levels will be estimated using a stratified analysis, 
where the strata-adjusted ORR difference is computed, and each stratum is weighted according 
to the inverse of variance. The 95% confidence interval will also be computed. 


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9.5.1.2. 
Secondary Efficacy Analyses 
The secondary endpoint of confirmed ORR by investigator assessment based on RECIST version 
1.1 will be analyzed using the same method as for the primary efficacy endpoint.  DoR, defined 
as time from the initial response (CR or PR), until documented tumor progression or death from 
any cause, will be summarized using Kaplan-Meier approach for each dose level. 
DCR is defined as the proportion of subjects who achieve CR, PR, or SD during study treatment.  
DCR based on BICR and DCR based on investigator assessments will both be determined.  
PFS, defined as the time from date of randomization until first objective radiographic tumor 
progression or death from any cause, will be analyzed using the Kaplan-Meier approach.  
Likewise, OS, defined as the time from date of randomization until death from any cause, will 
also be similarly analyzed.  The censoring rules for PFS and OS will be detailed in the SAP. 
9.5.1.3. 
Exploratory Analyses 
Time to response (TTR), defined as the time from the date of randomization to the date of the 
first documentation of objective response (CR or PR), will be summarized for each dose level.  
Best percent change from baseline in the sum of the diameters for all target lesions will be 
summarized with descriptive statistics by dose level. 
For the following subgroups, analyses using the same methods as for the FAS will be performed, 
provided that a minimum number (10) subjects in at least one treatment arm are available: 
 Region: US, European Union (EU), Asia-Pacific  
 Prior therapy:  subjects who (i) received prior anti-PD-1 and/or anti-PD-L1 treatment 
and (ii) those who received neither. 
9.5.1.4. 
Multiplicity Adjustment 
The evaluation of the study results at DCOs for both IAs and primary analysis will be based 
primarily on point estimation and 95% CI.  For both IAs, there is no plan to stop the trial in 
response to the efficacy results.  Hence, multiplicity adjustment is not applicable. 
9.5.2. 
Safety Analyses 
Safety analyses involving safety data (extent of exposure, TEAEs, clinical laboratory results, 
ECG, vital signs, and physical exam) will be performed on the Safety Analysis Set according to 
the actual treatment received by subjects. No inferential statistical analysis is planned for safety 
data, unless otherwise specified.  Descriptive statistics will be calculated for quantitative safety 
data and frequency counts and percentages will be compiled for classification of qualitative 
safety data. All percentages will be calculated based on the number of subjects in the Safety 
Analysis Set, unless otherwise indicated.  If the number of subjects with available data does not 
allow for the reliable estimation at a scheduled time point, no summary statistics will be 
presented for that time point, unless otherwise indicated.  Unless otherwise noted, baseline 
values will be the last non-missing assessment collected prior to first dose of study treatment. 
Safety analyses, primarily summaries by description statistics of safety variables, will be 
performed by dose level. 


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Adverse Events 
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 the initiating the study drug until 47 days after 
last dose of the study drug.  
Adverse Events will be coded using MedDRA version 24.0 and graded using CTCAE version 
5.0.  The number and percentage of subjects reporting TEAEs will be tabulated by system organ 
class (SOC), preferred term (PT), relationship to the study drug, the worst CTCAE grade and 
dose level.  Similarly, the number and percentage of subjects reporting serious TEAEs will be 
tabulated by dose level, as well as TEAEs leading to discontinuation of the study treatment. 
A by-subject AE (including TEAE) data listing including but not limited to the verbatim terms, 
SOC, PT, CTCAE grade, and relationship to study drug will be provided.  Deaths, other SAEs, 
AESIs, and other significant AEs, including those leading to discontinuation of the study 
treatment, will be listed. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for the clinical laboratory test results and changes from 
baseline by dose level at each scheduled time of evaluation.  In addition, mean change from 
baseline will be presented by dose level for the maximum and minimum posttreatment values 
and the values at the EOT visit. 
Abnormal clinical laboratory results will be graded according to CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
2-way frequency tabulation for baseline and the worst posttreatment value according to CTCAE 
grade, will be provided for clinical laboratory tests. 
A listing of abnormal clinical laboratory test results deemed of clinical significance or of Grade 3 
or 4 will be provided. 
ECG 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation and by treatment group, as well as for the change from baseline.  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).  
Maximum change from baseline will be tabulated (≤30 ms, >30 to ≤60 ms, >60 ms).  The QT 
intervals will be corrected for heart rate by Fridericia’s formula (QTcF). 
A listing of ECG data will be provided. 
Vital Signs 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation and by dose level, as well as for the change from baseline.  The baseline value is 
defined as the last non-missing value before the initial administration of study treatment.  A 
listing of vital sign data will be provided. 


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Other 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(WHODD) (June 2007).  Number and percentage of subjects taking concomitant medications 
will be summarized.  Concomitant medications will also be listed. 
All other safety data (eg, physical examination findings including ECOG PS, ECHO/MUGA, 
and ophthalmologic findings) will be listed. 
9.5.3. 
HEOR Analysis 
To assess patient HRQoL, the following PROs questionnaires will be administered: 
 A cancer specific PRO (EORTC QLQ-C30) along with tumor-specific modules 
(EORTC QLQ-LC13 & NSCLC-SAQ) to assess patient-reported tolerability and 
clinical benefit.  
 A generic health status questionnaire, the EQ-5D-5L module including EQ-VAS to 
assess patient-reported health utility for health economic evaluations. 
 Three global anchors (PGIS, PGIC, PGI-TT) included to estimate meaningful change 
thresholds for EORTC QLQ-C30 / LC13 
Descriptive statistics will be calculated to summarize change from the baseline in symptoms, 
physical functioning and general HRQoL scales in the C30 and LC13 study questionnaires at 
each scheduled assessment time point by dose level.  The number of subjects completing each 
patient questionnaire and the number of missing or incomplete assessments will be provided for 
each scheduled assessment time point by dose level. 
9.5.4. 
Other Analyses 
The following other analyses are planned in this study. 
Pharmacokinetics 
Pharmacokinetics (PK) analyses will be performed using the PK Analysis Set.  Serum 
concentrations for trastuzumab deruxtecan, total anti-HER2 antibody and MAAA-1181a will be 
listed and summarized using descriptive statistics at each time point by dose level.  PK 
parameters (Cmax, Tmax, AUC (AUClast [area under the concentration time-curve from time 
0 to the last measurable concentration] and AUC0-21d [area under the concentration time-curve 
from time 0 to 21 d]) of trastuzumab deruxtecan, total anti-HER2 antibody and MAAA-1181a 
may also be determined using non-compartmental analysis after the first dose and summarized 
using descriptive statistics by dose level.   
Population PK analysis may also be conducted by combining data from this study with other 
clinical studies of trastuzumab deruxtecan. In addition, ER analysis for key efficacy and safety 
endpoints may be conducted. The results of population PK and ER analyses will be provided in a 
separate report outside the CSR for this study. 
Immunogenicity Analyses 
Immunogenicity will be assessed through characterization of incidence and titer of the ADA.  
The number and percentage of subjects will be reported for the presence or absence of 


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development of ADA after the start of administration of study treatment, defining subjects who 
are negative for ADA at all-time points as negative and subjects who are positive for ADA at 
least one time point post-study drug treatment as positive.  The ADA titer values will be 
summarized by time point and dose level using descriptive statistics.  The treatment-emerging 
ADA incidence will be calculated.  Treatment-emergent ADA positive subject will be defined as 
subjects who are ADA negative at baseline and become ADA positive posttreatment, or who are 
ADA positive at baseline and posttreatment, but have an increase in ADA titer from baseline to 
posttreatment, or those who have missing ADA data at baseline but become ADA positive 
post-treatment.  The number and percentage of subjects positive for NAb of trastuzumab 
deruxtecan may also be determined. 
Biomarker 
Biomarker analysis will be performed using the FAS. 
Descriptive statistics including mean, standard deviation, coefficient of variation, geometric 
mean, median, minimum, and maximum will be computed by evaluation time for biomarkers 
listed in Section 8.7.  If possible, change from baseline and percent change from baseline will 
also be summarized.  Summaries and analyses for exploratory biomarkers will be documented in 
a separate analysis plan and will be reported outside the CSR in a separate report. 
Statistical Analysis - Assessment of the Impact of SARS-CoV-2 Infection 
If deemed appropriate, analyses will be performed to explore the impact of SARS-CoV-2 
infection on the safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of SARS-CoV-2 infection on study conduct, adjustments to the 
statistical analysis and interpretation will be made, if required.  These will be described in the 
SAP. 
9.6. 
Interim Analyses 
Two IAs are planned for this study.  The first IA will be performed when a total of at least 75 
subjects have been randomized to receive a dose of trastuzumab deruxtecan (5.4 mg/kg or 6.4 
mg/kg) and have had at least 4.5 months of follow-up before the DCO or have discontinued 
treatment.  The DCO of the second IA will be approximately 6 months after the DCO of the first 
IA.  If the planned DCO of the second IA is anticipated to fall within 3 months of the primary 
analysis DCO, when the data are sufficiently mature, then the second IA may not be performed.  
The main purpose of these IAs is to evaluate the safety and efficacy of each dose without the 
intent to modify the study design and study conduct.  There is no plan for stopping the trial for 
efficacy.  The evaluation of the study results will be based primarily on point estimation and 
95% CI.  Hence, futility and efficacy stopping boundaries are not defined for both IAs.  A PK 
assessment will also be performed.  Additionally, exposure-response analyses for key efficacy 
and safety endpoints may be performed at the time of these IAs.  
For each dose, the primary efficacy endpoint of confirmed ORR by BICR will be summarized 
using descriptive statistics including 2-sided exact 95% CI (Clopper-Pearson).  Other efficacy 
endpoints based on response rates will be summarized by dose level using the same methodology 
as the primary efficacy endpoint.  For time-to-event endpoints such as DoR, Kaplan-Meier 


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estimates of median and their corresponding 95% CIs using Brookmeyer and Crowley method 
will be provided.  Safety data related to AEs will be summarized using descriptive statistics.  
For the first IA, in addition to analyzing and presenting the FAS for efficacy and SAS for safety 
with respect to both DCO dates, data from the subset of subjects who were randomized at least 
4.5 months before the DCO will also be analyzed and presented to allow for a more robust 
assessment of the efficacy and safety data from this pre-defined subset. 


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10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS 
10.1. 
Appendix 1 Regulatory and Ethical Considerations 
10.1.1. 
Regulatory Compliance 
The study protocol, the Investigator Brochure, available safety information, recruitment 
procedures (eg, advertisements), subject information and consent form, any subject-written 
instructions to be given to the subject, information about payments and compensation available 
to the subjects, and documentation evidencing the Investigator’s qualifications should be 
submitted to the independent IRB or EC 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.  Written approval of all protocol amendments and changes to any of 
the above listed documents must be obtained from the IRB or EC. 
The Investigator should notify the IRB or EC 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. 
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 International Council for Harmonisation (ICH) 
consolidated Guideline E6 for GCP (CPMP/ICH/135/95), and applicable regulatory 
requirement(s) including the following: 
 European Commission Directive (2001/20/EC Apr 2001) and/or; 
 European Commission Directive (2005/28/EC Apr 2005) and/or; 
 US Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 (27 Mar 1997) 
and/or; 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 (25 Nov 2014); 
 Other applicable local regulations. 
In addition, the Investigator will inform the Sponsor in writing within 24 h of any urgent safety 
measures taken by the Investigator to protect the study subjects against any immediate hazard, 
and of any suspected/actual serious GCP non-compliance that the Investigator becomes aware of. 


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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, 
IECs/IRBs, 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 IEC/IRB.  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. 
10.1.2. 
Informed Consent 
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 ICF and any revision(s) should be approved 
by the IEC/IRB prior to being provided to potential subjects. 
The subject’s written ICF 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 ICF should be 
provided to the subject.  The date and time (if applicable) that informed consent was given must 
be recorded in the eCRF. 
If the subject cannot read, then according to International Conference on Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) GCP 
Guideline, Section 10.1.2, an impartial witness should be present during the entire informed 
consent discussion.  This witness should sign the ICF after the subject has consented to their 
participation.  By signing the ICF, the witness attests that the information in the ICF and any 
other written information was adequately explained to and apparently understood by the subject 
and that informed consent was freely given by the subject. 
A separate special consent for inherited genetic analysis will be obtained from subjects in 
accordance with health authorities in their particular region/country. 
Suggested model text for the ICF for the study and any applicable subparts (PK, 
pharmacodynamic, etc) is provided in the Sponsor’s ICF template for the Investigator to prepare 
the documents to be used at his or her study site.  Updates to applicable forms will be 
communicated via letter from the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA). 


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10.1.3. 
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 EU Regulation 
2016/679/General Data Protection Regulation (GDPR) 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 SID 
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(s), and the 
independent 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. 
10.1.4. 
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. 
Monitoring and Inspections 
The Sponsor and 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 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 is 
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. 


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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. 
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 DSI 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.  The information should be entered into the eCRF within 5 days of the 
visit and should be completed, reviewed, and signed off by the investigator within 2 weeks of the 
last subject visit.  Query resolution should be completed within 48 h. 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedure.  If a subject is not treated, the reason must be recorded on the eCRF.  All data 
collected during the study will be recorded in this individual, subject-specific eCRF.  Instructions 
will be provided for the completion of the eCRF and any corrections made will be automatically 
documented via an “audit trail.” 
Data Management 
Each subject will be identified in the database by a unique SID. 
To ensure the quality of clinical data across all subjects and study sites, a Sponsor or CRO 
Clinical and Data Management review will be performed on subject data according to 
specifications developed by the Sponsor.  Data will be vetted both electronically by programmed 
data rules within the application and manually.  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 laboratories will be reconciled to the clinical 
database. 
All AEs will be coded using MedDRA.  SAEs in the clinical database will be reconciled with the 
safety database. 
All concomitant medications and prior cancer therapies will be coded using the WHODD. 


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10.1.5. 
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 obtain informed consent and make 
entries and/or corrections on eCRFs will be included on the Signature List. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited information of the subjects, date and outcome of the screening process. 
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 code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
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. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, IEC/IRB 
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 (site specific 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 local 
laws or regulations 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 provide further instruction. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (site specific 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 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 independent IRB/EC and the Sponsor. 
 Records related to the study drug(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. 


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All essential documentation will be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years 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 laws or 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. 
Subjects’ 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 the 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. 
10.1.6. 
Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical study 
agreement with Sponsor or the CRO.  This agreement will include the financial information 
agreed upon by the parties. 
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. 
10.1.7. 
Publication, Public Disclosure Policy, and Data Sharing 
The Sponsor is committed to meeting the highest standards of publication and public disclosure 
of information arising from clinical studies sponsored by the company.  The Sponsor 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.  The Sponsor will 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 (ICMJE). 
In order to ensure compliance with the public disclosure policies and the ICMJE 
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 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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10.1.8. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by the 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IECs/IRBs. 
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. 
The Sponsor must be notified in writing of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, missed study visits) within 24 h or in accordance with 
the clinical study agreement between the parties. 
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 one 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the IEC/IRB of deviations from the protocol in 
accordance with local procedures. 
10.1.9. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the 
IEC/IRB or local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further study intervention development 
10.1.10. 
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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10.2. 
Appendix 2: Local Laboratory 
Table 10.1: 
Clinical Laboratory Tests 
Test 
Analytes 
Blood Chemistry 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase  
Aspartate aminotransferase  
Bilirubin (total) 
Bilirubin (direct) 
Blood urea nitrogen/urea 
Calcium 
Chloride 
Serum creatinine 
Creatinine clearance 
Lactate dehydrogenase 
Potassium 
Sodium 
Magnesium 
Total protein 
Troponin 
High-sensitivity troponin T (preferred) or 
Troponin-I 
Hematology 
Red blood cell count 
Hemoglobin 
Hematocrit 
White blood cell (WBC) count 
Differential WBC count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils) 
Platelet count 
Coagulation 
Prothrombin time- international normalized ratio 
Activated partial thromboplastin time or partial 
thromboplastin time 
Urinalysis (abbreviated) 
Protein 
Glucose 
Blood 
Microscopy assessment (if indicated) 
Specific gravity 


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Table 10.2: 
List of HER2 (ERBB2) Mutations  
HER2 mutations 
Exon 20 insertion (any) 
Tyr772_Ala775dup (Ala771_Tyr772insTyrValMetAla, Glu770_Ala771insAlaTyrValMet 
Ala775_Gly776insTyrValMetAla) 
Ala775_Gly776insVal 
Ala775_Gly776insThrValMetAla (Tyr772_Val773insValMetAlaThr) 
Gly776delinsLeuCys 
Gly776delinsValCys 
Gly776_Val777insLeu 
Gly778_Ser779insCysValGly (Gly776_Val777insValGlyCys) 
Val777_Gly778insCysGly (Gly776_Val777delinsCysValCysGly), 
Val777_Ser779dup (Gly776_Val777insValGlySer , Ser779_Pro780insValGlySer) 
Gly778_Ser779insLeuProSer 
Gly778dup (Val777_Gly778insGly) 
Gly778_Pro780dup (Val777_Gly778insGlySerPro, Pro780_Tyr781insGlySerPro) 
Ser310Phe 
Ser310Tyr 
Arg678Gln 
Thr733Ile 
Leu755Ala 
Leu755Met 
Leu755Pro 
Leu755Ser 
Leu755Trp 
Ile767Met 
Asp769Asn 
Asp769His 
Asp769Tyr 
Gly776Cys 
Gly776Ser 
Gly776Val 
Val777Leu 
Val777Met 
Val842Ile 
Thr862Ile 
Leu869Arg 
Arg896Cys 
Arg896His 
Gly778_Ser779insCysProGly (Val777_Gly778insGlyCysPro) 
Leu755_Glu757delinsSer 
Leu755_Thr759del 
Val777_Gly778insCysVal 
Ile767Phe 
Thr798Ile 
 


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10.3. 
Appendix 3: Reference Standards 
10.3.1. 
Cockcroft-Gault Equation 
The estimated creatinine clearance (CrCl; mL/min) will be calculated using the Cockcroft-Gault 
equation based on [actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds)19:  
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) =  
Female: 
CrCl (mL/min) = 
× 0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) =  
Female: 
CrCl (mL/min) = 
× 0.85 
10.3.2. 
Corrected Calcium Formula for Eligibility 
To correct calcium for serum albumin in case of hypoalbuminemia for eligibility, as referenced 
in inclusion criterion , please use one of the following formulas20:  
In mg/dL: 
Corrected Calcium [mg/dL] = (0.8 × (Normal Albumin - Albumin) + Calcium 
In mmol/L: 
Corrected Calcium [mmol/L] = (0.02 × (Normal Albumin - Albumin) + Calcium 
10.3.3. 
New York Heart Association (NYHA) 
The NYHA classifications are summarized below.21  
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 


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Table 10.3: 
New York Heart Association Classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Subjects 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. 
II 
Subjects 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. 
III 
Subjects 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. 
IV 
Subjects with cardiac disease resulting in inability to carry 
on any physical activity without discomfort.  Symptoms of 
heart failure or 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. Classification of Functional Capacity and Objective Assessment, Ninth edition 
March 14, 1994. 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of- 
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
10.3.4. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG performance status scale scores are summarized below.22  
Table 10.4: 
Eastern Cooperative Oncology Group Performance Status 
Score 
Performance Status 
0 
Fully active, able to carry on all pre-disease 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 housework, 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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10.3.5. 
Highly Effective Contraception 
Methods considered to be highly effective contraception include:23  
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence 
10.3.6. 
Calculation of Body Surface Area 
Body surface area as calculated using the Mosteller equation:24  
 
BSA =  
 
Source: Mosteller RD. Simplified Calculation of Body Surface Area. N Engl J Med. 1987;317(17):1098 (letter) 
10.4. 
Appendix 4: Response Criteria 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
Assessment of tumor responses will be performed according to revised RECIST guidelines, 
Version 1.1.25  Some of these definitions and criteria are highlighted below. 
Measurability of Tumor at Baseline Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 
ℎ𝑒𝑖𝑔ℎ𝑡 ×  𝑤𝑒𝑖𝑔ℎ𝑡 
3600
 


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 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
 10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Measurable malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm).  At baseline and in follow-up, only the 
short axis will be measured and followed.  See also notes below on “Baseline documentation of 
target and non-target lesions” for information on lymph node measurement. 
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.  Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, 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. 
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. 


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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 since the therapy. 
Specifications by Methods of Measurements 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and NEVER 
more than 4 weeks before the beginning of the treatment. 
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 done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by 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). 
Tumor Response Evaluation 
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 in the study. 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a total of two 
lesions per organ and a maximum of five lesions total representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only one or two organ sites involved a maximum of two and 
four 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 


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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.  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 two 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.  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 or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum 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 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 record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
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. 
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 must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
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, stable disease, and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions. 


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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 unlikely 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 retro-peritoneum).  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. 
If the radiologist is able to provide an actual measurement, 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’. 
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 
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 and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions.  (Note: the appearance of one or more new lesions is also considered 
progression. 
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 one or more non-target lesions is usually not sufficient to qualify for 


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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 extremely 
rare. 
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 pre-existing lesions).  This is particularly 
important when the subject’s baseline lesions show partial 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 
the subject who has visceral disease at baseline and while on study has a CT or MRI of the brain 
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 
that indicated its presence. 
Evaluation of Best Overall Response 
The best overall response is determined once all the data for the subject is known. 
Best response is defined as the lesser of the two best responses across two consecutive scans 
(eg, a subject who has PR at first assessment, SD at second assessment, and PD on last 
assessment; this would report as a best overall response of SD).  When SD is believed to be best 
response, it must also meet the protocol-specified minimum time from baseline, 6 weeks (±7 d).  
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 NE. 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 10.5 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 
All postbaseline scans must be anchored against the scan. 


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Table 10.5: 
Time Point Response: Subjects With Target (±Non-Target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
Stable disease 
Non-PD or not all evaluated 
No 
Stable disease 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; PD = progressive disease; and NE = not evaluable 
Missing Assessments and In-evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is not 
evaluable (NE) at that time point.  If only a subset of lesion measurements is 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 three measured lesions and at follow-up 
only two 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. 
Best Overall Response: All-Time Points 
The best overall response is determined once all the data for the subject are 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 weeks 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. 


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Table 10.6: 
Best Overall Response When Confirmation of CR and PR Required 
Overall response 
 
Overall response 
First time point 
Subsequent time point 
Best 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR
a 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
NE 
NE 
NE 
CR = complete response; PR = partial response; SD = stable disease; NE = not evaluable; PD = progressive disease 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
Source: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Table 3. Euro J of Can. 2009:45;228-47 
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 might 
not have a total sum of ‘0’ on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of trastuzumab 
deruxtecan without objective evidence of disease progression at that time should be reported as 
‘clinical progression.’  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study drug.  The objective response status of such subjects is 
to be determined by evaluation of target and non-target disease.  If a radiographic tumor 
assessment has not been performed within 4 weeks of the time of clinical progression, then 


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another radiographic assessment should be performed without waiting for the next regularly 
scheduled scan. 
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. 
Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted at Screening, and then at the intervals 
specified or sooner if clinically indicated.  The interval between scans is based on the last scan 
visit.  Tumor measurement will be performed during the EOT visit if it was not done within the 
previous 6 weeks or the previous assessment demonstrated disease progression. 
Baseline tumor assessments must be performed within 4 weeks prior to the first dose of study 
drug. 
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 the chest, abdomen, and 
pelvis.  Any additional suspected sites of disease should also be imaged.  All evaluations should 
meet the SOC 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. 
10.5. 
Appendix 5: General Information - Adverse Events 
10.5.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that 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.26  
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. 
Events Meeting the Adverse Event Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically relevant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 


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 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.   
Events NOT Meeting the Adverse Event Definition 
 Any clinically relevant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 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 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline or for administration of anticancer therapy after 
discontinuation of study drug is not considered an AE. 


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 Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
 Medical or scientific judgment should be exercised in deciding whether SAE 
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 medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These events should usually be 
considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Events Exempted from SAE Reporting 
Serious events that are also efficacy endpoints (eg, PD) and/or safety endpoints will be exempted 
from SAE processing and expedited reporting27.  Disease progression should not be reported as 
an AE/SAE (Section 8.4.1).   
10.5.2. 
Grade Assessment 
The severity of AEs will be graded using the latest CTCAE (version 5.0).  For each episode, the 
highest severity grade attained should be reported. 
The CTCAE guidelines do not allow certain grades for certain AEs.  For example, pain can be 
Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 or 
5 (ie, can only be life-threatening or fatal).  In addition, alopecia can only be Grade 1 or 2.  The 
CTCAE guidelines should be followed closely. 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe AE 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 


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Difference between Severity and Seriousness 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as "serious," which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
10.5.3. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug based on 
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 drug 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 drug 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 drug administration or 
can be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
10.5.4. 
Action Taken Regarding Study Drug(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Not Applicable: Subject died, study drug completed/permanently discontinued prior 
to reaction/event, or reaction/event occurred prior to start of treatment 
 Unknown: Subject is lost to follow-up 
10.5.5. 
Other Action Taken for Event 
 None. 
 No treatment was required. 


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 Medication required. 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
10.5.6. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no sequelae observed. 
 Recovered/Resolved with Sequelae 
 The subject fully recovered from the AE but with sequelae. 
 Recovering/Resolving 
 The AE is improving but not recovered 
 Not Recovered/Not Resolved 
 The AE continues without improving. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE 
 Unknown 
10.6. 
Appendix 6: Instructions Related to Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) Infection 
Due to the potential impact of SARS-CoV-2 infection, ie COVID-19, on subject safety, the 
following SARS-Cov-2 infection assessment and dose modification and management plan for 
subjects with confirmed or suspected COVID-19 while being treated with trastuzumab 
deruxtecan should be followed.  Dose modifications will be based on the worst CTCAE grade.  
Use CTCAE version 5.0 general grading criteria to evaluate COVID-19.  All dose 
modifications (discontinuation, interruptions or reductions) must be recorded on the AE and drug 
administration eCRFs. 
Dose modification criteria for suspected or confirmed SARS-CoV-2 infection 
If asymptomatic or symptomatic 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 Section 6.5. 
 If COVID-19 is confirmed or diagnosis is suspected after evaluation, follow dose 
modification as outlined in Table 10.7, below, and manage COVID-19 per local 
guidance until recovery of COVID-19.  COVID-19 recovery is defined as no 


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respiratory signs/symptoms of COVID-19 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 (Table 10.7). 
Table 10.7: 
COVID-19 Dose Modification Criteria 
COVID-19 Worst Toxicity NCI-CTCAE Version 
5.0 Grade (Unless Otherwise Specified) 
Schedule Modification for Trastuzumab 
Deruxtecan  
Grade 1 
After recovery, resume study treatment(s) at the same 
dose 
Grade 2 
After recovery, resume study treatment(s) at the same 
dose if chest CT findings are completely resolved 
Reduce by 1 dose level if chest CT findings are nearly 
resolved (equivalent to CT Severity Score of 1) 
Grade 3 
After recovery, reduce by 1 dose level if chest CT 
findings are completely resolved 
Discontinue drug if chest CT findings are not 
completely resolved 
Grade 4 
Discontinue study drug 
COVID-19 = coronavirus disease 2019; CT = computed tomography; CT Severity Score of 1 = Subtle Ground Glass 
Opacities and very few findings; NCI-CTCAE = National Cancer Institute- Common Terminology Criteria for 
Adverse Events  
 
Closely monitor subjects for signs/symptoms after resuming trastuzumab deruxtecan with a 
weekly phone call or a site visit, for a total of 6 weeks. 
In addition to the recommendations outlined in Table 10.7, 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/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline (Table 6.6) signs/symptoms.  
SARS-CoV-2 Infection Assessment(s) 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF.  If a 
subject presents to the clinic with symptoms suggestive of SARS-CoV-2 infection should be 
confirmed via NAAT (nucleic acid amplification test such as RT-PCR) or rapid antigen testing.  
SARS-CoV-2 antigen testing can be used to confirm infection, but not to rule it out. . 
Serum samples will be collected and may be used for SARS-CoV-2 testing from each subject 
who provides consent.  Samples will be collected prior to the study drug infusion (Table 1.1), 
shipped to a central laboratory and stored there until the testing is required. 
If subjects give their 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. 


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Statistical Analysis - Assessment of the Impact of SARS-CoV-2 Infection 
If deemed appropriate, analyses will be performed to explore the impact of SARS-CoV-2 
infection on the safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of SARS-CoV-2 infection on study conduct, adjustments to the 
statistical analysis and interpretation will be made, if required.  These will be described in the 
SAP. 


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11. 
REFERENCES 
1. Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J Clin. 
2011;61(2):69–90. 
2. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. v.2.2014. 
www.nccn.org. 
3. Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: 
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12. 
LIST OF ABBREVIATIONS 
Abbreviation 
 
Definition 
 
1L 
first line 
2L+ 
second-line or later 
40-D FUP 
40-day follow-up 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
anti-HBc 
hepatitis B core antibody 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BI 
before infusion 
BICR 
blinded independent central review 
CBC 
complete blood count 
CFR 
code of federal regulations 
CHF 
congestive heart failure 
CI  
confidence interval 
Cmax 
maximum serum concentration 
CO 
carbon monoxide 
COVID-19 
coronavirus 2019 
CR 
complete response 
CrCl 
creatinine clearance 
CRO 
Contract Research Organization 
CT 
computed tomography 
CTCAE 
common terminology criteria for adverse events 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DCO 
data cutoff 
DCR 
disease control rate 
DILI 
drug-induced liver injury 
DLT 
dose-limiting toxicity 


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Abbreviation 
 
Definition 
 
DoR 
duration of response 
DSI 
Daiichi Sankyo, Inc. 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EIU 
exposure in utero 
EOI 
end of infusion 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (Core) 
EORTC QLQ-LC13 
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire LC13 (Lung Cancer) 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQol 5 Dimension 5 Levels 
ER 
Exposure-Response 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FVC 
forced vital capacity 
GCP 
good clinical practice 
G-CSF 
granulocyte-colony stimulating factor 
GLP 
good laboratory practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
HEOR 
health economics and outcomes research 
HER2 
human epidermal growth factor receptor 2 
hERG 
Human ether-a-go-go-related gene 
HIPAA 
health insurance portability and accountability act 
HIV 
human immunodeficiency virus 
HRQoL 
health-related quality of life 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 


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Abbreviation 
 
Definition 
 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMJE 
International Council of Medical Journal Editors 
ICR  
Independent committee review 
IEC 
independent ethics committee 
ILD 
interstitial lung disease 
INN 
international non-proprietary name 
INR 
international normalized ratio 
IRB 
institutional review board 
IRR 
infusion-related reaction 
IRT 
interactive response technology 
IV 
intravenous 
LTSFU 
long-term survival follow-up 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose/regimen 
MUGA 
multi-gated acquisition 
NE 
not evaluable 
NSCLC 
non-small cell lung cancer 
NSCLC-SAQ 
Non-Small Cell Lung Cancer Symptom Assessment Questionnaire 
OATP 
organic anion-transporting polypeptide 
OCT 
organic cation transporter 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death receptor-1 
PDL-1 
programmed cell death ligand 1 
PFS 
progression-free survival 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PGI-TT 
Patient Global Impression of Treatment Tolerability 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcomes 


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Abbreviation 
 
Definition 
 
PS 
performance status 
PT 
prothrombin time 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
Q12W 
every 12 weeks 
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RECIST 
response evaluation criteria in solid tumors version 1.1 
RES 
response evaluable set 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SAS 
Safety Analysis Set 
SID 
subject identifier 
SMQ 
Standardised MedDRA Queries 
SOC 
standard of care 
SoE 
Schedule of Events 
SpO2 
peripheral oxygen saturation 
t1/2 
terminal elimination half-life 
T-DM1 
trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to reach maximum concentration 
TTR 
time to response 
ULN 
upper limit of normal 
WBC  
White blood cell 
WHODD 
World Health Organization Drug Dictionary 
wk 
week 
 


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