Conditions: Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
Keywords: Gastric Cancer Gastroesophageal Junction Adenocarcinoma HER2 Trastuzumab Deruxtecan T-DXd DS-8201a ERBB2
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 95
Healthy volunteers: no

Brief summary:
This is a Phase II, open-label, single-arm, multicentre, study in China assessing the efficacy and safety of T-DXd in participants with HER2-expressing advanced gastric or GEJ adenocarcinoma who have received at least 2 prior regimens including a fluoropyrimidine agent and a platinum agent

Detailed description:

Arms:
arm 1: T-DXd monotherapy

Interventions: intervention 1: Trastuzumab Deruxtecan
Intervention descriptions: intervention 1: Trastuzumab deruxtecan (T-DXd) by intravenous infusion

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Study Intervention
Trastuzumab deruxtecan 
(T-DXd, AZD4552, DS-8201a)
Study Code
D9676C00002
Version
2.0
Date
20DEC2021
A Single-arm Study of Trastuzumab Deruxtecan (T-DXd) Monotherapy for 
Patients with HER2-expressing Locally Advanced or Metastatic Gastric or 
Gastroesophageal Junction (GEJ) Adenocarcinoma Who Have Received 
2 or More Prior Regimens (DESTINY-Gastric06)
Sponsor Name: 
AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s)
This CSP has been subject to a peer review according to AstraZeneca Standard procedures. 
The CSP is publicly registered and the results are disclosed and/or published according to the 
AstraZeneca Global Policy on Bioethics and in compliance with prevailing laws and 
regulations.


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Protocol Number: D9676C00002
Amendment Number: 1
Study Intervention: Trastuzumab deruxtecan (T-DXd; DS-8201a)
The non-proprietary name of T-DXd is trastuzumab deruxtecan except in the United States where it is 
fam-trastuzumab deruxtecan-nxki.
Study Phase: Phase II
Short Title: 
Study of T-DXd Monotherapy in Patients with HER2-expressing Locally Advanced or 
Metastatic Gastric or GEJ Adenocarcinoma who have Received 2 or More Prior Regimens
Acronym: DESTINY-Gastric06
Study Physician Name and Contact Information will be provided separately
National Co-ordinating Investigator:
VERSION HISTORY
Version
Date
Amendment 1
20-Dec-2021
Original Protocol
17-Dec-2020
Amendment 1
Overall Rationale for the amendment
Section number and 
name
Description of change
Brief rationale
Substantial/Non-
substantial
Study title
Change ‘Her2-positive’ to ‘Her2-
expressing’.
Population expansion.
S
Short title


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1.1 Synopsis-Rationale
Throughout the CSP, the eligible 
patients is changed from HER2 IHC 3+ 
or IHC 2+/ISH+ to HER2 IHC 3+ or 
IHC 2+.
Add the background information 
relating to HER2 IHC2+ gastric cancer. 
Add the updating therapy of anti-HER2 
treatment in 3L+ GC. 
Add the efficacy results of T-DXd in 
HER2 IHC2+/ISH- and newly approved 
RC48 in HER2 IHC2+ population. 
Expand population to HER2 
IHC 3+ or IHC 2+ (regardless 
of ISH status) reflects the 
expected change of anti-
HER2 treatment, and the 
potential of T-DXd efficacy 
may extend to IHC2+/ISH-
population. 
S
1.2 Schema
1.3.1 Screening and 
Enrolment Period
2.1 Study Rationale
2.2.2 Current Treatment 
Options for HER2-
positive Gastric Cancer
Table 4 Objectives and 
Endpoints
4.1 Overall Design
4.2.1 Rationale for Study 
Design 
4.2.2 Rationale for T-DXd 
in HER2 expressing 
Gastric and GEJ 
Adenocarcinoma
5 STUDY POPULATION
5.1 Inclusion Criteria
9.2 
 
 
 
 
 
 
 
Expand population to HER2 
IHC 3+ or IHC 2+ (regardless 
of ISH status) reflects the 
expected change of anti-
HER2 treatment, and the 
potential of T-DXd efficacy 
may extend to IHC2+/ISH-
population. 
S
9.3 Population for 
Analyses
Defined corresponding analysis 
populations for the HER2-expressing 
population
9.4.2.4 Secondary 
Endpoints in HER2-
expressing Population
Added planned analyses for endpoints 
in the HER2-expressing population, 
which will follow the same approach for 
endpoints in theHER2-positive 
population


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9.1 Statistical Hypotheses
Added gated approach for the HER2-
expressing population analyses, through 
which type 1 error will be controlled 
9.4.5 Methods for 
Multiplicity Control
1.1 Synopsis
Update study name DS8201-A-J202 to 
DESTINY-Gastric01.
Correction
NS
4.2.1 Rationale for Study 
Design
4.2.2 Rationale for T-Dxd 
in Her2-expressing 
Gastric and GEJ 
Adenocarcinoma
4.3 Justification for dose 
of TDxd
4.4 End of Study 
Definition
9.2 Sample Size 
Determination
9.4.1 General 
Considerations
1.1 Synopsis-Objectives 
and Endpoints
Correct the definition of DCR
Correction
NS
3 OBJECTIVES AND 
ENDPOINTS
9.4.2.3.5 Disease Control 
Rate
1.1 Synopsis-Objectives 
and Endpoints
Evaluate the efficacy and safety of the 
HER2-expessing (IHC 3+ or IHC 2+) 
patients as a secondary endpoint in 
addition to the primary population of the 
HER2-positive patients being studied. 
HER2 IHC 3+ or IHC 2+ 
(regardless of ISH status)  
population is added in the 
study.
S
3 Objectives and 
Endpoints
1.1 Synopsis-Objectives 
and Endpoints
Update definition of PFS 
To be consistent with analysis 
population and ITT principle
NS


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3 Objectives and 
Endpoints
9.4.2.3.2 Progression-free 
Survival
1.1 Synopsis-Objectives 
and Endpoints
Update definition of OS 
To be consistent with 
analysis population and ITT 
principle
NS
3 Objectives and 
Endpoints
9.4.2.3.3 Overall Survival
2.2.3 Trastuzumab 
Deruxtecan
Trastuzumab Deruxtecan approval 
status updated.
Updated to reflect new 
indication approval of 
Trastuzumab Deruxtecan.
NS
4.1.1 Study Duration
Study duration is updated.
Enrolment period is extended 
due to this CSP amendment.
NS
Table 1  
Schedule of Activities: 
Screening and Enrolment
Change the timing of collecting the 
Tissue sample for central laboratory 
confirmation of HER2 status
To be more reasonable for 
actual site practice.
NS
4.1 Overall Design
8.6.1 Collection of 
Mandatory Samples for 
Central Biomarker 
Analysis
Table 1  
Schedule of Activities: 
Screening and Enrolment
To widen the inclusion of resolved or 
inactive HBV subjects, updated the 
exclusion criteria, added lab tests 
monitoring requirement and 
clarifications for eligible HBV infection 
subjects, add requirement for 
permitted/rescue therapies and reporting 
HBV reactivation case within 24 hours. 
TMG is updated to add management of 
HBV reactivation.
Patients with chronic 
Hepatitis B (CHB) infection 
are typically excluded from 
oncology trials, this study 
refined the existing exclusion 
criteria and allow resolved or 
inactive HBV subjects 
participate the study and to 
develop recommendations for 
screening, monitoring, 
and management.
S
Table 2 
Schedule of Activities: 
Study Intervention Period
2.3.1.4 Anti-cancer 
treatments and 
immunosuppressants in 
eligible patients with 
Hepatitis B infection. 
5.2 Exclusion Criteria for 
past or resolved HBV or 
inactive chronic HBV 
infection.


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6.5.2 Other Protocol 
Restrictions or Supportive 
Treatments
7.1.1 Follow-up of 
Participants Post 
Discontinuation of Study 
Intervention
8.2.5.5 Safety assessment 
for Eligible HBV infection 
only
8.3.1 Time Period and 
Frequency for Collecting 
AE and SAE Information
Appendix K Toxicity 
Management Guideline 
Table 2 
Schedule of Activities: 
Study Intervention Period
Wording updated following PSSR V6
Updated to reflect latest safety 
information.
S
2.3.1.1 Potential Risks of 
T-DXd
Table 6 
Adequate Treatment
Washout Period
5.1 Inclusion Criteria 
5.2 Exclusion Criteria for 
unresolved toxicities and 
for spinal cord 
compression or active 
central nervous system 
metastases.
8.2.3 Electrocardiograms
8.3.11 
Adverse Events of Special 
Interest
Appendix D2 
Definitions for potential 
Hy’s law and Hy’s law 
case
Appendix D3 
Identification of Potential 
Hy’s Law Cases


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Appendix F Contraception 
requirement 
Table 18 
For Highly Effective 
Methods of Contraception
Appendix J 
Guidance for Management 
of Participants with Drug 
induced ILD/Pneumonitis 
Appendix K Toxicity 
Management Guideline
6.2.1 T-DXd Preparation, 
Administration and 
Storage
Clarification on dose recalculation. 
Clarification.
NS
6.6 Dose Modification
Removal of 49 day discontinuation 
criteria, updated as 
 to be the 
time frame for discontinuation, the 
criteria for drug resuming is added.
To allow longer time frame 
for drug discontinuation.
S
1.1 Synopsis-Follow-up of 
participants post 
discontinuation of study 
intervention
Continue treatment is based on INV's 
tumour assessment, not 'by ICR 
assessment'.
Typo correction.
NS
8.1.1 Imaging Tumour 
Assessments
8.6.1  Collection of 
Mandatory Samples for 
Central Biomarker 
Analysis
To revise the wording more properly to 
reflect the actual requirement of tumour
submission to meet regulatory 
requirement.
To add CDx filing related wording to 
support potential CDx requirement.
NMPA CDx policies evolve 
rapidly, CDx filing might be 
required in the future.
NS
8.6.1  Collection of 
Mandatory Samples for 
Central Biomarker 
Analysis
Add computer-aided analysis to explore 
clinical response-associated biomarkers.
Develop digital algorithm to 
better select patient in future.
NS
Table 2 
Schedule of Activities: 
Study Intervention Period
Delete Tumour imaging (RECIST 1.1) 
in C1D1
Clarify that tumour imaging 
(RECIST 1.1) no need to be 
done on Cycle 1 day 1.
NS


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Table 9
Laboratory Safety 
Variables
Remove the duplicate testing items, add 
percentage of Leukocyte differential 
count and Urea
Typo correction of Laboratory 
Safety Variables. 
NS
Table 2 
Schedule of Activities: 
Study Intervention Period
Remove requirement of 
Pharmacokinetic Assessment(s) if 
Chloroquine or Hydroxychloroquine is 
Administered
It is not feasible to collect PK 
sample if patient is diagnosed 
as COVID19 in China.
NS
Appendix H
Instructions Related to 
Severe Acute Respiratory 
Syndrome Coronavirus 2 
(COVID 19)
Table 3
Schedule of Activities: 
Post-study Intervention 
Follow-up and Survival
Remove requirement of ADA sample 
collection at Long- term Follow-Up 
period
Immunogenicity of T-DXd is 
considered to be low risk.
NS
8.5.2 Immunogenicity 
Assessments
Appendix D 8 
Laboratory Tests
Clarify that  local laboratory will be 
used for safety tests and the Hy’s Law 
Laboratory Kit is not applicable.
Clarification added to reflect 
China practice.
NS
Table 10 Spirometry 
Components
Update FEV to FEV1.
Typo
NS
Appendix L 
Abbreviations
New abbreviations was added, as 
required.
Minor updates to reflect 
changes to the protocol.
NS
11 Reference
New references were added, as required.
Add references to reflect 
changes to the protocol.
NS


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
VERSION HISTORY ........................................................................................................... 2
TABLE OF CONTENTS ...................................................................................................... 9
LIST OF FIGURES ............................................................................................................ 12
LIST OF TABLES .............................................................................................................. 12
1
PROTOCOL SUMMARY ................................................................................ 14
1.1
Synopsis ........................................................................................................... 14
1.2
Schema............................................................................................................. 21
1.3
Schedule of Activities ....................................................................................... 21
1.3.1
Screening and Enrolment Period....................................................................... 22
1.3.2
Study Intervention Period ................................................................................. 23
1.3.3
Post-study Intervention Follow-up Period ......................................................... 23
2
INTRODUCTION............................................................................................ 33
2.1
Study Rationale ................................................................................................ 33
2.2
Background ...................................................................................................... 35
2.2.1
HER2-positive Gastric Cancer .......................................................................... 35
2.2.2
Current Treatment Options for HER2-positive Gastric Cancer .......................... 36
2.2.3
Trastuzumab Deruxtecan................................................................................... 37
2.3
Benefit/Risk Assessment................................................................................... 38
2.3.1
Risk Assessment ............................................................................................... 38
2.3.1.1
Potential Risks of T-DXd .................................................................................. 38
2.3.1.2
Potential Risks of HER2-targeted Agents.......................................................... 39
2.3.1.3
Potential Risks of Topoisomerase I Inhibitors.................................................... 40
2.3.1.4
Anti-cancer treatments and immunosuppressants in eligible patients with 
Hepatitis B infection. ........................................................................................ 41
2.3.2
Benefit Assessment........................................................................................... 41
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 42
3
OBJECTIVES AND ENDPOINTS................................................................... 42
4
STUDY DESIGN ............................................................................................. 46
4.1
Overall Design.................................................................................................. 46
4.1.1
Study Duration.................................................................................................. 47
4.1.2
Duration of Study Participation......................................................................... 47
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 47
4.2
Scientific Rationale for Study Design ............................................................... 48
4.2.1
Rationale for Study Design ............................................................................... 48
4.2.2
Rationale for T-DXd in HER2-expressing Gastric and GEJ Adenocarcinoma.... 49
4.2.3
Rationale for Study Endpoints .......................................................................... 50
4.3
Justification for Dose of T-DXd ........................................................................ 50


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4.4
End of Study Definition.................................................................................... 52
5
STUDY POPULATION.................................................................................... 52
5.1
Inclusion Criteria .............................................................................................. 53
5.2
Exclusion Criteria ............................................................................................. 56
5.3
Lifestyle Considerations ................................................................................... 60
5.4
Screen Failures ................................................................................................. 61
6
STUDY INTERVENTION ............................................................................... 61
6.1
Study Interventions Administered ..................................................................... 61
6.1.1
Investigational Products.................................................................................... 61
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 62
6.2.1
T-DXd Preparation, Administration and Storage ............................................... 63
6.3
Measures to Minimise Bias............................................................................... 64
6.4
Study Intervention Compliance......................................................................... 66
6.5
Concomitant Therapy........................................................................................ 66
6.5.1
Prohibited Concomitant Medications ................................................................ 67
6.5.2
Other Protocol Restrictions or Supportive Treatments....................................... 68
6.6
Dose Modification ............................................................................................ 69
6.7
Intervention after the End of the Study.............................................................. 72
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 73
7.1
Discontinuation of Study Intervention............................................................... 73
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention............... 74
7.1.2
Follow-up for Survival...................................................................................... 74
7.2
Participant Withdrawal from the Study.............................................................. 74
7.3
Lost to Follow-up ............................................................................................. 75
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 76
8.1
Efficacy Assessments........................................................................................ 77
8.1.1
Imaging Tumour Assessments........................................................................... 77
8.1.2
Central Reading of Scans.................................................................................. 78
8.1.3
Overall Survival................................................................................................ 78
8.1.4
Clinical Outcome Assessments.......................................................................... 78
8.2
Safety Assessments........................................................................................... 78
8.2.1
Physical Examinations...................................................................................... 79
8.2.2
Vital Signs ........................................................................................................ 79
8.2.3
Electrocardiograms........................................................................................... 80
8.2.4
Clinical Safety Laboratory Assessments............................................................ 81
8.2.5
Other Safety Assessments ................................................................................. 83
8.2.5.1
Echocardiogram/Multigated Acquisition Scan................................................... 83
8.2.5.2
Pulmonary Assessments.................................................................................... 83
8.2.5.3
ECOG Performance Status................................................................................ 85
8.2.5.4
Ophthalmological Assessments......................................................................... 86


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8.2.5.5
Safety assessment for Eligible HBV infection only ........................................... 86
8.3
Adverse Events and Serious Adverse Events..................................................... 86
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 87
8.3.2
Follow-up of AEs and SAEs ............................................................................. 88
8.3.3
Causality Collection.......................................................................................... 89
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 89
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 89
8.3.6
Hy’s Law.......................................................................................................... 90
8.3.7
Disease Progression.......................................................................................... 90
8.3.8
Disease Under Study......................................................................................... 90
8.3.9
New Cancers..................................................................................................... 90
8.3.10
Deaths .............................................................................................................. 91
8.3.11
Adverse Events of Special Interest.................................................................... 91
8.3.12
Safety Data to be Collected Following Final Study Data Cutoff........................ 92
8.3.13
Reporting of Serious Adverse Events ................................................................ 93
8.3.14
Pregnancy......................................................................................................... 93
8.3.14.1
Maternal Exposure............................................................................................ 93
8.3.14.2
Paternal Exposure............................................................................................. 94
8.3.15
Medication Error............................................................................................... 94
8.4
Overdose .......................................................................................................... 95
8.5
Human Biological Samples............................................................................... 95
8.5.1
Pharmacokinetics.............................................................................................. 95
8.5.1.1
Determination of Drug Concentration ............................................................... 96
8.5.2
Immunogenicity Assessments ........................................................................... 96
8.6
Human Biological Sample Biomarkers ............................................................. 96
8.6.1
Collection of Mandatory Samples for Central Biomarker Analysis.................... 96
9
STATISTICAL CONSIDERATIONS................................................................ 97
9.1
Statistical Hypotheses....................................................................................... 98
9.2
Sample Size Determination............................................................................... 98
9.3
Populations for Analyses................................................................................... 99
9.4
Statistical Analyses ......................................................................................... 100
9.4.1
General Considerations................................................................................... 100
9.4.2
Efficacy .......................................................................................................... 102
9.4.2.1
Calculation or Derivation of Tumour Response Variable ................................. 102
9.4.2.2
Primary Endpoint: Confirmed ORR by ICR per RECIST 1.1.......................... 102
9.4.2.3
Secondary Endpoints in HER2 Positive Population......................................... 103
9.4.2.4
Secondary Endpoints in HER2-expressing Population .................................... 107
9.4.3
Safety ............................................................................................................. 107
9.4.4
Other Analyses................................................................................................ 109
9.4.4.1
Pharmacokinetics............................................................................................ 109
9.4.4.2
Immunogenicity Data...................................................................................... 109
9.4.4.3
COVID-19...................................................................................................... 109
9.4.5
Methods for Multiplicity Control .................................................................... 110
9.5
Interim Analyses............................................................................................. 110


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9.6
Data Monitoring Committees.......................................................................... 110
9.6.1
ILD Adjudication Committee.......................................................................... 110
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 110
11
REFERENCES............................................................................................... 165
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 21
LIST OF TABLES
Table 1
Schedule of Activities: Screening and Enrolment..................................... 24
Table 2
Schedule of Activities: Study Intervention Period .................................... 27
Table 3
Schedule of Activities: Post-study Intervention Follow-up and Survival .. 31
Table 4
Objectives and Endpoints......................................................................... 42
Table 5
Parameters for Adequate Organ and Bone Marrow Function.................... 54
Table 6
Adequate Treatment Washout Period....................................................... 55
Table 7
Study Intervention: T-DXd ...................................................................... 62
Table 8
Dose Reduction Levels of T-DXd............................................................ 69
Table 9
Laboratory Safety Variables..................................................................... 82
Table 10
Spirometry Components .......................................................................... 84
Table 11
Populations for Analysis .......................................................................... 99
Table 12
Summary of Outcome Variables and Analysis Populations .................... 101
Table 13
Hy’s Law Laboratory Kit for Central Laboratories................................. 128
Table 14
Summary of Imaging Modalities for Tumour Assessment...................... 130
Table 15
RECIST 1.1 Evaluation of Target Lesions ............................................. 137
Table 16
RECIST 1.1 Evaluation of Non-target Lesions....................................... 138
Table 17
RECIST 1.1 Overall Visit Response ...................................................... 139
Table 18
Highly Effective Methods of Contraception (< 1% Failure Rate) ........... 143
Table 19
Restricted Medications/Therapies .......................................................... 144
Table 20
Prohibited Medications/Therapies.......................................................... 145
Table 21
Supportive Medications/Therapies......................................................... 146
Table 22
COVID-19 Dose Modification Criteria .................................................. 149
Table 23
Toxicity Management Guidelines for T-DXd......................................... 153


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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 111
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 116
Appendix C
Handling of Human Biological Samples ................................................ 121
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 124
Appendix E
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 130
Appendix F
Contraception Requirements.................................................................. 141
Appendix G
Concomitant Medications ...................................................................... 144
Appendix H
Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (COVID-19) ................................................................... 148
Appendix I
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 151
Appendix J
Guidance for Management of Participants with Drug-induced 
ILD/Pneumonitis ................................................................................... 152
Appendix K
Toxicity Management Guidelines .......................................................... 153
Appendix L
Abbreviations ........................................................................................ 161


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Single-arm Study of Trastuzumab Deruxtecan (T-DXd) Monotherapy for 
Patients with HER2-expressing Locally Advanced or Metastatic Gastric or Gastroesophageal 
Junction (GEJ) Adenocarcinoma Who Have Received 2 or More Prior Regimens 
(DESTINY-Gastric06)
Short Title: Study of T-DXd Monotherapy in Patients with HER2-expressing Locally 
Advanced or Metastatic Gastric or GEJ Adenocarcinoma who have Received 2 or More Prior 
Regimens
Rationale:
Human epidermal growth factor receptor 2 (HER2) is an important target protein for gastric 
cancer (GC) therapy. HER2-expression initiates a strong pro-tumorigenic signaling cascade 
and HER2-positive status is associated with decreased survival and several clinicopathological 
features of tumor progression. HER2 testing is recommended for all patients with gastric 
adenocarcinoma at the time of diagnosis if metastatic disease is documented or suspected. 
Hofmann et al refined HER2-positive as cases that have an immunohistochemistry (IHC) 
score of 3+ or an IHC score 2+ and in situ hybridization (ISH) positive. In China,  
HER2-positivity is reported in 12% to 13% of patients with GC. A score of IHC 0 or 1+ is 
considered to be HER2-negative. A score of IHC 2+ is considered equivocal and should be 
additionally examined by ISH methods. However, the testing rate of ISH in the IHC 2+ 
population in China is very low (<10%). Regardless of ISH results, there are 22% to 24% of 
GC patients in China have HER2 expressing (defined as IHC 3+ or IHC 2+ in this study) 
status. 
Metastatic GC has a poor prognosis. In China, approved treatment options after failure of 
trastuzumab are limited to single-agent chemotherapy, followed by third-line therapy 
(regardless of HER2 status) with apatinib, nivolumab or single agent chemotherapy, or with a 
recently (June 2021) NMPA conditionally approved (not recommended in guidelines) anti-
HER2 antibody drug conjugate (ADC) RC-48.
Given that most patients with HER2-positive advanced GC eventually acquire resistance or 
show intolerance to approved first- or second-line therapies and no HER2-targeting treatment 
recommended beyond the first-line setting in China, HER2-positive advanced GC is a serious, 
life-threatening disease with a high unmet medical need. Trastuzumab deruxtecan (T-DXd) is 
a HER2-targeting ADC being developed as a treatment for several HER2-expressing tumours, 
including GC. The current study aims to evaluate the efficacy and safety of T-DXd 
monotherapy in patients in China with HER2-positive locally advanced or metastatic gastric 
or gastroesophageal junction (GEJ) adenocarcinoma who have received 2 or more prior 
regimens in order to assess efficacy and safety in a Chinese population. The study population 
closely follows that of a recent study in Japan and Korea (Study DESTINY-Gastric01) in 


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which the efficacy and safety of T-DXd (6.4 mg/kg) were evaluated in participants with 
HER2-positive advanced gastric or GEJ adenocarcinoma who had progressed on at least 2 
prior regimens including a fluoropyrimidine agent, a platinum agent, and trastuzumab 
compared with the physician’s choice of treatment (irinotecan or paclitaxel monotherapy). At 
the data cutoff (DCO) for the primary analysis, the confirmed objective response rate (ORR) 
per Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 1.1) by independent 
central review (ICR) was 40.5% (95% confidence interval [CI]: 31.8, 49.6) in the T-DXd 
group with 51/126 participants having a best overall response of complete response (CR) (10 
[7.9%] participants) or partial response (PR) (41 [32.0%] participants) and significantly higher 
than that for the comparator group where the ORR was 11.3% (95% CI: 4.7, 21.9) with 
7/62 participants having a best overall response of PR (7 [11.3%] participants) (p < 0.0001). 
The unconfirmed ORR per RECIST 1.1 by ICR was 51.3% (95% CI: 41.9, 60.5) in the T-DXd 
group with 61/119 participants having a best overall response of CR (11 [9.2%] participants) 
or PR (50 [42.0%] participants), significantly higher than for the comparator group where the 
ORR was 14.3% (95% CI: 6.4, 26.2) with 8/56 participants having a best overall response of 
PR (8 [14.3%] participants) (p < 0.0001).
Primary analysis of another Phase 2 single arm trial (Study DESTINY-Gastric02) which 
investigated T-DXd (6.4 mg/kg) in western patients with HER2 positive unresectable or 
metastatic gastric or GEJ cancer who progressed on or after a Trastuzumab containing 
regimen showed comparable efficacy in US and European populations in addition to Korean 
and Japanese populations. The confirmed ORR was 38% (95% CI, 27.3-49.6) with 30/79 
participants having a best overall response of CR (3 [3.8%] participants) or PR (27 [34.2%] 
participants).
Given that no anti-HER2 therapy is recommended for HER2-positive GC patients in China 
who have failed a trastuzumab-containing regimen and that the ORR for the current standard 
of care (SoC) in the third-line setting in China is approximately 
 (consistent with the 
findings of Study DESTINY-Gastric01), there is a clear rationale for evaluating the potential 
of T-DXd in the treatment of HER2-positive GC patients in China who have received 2 or 
more prior regimens, including a fluoropyrimidine agent and a platinum agent. 
Results from Study
 also showed T-DXd has benefit 
in 
population, confirmed ORR by ICR (FAS) in
 
 [95% CI: 
])was comparable to that in 
 population (
 
[95% CI: 
]). These data suggest that the antitumor activity of T-DXd may also 
extend to 
population and this warrants further evaluation.
The similar efficacy results in HER2 IHC 2+ population were seen in another anti-HER2 
ADC, RC-48, which is a novel recombinant human anti-HER2 monoclonal antibody 
conjugated with a microtubule inhibitor (monomethyl auristatin E) via a cleavable linker. In a 








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efficacy and safety will be evaluated as secondary endpoints. Participant eligibility with
respect to HER2 status will be determined locally, however, the analyses of primary and 
secondary efficacy endpoints will be performed on participants whose HER2-
positive/expressing status is confirmed by central laboratory.
Number of Participants:
Approximately
 will be screened in order to enroll approximately 
participants with HER2-expressing (IHC 3+ or IHC 2+, based on local laboratory report) 
advanced gastric or GEJ adenocarcinoma who have received at least 2 prior regimens 
including a fluoropyrimidine agent and a platinum agent to study intervention. This is to 
ensure that approximately 
participants enrolled in the study have HER2-positive (IHC3+, 
or IHC2+/ISH +) status confirmed by central laboratory as these participants will form the 
basis of the primary analysis population. This also provides opportunity for the secondary 
objective of the study which is to assess efficacy using confirmed ORR as endpoint in 
approximately 
 participants who have HER2-expressing (IHC 3+ or IHC 2+) status 
confirmed by central laboratory. 
Assuming the true ORR (by ICR) of T-DXd is
 approximately 
participants with 
HER2-positive (defined as IHC 3+ and IHC 2+/ISH + by central laboratory) advanced gastric 
or GEJ adenocarcinoma will provide approximately 
 probability for the 
 
 of the study intervention ORR to 
 For the 
ORR in the HER2-expressing population the 
 and 
therefore the 
 Refer to Section 9.2
for further information.
Note: Potential participants who are screened for the purpose of determining eligibility for the 
study but are not enrolled, are considered “screen failures”, unless otherwise specified by the 
protocol.
Intervention Groups and Duration:
Following confirmation of eligibility during screening (28-day screening period), all enrolled 
participants will be assigned to treatment with open-label T-DXd 6.4 mg/kg as an intravenous 
infusion once every 3 weeks, on Day 1 of each 3-week cycle. Study intervention may continue 
until RECIST 1.1-defined progressive disease (PD) or any other criterion for discontinuation 
of study intervention is met.
Study intervention (T-DXd) beyond RECIST 1.1-defined PD is not permitted in this study. 
Follow-up of participants post discontinuation of study intervention:
After study intervention discontinuation, all participants will undergo an end of treatment visit 
(within 7 days after discontinuation) and will be followed up for safety assessments 40 (+ 7)


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days after their last dose of study intervention (ie, the safety follow-up visit).
Participants who have discontinued study intervention in the absence of RECIST 1.1 defined 
radiological progression confirmed by investigator will be followed up with tumour 
assessments according to the Schedule of Activities (SoA) until RECIST 1.1 defined PD or 
death regardless of whether or not they start a subsequent anticancer therapy, unless they have 
withdrawn all consent to study-related assessments.
In addition, all participants who discontinue study intervention will be followed up for 
long-term safety, including survival status, every 3 months (± 14 days) from the date of the 
safety follow-up visit until death, withdrawal of consent, or the end of the study, as per the 
SoA.
See Section 6.7 for a description of assessments following study DCO.
Statistical methods
This is a single-arm, Phase II open-label study in which all participants will receive the same 
study intervention. The primary objective of the study is to evaluate the efficacy of T-DXd by 
assessing the confirmed ORR by ICR in participants with HER2-positive (defined as IHC 3+ 
and IHC 2+/ISH + by central laboratory) advanced gastric or GEJ adenocarcinoma who have 
received at least 2 prior treatment regimens. A secondary objective of the study is to evaluate 
the efficacy of T-DXd by assessing the confirmed ORR by ICR in participants with HER2-
expressing (defined as IHC 3+ and IHC 2+ by central laboratory) advanced gastric or GEJ 
adenocarcinoma who have received at least 2 prior treatment regimens. 
The primary endpoint of the study is confirmed ORR, defined as the number (%) of 
participants with confirmed CR or PR as determined by ICR per RECIST 1.1. ORR by ICR 
will be estimated with a 2-sided 95% exact CI.
To ensure strong control of type 1 error amongst the primary and secondary ORR endpoints in 
the HER2-positive and HER2-expressing populations, 
 will be applied to the 
analysis of ORR in the 
. The analysis of ORR in the 
 See Section 9.4.5 for details.
The DCO for the primary analysis of ORR by ICR will occur approximately months after 
the last participant has initiated study intervention. Duration of response (DoR), disease 
control rate (DCR), tumour size change, and available safety, tolerability, and pharmacokinetic 
(PK) data will also be summarised at this time.
The DCO for the full final analysis of ORR by ICR will occur approximately 
months after 
the last participant has initiated study intervention. Based on data from Study DESTINY-




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Schedules of activities (SoA) are provided in Table 1 (screening and enrolment), Table 2
(study intervention), and Table 3 (post-study intervention follow-up and survival). Additional 
information is provided in Sections 1.3.1, 1.3.2, and 1.3.3, respectively. Additional general 
information is provided below:

If vital signs and blood draws are scheduled for the same nominal time, vital signs should 
be assessed before blood draws. 

If electrocardiograms (ECGs), vital signs, and blood draws are scheduled for the same 
nominal time, the assessments should occur in the following order: ECG, vital signs, 
blood draws. The timing of the first 2 assessments should be such that it allows the blood 
draw to occur at the timepoints indicated in the SoA.

On visits where participants do not receive study intervention, they should undergo a 
physical examination and vital signs assessment with additional assessments at the 
discretion of the investigator. 
1.3.1
Screening and Enrolment Period
Screening and enrolment procedures are presented in the SoA (Table 1). 
After signing the main informed consent form (ICF), participants will begin screening 
procedures. Screening will take place in the 28 days prior to enrolment. The SoA (Table 1) 
indicates which screening procedures should be completed in the 14 days prior to enrolment. 
Eligible participants must have documented HER2 status as IHC 3+ or IHC 2+. For the 
purposes of determining study eligibility during screening, HER2-positivity should be 
determined at site based on a documented pathology result obtained from either a local 
laboratory or from a previous pathology report that has been confirmed by the investigator. 
HER2 status will subsequently be confirmed by a central laboratory but the result of central 
HER2 testing will not determine study eligibility. To enable confirmation of HER2 status by 
central laboratory, an adequate newly acquired tumour sample should be provided during 
screening for all participants where the primary tumour is accessible by endoscopy or if 
metastatic tissue can be biopsied. If a newly acquired sample is not available, an archived 
sample is acceptable and should be based on the most recent archived tumour tissue sample.
Following completion of all screening procedures and documentation of all baseline 
assessments, eligible participants will be enrolled in the study. The date of enrolment is 
defined as the date the participant is confirmed as eligible in the interactive response 
technology (IRT). Thus, a treatment assignment number should be obtained from the IRT on 
the day the participant’s eligibility is confirmed and they are enrolled in the study.
Participants who fail to meet the eligibility criteria will be termed “screen failures”. Screen 


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failures may be rescreened once (see Section 5.4).
Every effort should be made to minimize the time between the completion of 
screening/baseline assessments and the first dose of study intervention (no more than 3 days).
If it is anticipated that dosing cannot occur within 3 days, a discussion with the AstraZeneca 
study physician is required. 
1.3.2
Study Intervention Period
Procedures to be conducted during the study intervention period until the end of treatment are 
presented in the SoA (Table 2). Participants must not receive study intervention unless all 
eligibility criteria have been met.
1.3.3
Post-study Intervention Follow-up Period
Procedures to be conducted during the post-study intervention follow-up period (including 
survival assessments) are presented in the SoA (Table 3).


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Table 1
Schedule of Activities: Screening and Enrolment
Procedures
Screening/Baseline
(Days -28 to -1)
Notes
For Details, see 
Section or 
Appendix:
Written informed consent a
X
5.1 and A 3
Contact IRT to obtain E-code
X
Obtain E-code once participant signs the ICF
6.3
Study Procedures and Assessments
Documentation of HER2-positivity for eligibility b
X
HER2-positivity should be determined at site based on a documented 
pathology result obtained from either a local laboratory or from a 
previous pathology report that has been confirmed by the investigator
5.1 and 8.6.1
Provision of mandatory tumour sample for confirmation of 
HER2 status by central laboratory c
X
Tissue sample for central laboratory confirmation of HER2 status 
must be provided after enrolment and prior to first dose of study 
intervention
5.1 and 8.6.1
Inclusion and exclusion criteria
X
Re-check prior to first dose of study intervention
5.1 and 5.2
Demography
X
5.1
Full physical examination
X d
8.2.1
Height and weight
X d
8.2.1
Medical history (includes substance usage and family 
history of premature cardiovascular disease)
X
Include: drugs, alcohol, caffeine, and tobacco (including history 
[dates], type, and frequency of tobacco use, e-cigarette use, vaping)
5.1, 5.2 and 5.3
Primary cancer history
X
Include prior anticancer therapy
5.1 and 5.2
Tumour Assessment
Tumour imaging (RECIST 1.1) 
X
8.1.1
Safety Assessments
ECOG performance status
X d
8.2.5.3
12-lead ECG
X d
Performed in triplicate completed within 5 minutes
8.2.3
Vital signs
X d
8.2.2
ECHO or MUGA
X
8.2.5.1
Lung Function
Pulmonary function tests 
X
8.2.5.2
SpO2
X
8.2.5.2


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Procedures
Screening/Baseline
(Days -28 to -1)
Notes
For Details, see 
Section or 
Appendix:
High-resolution computed tomography scan
X
8.2.5.2
Laboratory Assessments
Serum pregnancy test (WOCBP only)
X
Negative serum pregnancy test must be available within 72 hours 
prior to enrolment for WOCBP
5.1, 5.2, and 8.2.4
Hepatitis B/C serologyf
X
5.2 and 8.2.4
HIV antibody test (as required by local regulations or IEC)
X
5.2 and 8.2.4
Clinical safety laboratory assessments (clinical chemistry, 
haematology)
X d
Clinical laboratory assessments must be completed within 14 days 
prior to enrolment. See inclusion criterion 8
8.2.4
Coagulation
X d
Coagulation tests performed only at screening include PT/INR and 
PTT/aPTT
8.2.4
Urinalysis
X d
8.2.4
Troponin
X d
8.2.3 and 8.2.4
Other Safety Assessments
Ophthalmologic assessments
X
8.2.5.4
Adverse events
X
Collect AEs and SAEs from provision of informed consent
8.3
Concomitant therapy
X
6.5
Treatment Assignment
Contact IRT to obtain treatment assignment number on the 
day the participant is enrolled (ie, confirmed as eligible)
X e
Once a participant has completed screening and been confirmed as 
eligible
6.3
a
Written informed consent and any locally required privacy act document authorisation must be obtained prior to performing any protocol-specific procedures, including 
screening/baseline evaluations.
b
If the participant’s HER2 status has not been documented previously, a tissue sample must be provided for local HER2 status testing. If the primary tumour is accessible by 
endoscopy or if metastatic tissue can be biopsied, this should be a newly-acquired tumour tissue sample. If a newly acquired sample is not available, an archived sample is 
acceptable and should be based on the most recent archived tumour tissue sample. Providing the sample should be given the highest priority so eligibility can be confirmed 
within the 28-day screening period. See Section 8.6.1.
c
All participants must provide a tumour sample for confirmation of HER2 status by central laboratory. If the primary tumour is accessible by endoscopy or if metastatic tissue 
can be biopsied, this should be a newly-acquired tumour tissue sample. If a newly acquired sample is not available, an archived sample is acceptable and should be based on 
the most recent archived tumour tissue sample. The results of central laboratory testing are not used to determine participant eligibility. See Section 8.6.1.
d
Assessment must be completed within the 14 days prior to enrolment, ie, Days -14 to -1.
e
Participants may only be confirmed as eligible and enrolled into the study once all screening procedures have been completed. 


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f
HBsAg; anti-HBc (IgG or total Ig) for all patients. HBeAg and HBV DNA are additionally required if HBsAg positive;  anti-HBs and HBV DNA are additionally required if 
HBsAg negative, anti-HBc positive, at screening (See Section 8.2.4 Clinical Safety Laboratory Assessments)
AE = adverse event; aPTT = activated partial thromboplastin time; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; HER2 =
human epidermal growth factor receptor 2; HIV = human immunodeficiency virus; ICF = informed consent form; IEC = independent ethics committee; INR = international 
normalised ratio; IRT = interactive response technology; MUGA = multigated acquisition; PT = prothrombin time; PTT = partial thromboplastin time; RECIST 1.1 = Response 
Evaluation Criteria in Solid Tumours, Version 1.1; SAE = serious adverse event; SpO2 = pulse oximetry; WOCBP = women of childbearing potential.


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Table 2
Schedule of Activities: Study Intervention Period
Procedure
Study Intervention
EOT or ED
Notes
For Details, 
see Section 
or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and 
subsequent 
cycles until 
PD
Day
1
8
15
1
1
1
Visit Window (days)
± 1
± 1
± 2
± 2
± 2
+ 7
Study Procedures and Assessments
Inclusion and exclusion criteria
X
Re-check clinical status 
before first dose of study 
intervention
5.1 and
5.2
Targeted physical examination
X a
X
X
X a
X a
X a
X
8.2.1
Weight
X a
X a
X a
X a
X
8.2.1
Tumour Assessment
Tumour imaging (RECIST 1.1)
Every 6 weeks (± 7 days) from first dose of study intervention until RECIST 1.1-defined 
radiological PD
8.1.1
Safety Assessments
ECOG performance status
X a
X a
X a
X a
X
8.2.5.3
12-lead ECGd
X a
X a (C5 and 
every 4 cycles 
thereafter)
X
Single ECG trace, unless 
abnormalities noted
8.2.3
Vital signs 
X a
X
X
X a
X a
X a
X
Before and at end of 
infusion on Day 1 of each 
cycle
8.2.2
ECHO or MUGAe
X a (C5 and 
every 4 cycles 
thereafter)
X
8.2.5.1


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Table 2
Schedule of Activities: Study Intervention Period
Procedure
Study Intervention
EOT or ED
Notes
For Details, 
see Section 
or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and 
subsequent 
cycles until 
PD
Day
1
8
15
1
1
1
Visit Window (days)
± 1
± 1
± 2
± 2
± 2
+ 7
Lung Function
SpO2
X a
X
X
X a
X a
X a
X
Before and at end of 
infusion on Day 1 of each 
cycle
8.2.5.2
Pulmonary function tests
If ILD/pneumonitis is suspected
8.2.5.2
High-resolution computed tomography c
If ILD/pneumonitis is suspected
8.2.5.2
ILD/pneumonitis investigation
If ILD/pneumonitis is suspected
8.2.5.2.1
Laboratory Assessments
Serum or urine pregnancy test (WOCBP 
only)
X
X
X
X
X
Negative pregnancy test 
required within 72 hours 
prior to each dose of 
study intervention
5.1, 5.2,
and 8.2.4
Clinical safety laboratory assessments 
(clinical chemistry, haematology)
X a
X
X
X a
X a
X a
X
8.2.4
Laboratory tests
Eligible HBV infection only g
X
X(alternate 
cycles)
X
X q3 mo F/U 
(± 14 days)
8.2.5.5
Coagulation
As clinically indicated
8.2.4
Urinalysis
As clinically indicated
8.2.4
Troponin
Whenever a participant reports signs or symptoms suggesting CHF, 
MI, or other causes of myocyte necrosis
X
8.2.3 and 
8.2.4
Other Safety Assessments
Ophthalmologic assessments
As clinically indicated
X
8.2.5.4


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Table 2
Schedule of Activities: Study Intervention Period
Procedure
Study Intervention
EOT or ED
Notes
For Details, 
see Section 
or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and 
subsequent 
cycles until 
PD
Day
1
8
15
1
1
1
Visit Window (days)
± 1
± 1
± 2
± 2
± 2
+ 7
Adverse events f
At every visit. May be conducted by phone if not tied to a visit
Collect AEs/SAEs 
throughout study 
intervention, until 
completion of safety 
follow-up visit
(see Table 3)
8.3
Concomitant therapy 
At every visit and may be conducted by phone if not tied to a visit
6.5
Pharmacokinetic and Immunogenicity Assessments
Pre-dose blood sample for T-DXd PK 
testing
X
X
X
X (Cycles 4, 6, 
and 8)
Take samples within 
8 hours before infusion
8.5.1
End of infusion blood sample for T-DXd 
PK testing
X
X
X
X (Cycle 4)
Take samples within 
15 minutes after end of 
infusion
8.5.1
5 hours post-dose blood sample for 
T-DXd PK testing
X
Take sample within 
5 (± 2) hours after start of 
infusion (C1 D1)
8.5.1
Additional blood sample for T-DXd PK 
testing (if feasible)
If ILD/pneumonitis is suspected
8.5.1
Pre-dose blood sample for 
immunogenicity testing
X
X
X (C4 and 
every 4 cycles 
thereafter, ie, 
Cycles 4, 8, 12, 
etc)
Take samples within 
8 hours before infusion at 
time points indicated
8.5.2
Study Intervention Administration b


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Table 2
Schedule of Activities: Study Intervention Period
Procedure
Study Intervention
EOT or ED
Notes
For Details, 
see Section 
or 
Appendix
Cycle 1
Cycle 2
Cycle 3
Cycle 4 and 
subsequent 
cycles until 
PD
Day
1
8
15
1
1
1
Visit Window (days)
± 1
± 1
± 2
± 2
± 2
+ 7
T-DXd b
6.4 mg/kg intravenous infusion on Day 1 of each 3-week cycle
Do not co-administer 
other drugs through the 
same infusion line
6 and 7
a
Within 3 days prior to administration of study intervention. 
b
Every effort should be made to minimise the time between enrolment (confirmation of eligibility) and starting study intervention (ie, within 3 days).
c
HRCT is preferred and recommended, CT Scan should be used only when HRCT is not available.
d
ECG will be taken in triplicate before infusion on C1D1. Subsequent ECGs will be performed in triplicate in close succession only if an abnormality is noted. ECGs will be 
taken while in a supine/semi-recumbent position. ECGs will then be taken at every 4th cycle (i.e. C5, 9, 13…) If ECG is abnormal follow institutional guidelines.
e
ECHO or MUGA scan assessments (note: the same test must be used for the subject throughout the study) will be performed before infusion on Day 1 of Cycle 5 and then 
every 4 cycles (within7 days of IMP administration) (e.g. Cycle 5, 9, 13…)
f
All adverse events and SAEs (other than ILD/pneumonitis and reactivation of Hepatitis B) will be collected from the time of signature of the ICF throughout the treatment 
period and including the safety follow-up (which is 40 +7 days after the discontinuation of all IPs or until initiation of another therapy). For ILD/pneumonitis or Hepatitis B 
reactivation, safety follow up will be continued until resolution of ILD/pneumonitis or Hepatitis B reactivation. If an event that starts post the defined safety follow up period 
noted above is considered to be due to a late onset toxicity to study treatment, including reactivation in eligible patients with Hepatitis B infection, then it should be reported 
as an AE or SAE as applicable.
g
For eligible patients with HBsAg (-), anti-HBc (+) (IgG or total Ig) serology: HBsAg, ALT, and HBV DNA should be measured within 7 days before administration of cycle 
2 and alternate cycles thereafter. For eligible patients with HBsAg (+), and HBV DNA <2000IU: ALT and HBV DNA should be measured within 7 days before 
administration of cycle 2 and alternate cycles thereafter. For all eligible HBV patients, if study medication is interrupted monitoring should be continued at least 3–monthly 
or if study medication is discontinued, monitoring should be continued at least 3-monthly for at least 12 months. (See Section 8.2.5.5 Safety assessment for Eligible HBV 
infection only)
Note: All assessments on study intervention days are to be performed prior to study intervention administration, unless otherwise indicated. Data collection following study 
analysis until the end of the study is described in Section 8.
AE = adverse event; C = cycle; CHF = congestive heart failure; D = day; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; ED
= Early Study Intervention/Discontinuation; EOT = End of Treatment; ILD = interstitial lung disease; MI = myocardial infarction; MUGA = multigated acquisition; PD =
progressive disease; PK = pharmacokinetic; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours, Version 1.1; SAE = serious adverse event; SpO2 = pulse oximetry; 
T-DXd = trastuzumab deruxtecan; WOCBP = women of childbearing potential.


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Table 3
Schedule of Activities: Post-study Intervention Follow-up and Survival
Procedures
Post-intervention Follow-up Period
Notes
For Details, 
see Section
Safety Follow-up
Long-term Follow-up
Days
40 days after last dose
Every 3 months
Window
+ 7 days
± 14 days
Targeted physical examination
X
8.2.1
Weight
X
8.2.1
Subsequent anticancer therapy, including surgery 
and radiation therapy
X
X
7.1.1
Tumour Assessment
Tumour imaging (RECIST 1.1)
Every 6 weeks (± 7 days) from first dose of 
treatment until RECIST 1.1-defined PD
All participants should have IV contrast-enhanced CT 
or MRI of the chest, abdomen, and pelvis every 6
weeks (± 7 days) until RECIST 1.1-defined 
radiological PD
Participants who discontinue study intervention due to 
reasons other than PD or death (regardless of whether 
they have started subsequent anticancer therapy): IV 
contrast-enhanced CT or MRI of the chest, abdomen, 
and pelvis every 6 weeks (± 7 days) for the first 
48 weeks after the date of the first dose of study 
intervention, then every 12 weeks (± 7 days) thereafter, 
until RECIST 1.1-defined radiological PD
8.1.1
Safety Assessments
ECOG performance status
X
8.2.5.3
Vital signs
X
8.2.2
SpO2
X
8.2.5.2
Laboratory Assessments
Serum or urine pregnancy test (WOCBP only)
X
8.2.4
Clinical safety laboratory assessments (clinical 
chemistry, haematology)
X
8.2.4
Coagulation
As clinically indicated
8.2.4
Urinalysis
As clinically indicated
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Procedures
Post-intervention Follow-up Period
Notes
For Details, 
see Section
Safety Follow-up
Long-term Follow-up
Days
40 days after last dose
Every 3 months
Window
+ 7 days
± 14 days
Other Safety Assessments
Adverse events
At every visit. 
May be conducted by phone if not tied to a visit
Collect AEs/SAEs until completion of SFU visit. 
Follow-up events of ILD/pneumonitis to resolution. If 
an event that starts after the SFU visit is considered due 
to a late onset toxicity to study intervention, report as 
an AE/SAE, as applicable
8.3
Concomitant therapy
At every visit. 
May be conducted by phone if not tied to a visit
6.5
Immunogenicity Assessments
Blood sample for immunogenicity testing
X a
a Take SFU visit sample at 40 (+ 7 days) after last study 
intervention or before starting new anticancer 
treatment, whichever occurs first
8.5.2
Other Assessments
Survival status
X
X
Until death, withdrawal of consent, or end of study
7.1.2
ADA = anti-drug antibody; AE = adverse event; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; ILD = interstitial lung disease; IV = intravenous; 
MRI = magnetic resonance imaging; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours, Version 1.1; SAE = serious adverse event; SFU =
safety follow-up; SpO2= pulse oximetry; WOCBP = women of childbearing potential.


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2
INTRODUCTION
Trastuzumab deruxtecan (T-DXd; also known as DS-8201a) is a HER2-targeting 
antibody-drug conjugate (ADC) in development as a candidate therapy for breast cancer and 
other HER2-expressing tumours. The non-proprietary name for T-DXd is trastuzumab 
deruxtecan except in the United States where it is fam-trastuzumab deruxtecan-nxki.
2.1
Study Rationale
Human epidermal growth factor receptor 2 (HER2) is an important target protein for gastric 
cancer (GC) therapy (Huang et al 2013). HER2 expression initiates a strong pro-tumourigenic 
signalling cascade and it has been shown that HER2-positive status is associated with 
decreased survival and clinicopathological features of tumour progression, such as invasion, 
metastases, and higher disease stage (Gravalos and Jimeno 2008). HER2 testing is therefore 
recommended for all gastric adenocarcinoma patients at the time of diagnosis if metastatic 
disease is documented or suspected. Immunohistochemistry (IHC) and in situ hybridisation 
(ISH) are the gold standard methods for HER2 testing.
HER2-positive was refined by Hofmann et al in 2008 (Bang et al 2010, Hofmann et al 2008)
and was validated in a subsequent study (Ruschoff et al 2010). A score of 0 or 1+ is 
considered to be HER2-negative. A score of 2+ is considered equivocal and should be 
additionally examined by ISH methods. Cases that have an IHC score of 3+ or an IHC score 
2+ and ISH positive are considered HER2-positive. Across Asian populations, HER2 
positivity (defined as IHC 3+ and IHC 2+/ISH +) in GC is reported in approximately 9.8% to 
23.0% of cases (Cho et al 2013, Kim et al 2011, Park et al 2006, Shan et al 2013, Yano et al 
2006, Yoon et al 2018). In China, HER2-positivity is reported in 12% to 13% of patients with 
GC (Sheng et al 2013,Huang et al 2013). Although ISH testing is recommended to verify 
HER2 status for IHC 2+ patients, the testing rate of ISH in the IHC 2+ population in China is 
very low (<10%) (Huang et al 2018). Regardless of ISH results, there are 22% to 24% of GC 
patients in China have HER2 expressing (defined as IHC 3+ or IHC 2+ in this study) status 
(Sheng et al 2013, Fan et al 2013, Shan et al 2013).The prognostic significance of HER2 
status in GC remains to be fully elucidated. While some studies suggest that HER2-positivity 
is associated with poor prognosis (Cho et al 2013, Chua and Merrett 2012, Gomez-Martin et al 
2012, Gravalos and Jimeno 2008, Jorgensen and Hersom 2012, Kato et al 2018), others report 
that HER2 could be an independent prognostic factor of outcome in a subgroup of patients 
with intestinal histology (Grabsch et al 2010, Janjigian et al 2012, Kunz et al 2012). GC is 
characterised as a tumour with a high degree of heterogeneity, such as in histology 
(differentiated or undifferentiated type) and site of tumour progression (hepatic or peritoneal 
metastases); heterogeneity in HER2-expression between metastatic sites and within the 
tumour has also been observed, and this is one of the key hurdles for the development of anti-
HER2 drug for GC (Lee et al 2013, Ruschoff et al 2012,Thuss-Patience et al 2017). In 
addition, a decrease in HER2-expression after anti-HER2 treatment has been reported in 


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approximately 30% to 60% of HER2-positive GC patients (Pietrantonio et al 2016, Saeki et al 
2018).
The prognosis of metastatic GC is poor. After relapse or progression, trastuzumab is the only 
approved HER2-targeted therapy and is indicated, in combination with cisplatin and 
capecitabine or 5-fluorouracil for the treatment of patients with HER2-positive metastatic 
gastric or gastroesophageal junction (GEJ) adenocarcinoma who have not received prior 
treatment for metastatic disease. However, after treatment failure of trastuzumab, there is no 
further antiHER2-specific treatment available in second line setting in China, treatment 
options in these patients are limited to single agent chemotherapy, followed by third-line 
treatment (regardless of HER2 expression status) with apatinib, nivolumab or single agent
chemotherapy, or participation in a clinical trial (Li et al 2018), or with a recently (June 2021) 
NMPA conditionally approved (not recommended in guidelines) anti-HER2 ADC RC-48. 
Given that the majority of patients with HER2-positive advanced GC eventually acquire 
resistance or show intolerance to drugs approved for use in the first- or second-line settings 
and that there is no recommended HER2-specific treatment available beyond the first-line 
setting, HER2-positive advanced GC is considered a serious and life-threatening disease and 
this patient population has a high unmet medical need. 
In DESTINY-Gastric01 and DESTINY-Gastric02 studies, T-DXd showed promising efficacy 
in Korean and Japanese patients (confirmed ORR by ICR was 40.5% [95% CI: 31.8, 49.6] in 
T-DXd group vs 11.3% [95% CI: 4.7, 21.9] in the comparator group (p < 0.0001) (Shitara et al 
2020) in addition to US and European patients (confirmed ORR was 38% [95% CI, 27.3-
49.6]) (Cutsem et al 2021).
Results from Study 
 also showed T-DXd has benefit 
in 
population, confirmed ORR by ICR (FAS) in 
 
 [95% CI: 
]) was comparable to that in 
 population (N= 
 
[95% CI: 
 These data suggest that the antitumor activity of T-DXd may also 
extend to 
population and this warrants further evaluation.
The similar efficacy results in HER2 IHC 2+ population were seen in another anti-HER2 
ADC, RC-48. In a single-arm, open-label, phase II trial, which enrolled 125 HER2 
overexpression (defined as IHC 3+ or IHC 2+ in RC-48 label) locally advanced or metastatic 
gastric or GEJ adenocarcinoma subjects who have had progression or intolerance following 
receipt of at least two systemic chemotherapy, the ORR of RC-48 was 24.8% (95% CI: 
17.5%-33.3%), and showed similar ORR (FAS) in IHC 2+ (23.0% [95% CI: 13.2, 35.5]) and 
IHC 3+ population (26.6% [95% CI: 16.3, 36.1]) (Peng et al 2021).
On the above basis, the current study aims to evaluate the efficacy and safety of T-DXd 
monotherapy in patients in China with HER2-positive (IHC 3+ or IHC 2+/ISH +, confirmed 


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by central laboratory), in addition to HER2-expressing (IHC 3+ or IHC 2+, confirmed by 
central laboratory) locally advanced or metastatic gastric or GEJ adenocarcinoma who have 
received 2 or more prior regimens in order to assess the opportunity to bring new HER2-
targeted agents into this challenging setting.
2.2
Background
T-DXd is being developed for the treatment of HER2-expressing cancers and HER2-mutant 
tumours. Clinical observations in Phase I and II studies indicate that T-DXd has antitumour 
activity in HER2-expressing cancers, including GC. In China, there are currently no 
anti-HER2 therapies recommended for patients with GC who have failed a trastuzumab 
containing regimen (Li et al 2018, Treatment Guidelines 2019), demonstrating a clear unmet 
medical need for patients with HER2-positive GC in the third-line setting. As detailed below, 
this Phase II study will evaluate the efficacy and safety of T-DXd monotherapy in patients in 
China with HER2-positive (confirmed by central laboratory) locally advanced or metastatic 
gastric or GEJ adenocarcinoma who have received 2 or more prior regimens.
2.2.1
HER2-positive Gastric Cancer
Gastric cancer is the fifth most common cancer worldwide. There are approximately 950000 
newly diagnosed cases and 780000 deaths annually worldwide, making GC the third leading 
cause of cancer-related deaths in the world (GLOBOCAN 2018a, Torre et al 2012). Globally, 
the highest incidence of GC is reported in East Asian countries, particularly China (with 
nearly half of global cases), Japan, and South Korea. In China, GC is now the second most 
commonly diagnosed cancer and is the second leading cause of cancer-related death (Chen et 
al 2016). GLOBOCAN statistics estimate that there were 456124 new cases of GC and 
390182 deaths caused by GC in China in 2018 (GLOBOCAN 2018b). 
Gastric cancer is often diagnosed at an advanced inoperable stage; disease-related symptoms 
include fatigue, nausea, vomiting, decreased appetite, abdominal pain, weight loss, and 
anaemia. In addition, patients might have difficulty taking oral food due to their advanced 
disease, leading to a reduction in quality of life. Worldwide, approximately 65% of GC 
patients present with locally advanced or metastatic disease, with a poor outcome (Meza-
Junco and Sawyer 2012). In China, this figure is higher, with approximately 80% of patients 
presenting with advanced disease and likely to have a poor outcome: the 5-year relative 
survival rate was 35.9% in patients with GC in the period 2010-2014 (Yang et al 2018). In 
patients with GC who are refractory to standard therapies, the median life expectancy is 
approximately 6 months, underlining the high unmet medical need (Minashi and Hironaka 
2015). 
Over 95% of GC including GEJ are adenocarcinomas, which are typically classified based on 
histological features such as diffuse or intestinal subtype. The intestinal subtype is more 
common. A specific diagnosis of gastric adenocarcinoma should be established for staging and 


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treatment purposes, while sub-classification of gastric adenocarcinoma as an intestinal or 
diffuse subtype may have implications for therapy since intestinal subtype tumours are more 
likely to be HER2-positive (NCI 2019).
2.2.2
Current Treatment Options for HER2-positive Gastric Cancer
For patients with relapsed or progressed early-stage GC after gastrectomy and for those with 
de novo unresectable or metastatic GC, trastuzumab is the only approved HER2-targeted 
therapy and, as indicated is used in combination with cisplatin and capecitabine or
5-fluorouracil in patients with HER2-overexpressing metastatic gastric or GEJ 
adenocarcinoma who have not received prior treatment for metastatic disease.
Neither the National Comprehensive Cancer Network (NCCN) treatment guideline for GC 
(NCCN 2021) or relevant guidelines in China (Li et al 2018, Treatment Guidelines 2019) are 
supportive of continuing trastuzumab beyond the first-line treatment of HER2-positive locally 
advanced or recurrent GC. In the absence of an approved anti-HER2 therapy for 
HER2-positive GC patients who have received a trastuzumab-containing regimen, the NCCN 
guidelines recommend treatment with CYRAMZA®(ramucirumab) as a single agent or in 
combination with paclitaxel. An overall response rate (ORR) for ramucirumab in combination 
with paclitaxel of 28% (95% confidence interval [CI]: 23, 33), a median overall survival (OS)
of 9.6 months (95% CI: 8.5, 10.8), and an OS hazard ratio (HR) of 0.807 (95% CI: 0.678, 
0.962) (p = 0.017) versus paclitaxel alone (median OS: 7.4 months [95% CI: 6.3, 8.4]) (p =
0.017) has been reported in HER2-expressing patients who progressed on or after a 
trastuzumab-containing regimen (Li et al 2018). However, ramucirumab is not approved in 
China, and second-line treatment options for HER2-positive patients following progression on 
a trastuzumab-containing regimen are limited to single-agent chemotherapy (docetaxel, 
paclitaxel, and irinotecan) or clinical trial participation (Li et al 2018). 
Third-line therapy is generally considered in patients with good performance status and two 
National Medical Products Administration (NMPA)-fully approved agents show a minimal 
increase in OS compared with placebo:

Apatinib (AITAN®) is a highly selective vascular endothelial growth factor receptor 2 
inhibitor, which was approved by the NMPA in October 2014 as a third-line or later 
therapy for late-stage GC, based on a Phase III clinical study which enrolled 273 patients 
who had treatment failure after second-line/subsequent-lines chemotherapeutic regimens. 
Compared with placebo, apatinib prolonged median progression-free survival (PFS) (2.6
vs 1.8 months, p < 0.001) and increased the disease control rate (DCR) (42.05% vs 
8.79%, p < 0.001). The ORRs for the apatinib and placebo groups were 2.84% and 0%, 
respectively (Li et al 2016). 

Nivolumab (OPDIVO®) was approved in March 2020 by NMPA for patients with 
advanced or recurrent gastric or gastroesophageal adenocarcinoma who have received 2


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or more systemic treatment regimens. Compared with placebo, nivolumab improved 
median OS (5.26 vs 4.14 months) at the 2-year follow-up (HR ratio [95% CI], 0.62 [0.51, 
0.76]; p < 0.0001). The ORRs for the nivolumab and placebo groups were 11.2% and 0%, 
respectively (Chen et al 2020).
Except the above two agents, RC-48 (AIDIXI®) was granted by NMPA conditional marketing 
approval after initiation of DESTINY-Gastric06 study (in Jun 2021) for the treatment of HER2 
IHC 3+ or IHC 2+ (regardless of ISH status),locally advanced or metastatic gastric or GEJ 
adenocarcinoma patients who have had progression or intolerance following receipt of at least 
two systemic chemotherapy, but has not been recommended in guidelines. The ORR of RC-48 
monotherapy was 24.8% (95% CI: 17.5%-33.3%), the median PFS and OS were 4.1 months 
(95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively (Peng et al 
2021). Confirmatory phase 3 study of RC48-007 (RC-48 vs. chemotherapy) is ongoing to 
further evaluate the efficacy and safety of RC-48 in 3L+ HER2 IHC 2+ or IHC 3+ GC 
patients. 
Thus, for third-line treatment of GC patients regardless of HER2 expression status, Chinese 
guidelines recommend treatment with apatinib, nivolumab, single-agent chemotherapy or 
participation in a clinical trial (Li et al 2018). Given that no anti-HER2 therapy is 
recommended by NCCN or in China for GC patients who have failed a trastuzumab 
containing regimen (Li et al 2018, Treatment Guidelines 2019), there is a clear unmet medical 
need for HER2-positive GC patients who have received 2 or more prior regimens.
2.2.3
Trastuzumab Deruxtecan
As of 28 March 2019, AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) 
entered into a joint global development and collaboration agreement for T-DXd, a 
HER2-targeting ADC that is being developed as a therapeutic candidate for HER2-expressing 
tumours. 
Trastuzumab deruxtecan, under the tradename ENHERTU®, is approved for the treatment of 
patients with unresectable or metastatic HER2-positive (IHC 3+ or IHC 2+/ISH +) GC that 
has progressed after cancer chemotherapy (in Japan) or after trastuzumab containing 
chemotherapy (in the US, Israel and Singapore). Trastuzumab deruxtecan is also approved for 
the treatment of patients with unresectable or metastatic HER2-positive breast cancer who 
have received ≥2 prior anti-HER2-based regimens in the metastatic setting (in the US, 
European Union, United Kingdom, and Israel), or who have progressed after cancer 
chemotherapy (in Japan), or who have received prior trastuzumab emtansine treatment (in 
Canada).
T-DXd consists of an anti-HER2 antibody, MAAL-9001, covalently linked to ~8 molecules of 
MAAA-1162a (GGFG tetrapeptide cleavable linker and a topoisomerase I inhibitor 


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[MAAA-1181a]). The antibody MAAL-9001 has the same amino acid sequence as 
trastuzumab (HERCEPTIN®), and thus T-DXd is similarly targeted to HER2 expressing 
tumours. The drug MAAA-1181a (deruxtecan [DXd]), a derivative of exatecan, is released 
after internalisation and leads to apoptosis of the target tumour cells via the inhibition of 
topoisomerase I.
Due to incorporation of a novel linker, T-DXd achieves a higher drug-antibody ratio (DAR) of 
approximately 8 with homogeneous conjugation of DXd, compared with other currently 
approved ADCs, which have a DAR of 3 to 4 (Ogitani et al 2016). In addition, the cleavable 
linker in T-DXd is stable in plasma, conferring a favourable safety profile as observed in 
nonclinical toxicology rat and monkey studies.
T-DXd exhibits HER2 specific antitumour activity via a mechanism of action that combines 
the monoclonal antibody (mAb) specificity with the broad cytotoxicity of the released drug. 
After binding to HER2 and internalisation, T-DXd is cleaved by lysosomal enzymes 
preferentially expressed in tumour cells and releases the drug DXd in the cytoplasm. DXd is 
an exatecan derivative with greater potency than SN-38, the active metabolite of irinotecan 
(Ogitani et al 2016). T-DXd is expected to exhibit antitumour activity through DXd-induced 
apoptosis and, potentially, the antibody-dependant cellular cytotoxic activity of MAAL-9001, 
which leads to the inhibition of Akt phosphorylation.
There are completed and ongoing clinical trials with T-DXd, either alone or in combination, 
across multiple HER2-expressing tumour types including GC, breast cancer, non-small cell 
lung cancer, and colorectal cancer (please refer to the T-DXd Investigator’s Brochure [IB] for 
a list of completed and ongoing trials and most recent patient exposure data).
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of T-DXd is provided in the T-DXd IB.
2.3
Benefit/Risk Assessment
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation 
(ICH)/Good Clinical Practice (GCP), and applicable regulatory requirements.
More detailed information about the known and expected benefits and potential risks of 
T-DXd may be found in the IB.
2.3.1
Risk Assessment
2.3.1.1
Potential Risks of T-DXd
Based on data from clinical trials, toxicities considered to be associated with administration of 
T-DXd include the important identified risks of interstitial lung disease (ILD)/pneumonitis and 


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neutropenia (including febrile neutropenia). Other identified risks of T-DXd are 
infusion-related reactions (IRRs), haematological adverse events (AEs) (anaemia, leucopenia, 
lymphopenia, thrombocytopenia), pulmonary/respiratory AEs (cough, dyspnea, upper 
respiratory tract infection, epistaxis), gastrointestinal (GI) AEs (abdominal pain, constipation, 
diarrhoea, dyspepsia, nausea, stomatitis, vomiting), hepatic AEs (hepatic function abnormality, 
alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase 
increased), skin AEs (alopecia, rash, pruritis), blood bilirubin increased,  pneumonia, dry eye, 
dehydration, hypokalaemia, decreased appetite, dizziness, fatigue,  peripheral oedema, pyrexia 
and headache.
Based on the available pre-clinical data, review of the cumulative literature, reported toxicities 
for the same class of agents, the important potential risks for T-DXd are left ventricular 
ejection fraction (LVEF) decrease (re-labelled as ‘Left ventricular dysfunction’ as the 
undesirable clinical outcome of LVEF reductions, in accordance with Revision 2 of the 
European Medicines Agency guidelines on Good Pharmacovigilance Practice. This relabelling 
of the risk does not affect the nature or monitoring methods of LVEF decrease as a potential 
risk associated with T-DXd) and embryo-foetal toxicity. Keratitis is considered a potential risk 
for T-DXd.
Interstitial lung disease/pneumonitis and LVEF decrease are considered to be adverse events 
of special interest (AESI) and are closely monitored in the T-DXd clinical development 
programme.
T-DXd has not been studied in participants with severe/moderate hepatic impairment or severe 
renal impairment.
These identified and potential risks are generally manageable through dose modification and 
routine clinical practice. 
2.3.1.2
Potential Risks of HER2-targeted Agents
Several agents, that target HER2 and prevent its activation or heterodimerisation, have been 
developed and marketed for the treatment of HER2-positive cancers. These include the mAbs 
trastuzumab (Herceptin) and pertuzumab (PERJETA®), the ADC trastuzumab emtansine 
(T-DM1) (KADCYLA®), and HER1- and 2-associated tyrosine kinase inhibitors, lapatinib 
(TYKERB®) and neratinib (NERLYNX®). The safety profile of these HER2-targeted agents 
has been well described. The main safety risks identified in participants receiving 
HER2-targeted products are described below; these could potentially be expected to occur in 
participants receiving T-DXd.
Cardiotoxicity: Participants treated with trastuzumab are at increased risk for developing 
congestive heart failure (CHF) (New York Heart Association [NYHA] Class II to IV) or 
asymptomatic cardiac dysfunction, including LVEF decrease. Cardiac dysfunction, mainly 


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asymptomatic LVEF decrease, has also been observed with pertuzumab in combination with 
trastuzumab. Similarly, cardiac dysfunction has been observed in participants receiving T-
DM1, at a lower incidence than in trastuzumab-treated participants. The majority of cases 
have been asymptomatic decreases in LVEF. Cardiac dysfunction with lapatinib has occurred 
mainly in participants receiving the combination of trastuzumab and lapatinib and has 
consisted of predominantly asymptomatic LVEF decrease.
Pulmonary toxicity: Cases of pulmonary toxicity, including ILD and pneumonitis, have been 
observed in participants receiving trastuzumab, T-DM1, and lapatinib. Occasionally, these 
cases have been severe in nature and have resulted in fatal outcomes. Risk factors associated 
with ILD/pneumonitis include prior or concomitant therapy with other antineoplastic therapies 
known to be associated with it such as taxanes, gemcitabine, vinorelbine, and radiation
therapy.
Hypersensitivity/IRRs: The administration of therapeutic proteins is associated with a risk of 
hypersensitivity and/or IRRs. Hypersensitivity/IRRs have been reported with trastuzumab, 
pertuzumab, and T-DM1. These can range from mild reactions to severe anaphylactic shock 
with fatal outcome, as has been the case for trastuzumab.
Hepatic toxicity: Cases of hepatic toxicity have occurred with T-DM1, lapatinib, and 
trastuzumab. In participants receiving T-DM1, hepatic toxicity has manifested mainly as
transient asymptomatic liver transaminase elevations, although serious cases of drug-induced 
liver failure and nodular regenerative hyperplasia have also been reported. Lapatinib has also 
been associated with serious cases of drug-induced liver injury (DILI).
Haematological toxicity: Haematological toxicity has been observed with all HER2-targeted 
therapies. Neutropenia, febrile neutropenia, leucopenia, and anaemia have occurred commonly 
with trastuzumab, pertuzumab, and T-DM1. Thrombocytopenia, including Grade 3 and 4, is a 
common occurrence in T-DM1-treated participants. Although rare, serious haemorrhagic 
events have been reported in the setting of thrombocytopenia. Lower rates of 
thrombocytopenia have also occurred with trastuzumab and pertuzumab when used in 
combination with chemotherapy.
Refer to Appendix K for T-DXd toxicity management guidelines (TMGs).
2.3.1.3
Potential Risks of Topoisomerase I Inhibitors
DXd is a derivative of exatecan (DX-8951f), a topoisomerase I inhibitor. Other products of the 
same class include irinotecan and topotecan. Exatecan is a campothecin derivative, which has 
previously been developed by the former Daiichi Pharmaceuticals Co, Ltd. as an anticancer 
therapy.
The main risks associated with the use of topoisomerase I inhibitors include haematological 


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and GI toxicities. Haematological toxicities, manifesting as neutropenia, febrile neutropenia, 
anaemia, thrombocytopenia, and pancytopenia are commonly observed. An increased risk of 
infections, including neutropenic colitis and neutropenic sepsis has been reported with these 
agents.
Diarrhoea and delayed onset diarrhoea, which can be severe and lead to dehydration, have 
been associated with topoisomerase I inhibitors. Other significant risks include 
ILD/pneumonitis, liver impairment, immune system disorders, and alopecia. Acute cholinergic 
syndrome, manifesting as diarrhoea and other cholinergic symptoms has been reported with 
irinotecan.
The safety profile of exatecan is broadly similar to the safety profile of other topoisomerase I 
inhibitors, with haematological toxicities and GI toxicities being the most significant groups 
of events.
2.3.1.4
Anti-cancer treatments and immunosuppressants in eligible patients with 
Hepatitis B infection. 
Treatment with some anti-cancer treatments and immunosuppressants such as corticosteroids 
increase the risk of reactivation of Hepatitis B infection. For eligible patients with Hepatitis B 
infection, prophylaxis with anti-viral therapy, if not already part of ongoing therapy, may be 
required to be started prior to study treatments, or during treatments with moderate to high 
doses of corticosteroids (at doses equivalent to > 20 mg prednisolone of duration ≥ 4 weeks). 
Anti-viral therapy (if not already ongoing) should be started prior to or at least simultaneously 
with the initiation of moderate to high doses of corticosteroid treatment if anticipated to be ≥ 4 
weeks duration. In the event of Hepatitis B infection reactivation, anti-cancer treatment may 
be interrupted, and anti-viral treatment started. Management decisions should be taken in 
consultation with the local Hepatitis B expert.
2.3.2 Benefit Assessment
T-DXd is under development for the treatment of HER2-expressing cancers and HER2-mutant 
tumours. Based on preliminary clinical observations in a Phase I study (Study DS8201-A-J101 
[NCT02564900]) and in two Phase II studies (Study DS8201-A-U201 DESTINY-Breast01; 
NCT03248492 and the DESTINY-Gastric01; NCT03329690), T-DXd demonstrated 
antitumour activity in 
 cancers, including GC and breast cancer, and a 
generally acceptable safety profile in these populations. Data from the Phase II 
DS8201-A-U204 (DESTINY-Lung01; [NCT03505710]) study also provides encouraging 
preliminary evidence of antitumour activity of T-DXd in tumours with 
. This 
observation is of particular relevance in China where there are currently no approved 
HER2-targeted therapies for GC patients with HER2-overexpression after first-line therapy.








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Table 4
Objectives and Endpoints
Objectives
Endpoints
ADAs = anti-drug antibodies; AE = adverse event; AESI = adverse event of special interest; CR = complete 
response; DCO = data cut off; DCR = disease control rate; DoR = duration of response; ECG =
electrocardiogram; ECHO = echocardiogram; GEJ = gastroesophageal junction; HER2 = human epidermal 
growth factor receptor 2; ICR = independent central review; IHC = immunohistochemistry; ISH = in situ 
hybridisation; MUGA = multigated acquisition scan; ORR = objective response rate; OS = overall survival; PFS
= progression-free survival; PK = pharmacokinetics; PR = partial response; RECIST 1.1 = Response Evaluation 
Criteria in Solid Tumours version 1.1; SAE = serious adverse event; SD = stable disease; T-DXd = trastuzumab 
deruxtecan; TEAE = treatment-emergent adverse event.


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4
STUDY DESIGN
4.1
Overall Design
This is a Phase II, open-label, single-arm, multicentre, study in China assessing the efficacy 
and safety of T-DXd in participants with HER2-positive advanced gastric or GEJ 
adenocarcinoma who have received at least 2 prior regimens including a fluoropyrimidine 
agent and a platinum agent (Figure 1).
Following screening of approximately 
participants, approximately
participants who 
have  HER2-expressing (defined as IHC 3+ or IHC 2+ based on local laboratory report) will 
be enrolled and assigned to treatment with TDXd monotherapy at a dose of 6.4 mg/kg 
administered intravenously (IV) every 3 weeks until Response Evaluation Criteria in Solid 
Tumours, Version 1.1 (RECIST 1.1)defined- progressive disease (PD), unacceptable toxicity, 
withdrawal of consent, or any other criterion for discontinuation of study intervention is met. 
This is to ensure that approximately 
participants enrolled in the study have HER2-positive 
(defined as IHC 3+ or IHC 2+/ISH +) status confirmed by central laboratory as these 
participants will form the basis of the primary analysis population. This also provides that 
approximately 
participants enrolled in the study have HER2-expressing status (defined as 
IHC 3+ or IHC 2+) confirmed by central laboratory as these participants will form the basis of 
the analysis population for the secondary objectives in this population.
The primary endpoint of the study is confirmed ORR by independent central review (ICR) per 
RECIST 1.1. The study will also evaluate other measures of efficacy (investigator-assessed 
ORR, DCR, duration of response [DoR], PFS, OS, tumour size change) and further 
characterise the safety, tolerability, pharmacokinetics (PK) and immunogenicity of T-DXd in 
participants in China.
Efficacy assessments will be based on tumour assessments performed at screening and every 6
weeks (± 7 days) from the first dose of study intervention (Cycle 1 Day 1) until RECIST 1.1
defined radiological PD. All imaging scans (computer tomography [CT] or magnetic 
resonance imaging [MRI]) should be sent to the central imaging vendor selected by 
AstraZeneca to confirm the existence of a measurable lesion by RECIST 1.1. Scans (CT or 
MRI) of the chest, abdomen, and pelvis are mandatory. Brain CT or MRI is required only in 
cases of pre-existing brain metastases or symptoms. Imaging assessments should be conducted 
in the same way on each occasion.
All participants are required to have documented HER2-positivity (IHC 3+ or IHC 2+) at 
screening. For the purposes of study eligibility, HER2-positivity will be determined at site 
based on a documented pathology result obtained from either a local laboratory or from a 
previous pathology report that has been confirmed by the investigator.
In addition, formalin-fixed paraffin-embedded (FFPE) tumour tissue slides will be provided 


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for central laboratory confirmation of HER2 status after enrolment and prior to first dose of
study intervention. If the primary tumour is accessible by endoscopy or if a metastatic tumour 
can be biopsied, FFPE tumour slides generated from a newly-acquired tumour sample will be 
provided to the central laboratory during screening. If it is not possible to obtain a newly-
acquired tumour tissue sample, archived FFPE tumour slides are acceptable and should be 
based on the most recent archived tumour tissue sample.
4.1.1
Study Duration
Enrolment of participants will take place over approximately 
 at approximately 
sites in mainland China. The data cutoff (DCO) for the full final analysis will occur 
approximately 
months after the last participant has initiated study intervention. Thus, the 
total study duration will be approximately 
months.
4.1.2
Duration of Study Participation
The screening period for the study is 28 days. Following completion of screening and 
inclusion in the study, participants will receive the study intervention (T-DXd) on Day 1 of 
each 3-week cycle. The number of treatment cycles is not fixed and participants may continue 
to receive study intervention until RECIST 1.1-defined PD, unacceptable toxicity, withdrawal 
of consent, or any other criterion for discontinuation of study intervention is met (see Section
7.1). An end of treatment/early discontinuation visit will be performed within 7 days of 
discontinuation of study intervention or early discontinuation from the study.
Participants will have a post-treatment follow-up visit 40 (+ 7) days after the last 
administration of study intervention. Thereafter, participants will have long-term/survival 
follow-up visits every 3 months (± 14 days) until death, withdrawal of consent, or study 
closure, whichever occurs first. Long-term/survival follow-up visits may be conducted by 
telephone or as site visits. 
4.1.3
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study participants become infected with COVID-19 or similar pandemic 
infection), which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the participant’s ability to conduct the study. The 
investigator or designee should contact the study sponsor to discuss whether the mitigation 
plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 


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compliance with GCP, and minimise risks to study integrity. Where allowable by local health 
authorities, ethics committees, healthcare provider guidelines (eg, hospital policies), or local 
government, these changes may include the following options:

Obtaining reconsent for the mitigation procedures (note, in the case of verbal reconsent, 
the informed consent form (ICF) should be signed at the participant’s next contact with 
the study site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. The 
investigator should confirm this with the designated study physician.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix I.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design
The primary population (HER2 IHC 3+ or IHC 2+/ISH +) of the current study closely follows 
the primary cohort in a completed multicentre, open-label Phase II study conducted by Daiichi 
Sankyo in Japan and South Korea (DESTINY-Gastric01; NCT03329690). In DESTINY-
Gastric01, the efficacy and safety of T-DXd (6.4 mg/kg) in participants with HER2-positive 
(IHC 3+ or IHC 2+ / ISH +) advanced gastric or GEJ adenocarcinoma who had progressed on 
2 prior regimens including a fluoropyrimidine agent, a platinum agent, and trastuzumab was 
compared with the physician’s choice of treatment. Analysis of the primary cohort in 
DESTINY-Gastric01 performed once all participants had completed 
 of treatment or 
discontinued study intervention confirmed the anticipated efficacy of T-DXd in participants 
with advanced GC/GEJ. 
The primary population (HER2 IHC 3+ or IHC 2+/ISH +) of the current study closely follows 
the primary cohort in a completed multicentre, open-label Phase II study conducted by Daiichi 
Sankyo in Japan and South Korea (DESTINY-Gastric01; NCT03329690). In DESTINY-
Gastric01, the efficacy and safety of T-DXd (6.4 mg/kg) in participants with HER2-positive 
(IHC 3+ or IHC 2+ / ISH +) advanced gastric or GEJ adenocarcinoma who had progressed on 
2 prior regimens including a fluoropyrimidine agent, a platinum agent, and trastuzumab was 
compared with the physician’s choice of treatment. Analysis of the primary cohort in 
DESTINY-Gastric01 performed once all participants had completed 
 of treatment or 
discontinued study intervention confirmed the anticipated efficacy of T-DXd in participants 
with advanced GC/GEJ. 

As of the DCO (08 November 2019) for the primary analysis, confirmed ORR per 
RECIST 1.1 by ICR for the primary cohort was significantly higher in the T-DXd group 


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than in the physician’s choice group (p < 0.0001). ORR was 40.5% (95% CI: 31.8, 49.6) 
in the T-DXd group with 51/126 participants having a best overall response of complete 
response (CR) (10 [7.9%] participants) or partial response (PR) (41 [32.0%] participants), 
and 11.3% (95% CI: 4.7, 21.9) in the physician’s choice group with 7/62 participants 
having a best overall response of PR (7 [11.3%] participants). 

The unconfirmed ORR per RECIST 1.1 by ICR was 51.3% (95% CI: 41.9, 60.5) in the 
T-DXd group with 61/119 participants having a BOR of CR (11 [9.2%] participants) or 
PR (50 [42.0%] participants), and 14.3% (95% CI: 6.4, 26.2) in the physician’s choice 
group with 8/56 participants having a BOR of PR (8 [14.3%] participants) (p > 0.0001). 

The confirmed ORR per RECIST 1.1 by ICR in response evaluable participants was 
42.9% (95% CI: 33.8, 52.3) in the T-DXd group, with 51/119 participants having a BOR 
of CR (10 [8.4%] participants) or PR (41 [34.5%] participants), and 12.5% (95% CI: 5.2,
24.1) in the physician’s choice group, with 7/56 participants having a BOR of PR (7
[12.5%] participants).
Similar benefits were reported in OS and PFS and the safety profile of T-DXd in the study
population was generally manageable and tolerable.
In China, the standard of care (SoC) in the third-line setting is limited to treatment with 
individual chemotherapy agents, nivolumab, or apatnib. As the efficacy of these agents is 
modest (ORR 
 median PFS 
, and median OS
and unfavorable compared with T-DXd, a comparator arm is not considered appropriate for 
this study (Xuan 2014, Li et al 2016, Chen et al 2020). Thus, while the design of the current 
study is very similar to that of Study DESTINY-Gastric01, this will be a single-arm study and 
all eligible participants will receive T-DXd monotherapy.
Results from Study 
 also showed T-DXd has benefit 
in
population, confirmed ORR by ICR (FAS) in 
 
comparable to that in 
 population 
 [95% CI: 
 These data 
suggest that the antitumor activity of T-DXd may also extend to 
population and this warrants further evaluation. The similar efficacy results in HER2 IHC 2+ 
population were seen in another anti-HER2 ADC, RC-48. The ORR of RC-48 was 24.8% 
(95% CI: 17.5%-33.3%), and showed almost similar ORR (FAS) in IHC 2+ (23.0% [95% CI: 
13.2, 35.5]) and IHC 3+ population (26.6% [95% CI: 16.3, 36.1]).
So there is rationale to evaluate the efficacy and safety of T-DXd in the expanded population 
(HER2-expressing: IHC 3+ or IHC 2+) in this study.  
4.2.2
Rationale for T-DXd in HER2-expressing Gastric and GEJ 
Adenocarcinoma
Nonclinical pharmacology data have demonstrated the potent HER2-targeting antitumour 


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activity of T-DXd through the released drug, MAAA-1181a, inducing DNA damage and 
apoptosis by topoisomerase I inhibition. T-DXd also exhibits antibody-dependent cellular 
cytotoxic activity and HER2-mediated Akt phosphorylation inhibition. In vitro studies indicate 
that T-DXd specifically binds to HER2 and exhibits HER2-expression-dependent cell growth 
inhibitory activity. In vivo studies indicate that the HER2-targeting antitumour activity of 
T-DXd is more potent than that of the anti-HER2 antibody, MAAL-9001 and of T-DM1.
In China, HER2-expressing (IHC 3+ or 2+) rate is reported in 22% to 24% of GC patients 
(Fan et al 2013, Shan et al 2013,Sheng et al 2013) and, as discussed in Section 2.1, HER2 is 
considered an important target protein for GC therapy. The rationale for inclusion of 
participants in China with HER2-expressing gastric and GEJ adenocarcinoma reflects the 
positive efficacy and safety outcomes reported in Study DESTINY-Gastric01 and Study
DESTINY-Gastric01 exploratory cohort 1 in which participants with HER2-expressing 
(IHC 3+ or IHC 2+) advanced gastric or GEJ adenocarcinoma were treated with T-DXd 6.4
mg/kg every 3 weeks. 
4.2.3
Rationale for Study Endpoints
The primary endpoint is:

Confirmed ORR, defined as the proportion of participants who have a confirmed CR or 
confirmed PR, as determined by ICR per RECIST 1.1.
Confirmed ORR by ICR represents the percentage of participants whose disease decreases in 
size or disappears and provides an early signal for clinical benefit. It is an appropriate and 
reasonable efficacy endpoint for single-arm studies performed in China provided, in 
accordance with the requirements of NMPA’s Center for Drug Evaluation, efficacy response 
assessment is performed by independent review.
Additional secondary efficacy endpoints (ORR, DCR, DoR, PFS, and tumour size change by 
investigator assessment, and OS) will be used to further evaluate efficacy and to corroborate 
the benefits of antitumor effects demonstrated by ORR. 
As part of the secondary endpoint assessment, blood samples will be taken to allow for 
research into the PK and immunogenicity of T-DXd in Chinese participants.
4.3
Justification for Dose of T-DXd
The recommended dosage and administration of T-DXd for patients with locally advanced or 
metastatic HER2-positive GC or GEJ adenocarcinoma is 6.4 mg/kg every 3 weeks, as 
established based on efficacy and safety results from Studies DS8201-A-J101 and DESTINY-
Gastric01, comparison of dose-exposure relationship between participants with breast cancer 
in Study DS8201-A-J101 and participants with GC in Study DESTINY-Gastric01, and 


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exposure-response (ER) analyses for both efficacy and safety.
Following administration of T-DXd every 3 weeks at 5.4 mg/kg or 6.4 mg/kg to participants 
with HER2-positive GC enrolled in Part 2b of Study DS8201-A-J101, the 6.4 mg/kg group 
showed a higher ORR (
) than the 5.4 mg/kg (
), and the response in the 6.4 mg/kg 
group was durable. Though the incidence and severity of AEs tended to be higher in the 6.4
mg/kg group than the 5.4 mg/kg group, the AEs were tolerable and generally manageable in 
both treatment groups. A comparison of the exposure of T-DXd in participants with GC given 
a 6.4 mg/kg dose was 
 lower than the exposure of T-DXd in participants with breast 
cancer who were given a 6.4 mg/kg dose. Based on the tolerability, safety, efficacy, and PK 
profile in Study DS8201-A-J101, 6.4 mg/kg every 3 weeks was selected as the dose regimen 
for Study DESTINY-Gastric01.
In Study DESTINY-Gastric01, the 6.4 mg/kg dose showed clinically meaningful efficacy with 
respect to ORR and OS. The ORR in the T-DXd 6.4 mg/kg group was statistically 
significantly higher (40.5% [95% CI: 31.8, 49.6]) than that in the physician’s choice group 
(11.3% [95% CI: 4.7, 21.9]) (Cochran–Mantel–Haenszel test, p < 0.0001). There was a 
statistically significant and clinically meaningful prolongation of OS in the T-DXd arm 
compared with the physician’s choice group (stratified log-rank test, p = 0.0097). The safety 
in participants with GC in the 6.4 mg/kg arm was acceptable compared with the physician’s 
choice group, and was manageable.
The population PK (popPK) analysis showed that the exposure of T-DXd in participants with 
GC given a 6.4 mg/kg dose was 
to that in participants with 
 given the 
approved 
 dose. 
The ER analysis for efficacy showed that after administration of T-DXd at 6.4 mg/kg, 
participants with higher exposure of T-DXd tended to exhibit higher efficacy, indicating added 
benefit from using the higher 6.4 mg/kg dose.
The ER analysis for safety showed that the incidence of ILD tended to be higher in 
participants with higher exposure of T-DXd. The incidence of ILD at 6.4 mg/kg in participants 
with GC was estimated to be 
 to that after administration of 
 to participants 
with 
, 
 
 of T-DXd and DXd at 6.4 mg/kg in 
GC compared with 
mg/kg in 
 There was a clear trend for higher rates of AEs 
in participants with higher average serum concentration of DXd, with the notable exception of 
AEs associated with study drug discontinuation, 
 
 
AEs with a higher incidence in participants with GC than those with 
 were 
mainly 
 and the incidence of these events increased with increasing exposure 
of DXd. However, these AEs were generally manageable without discontinuing treatment by 
dose modification and routine clinical practice.


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Based on the benefit-risk analysis, the dosing regimen of T-DXd 6.4 mg/kg every 3 weeks is 
considered to be appropriate in participants with locally advanced or metastatic 
HER2-positive GC or GEJ adenocarcinoma who have received 2 or more prior regimens.
Refer to the IB for further information on the nonclinical and clinical data for T-DXd.
Information on dose modifications for T-DXd is provided in Section 6.6.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the SoA (Section 1.3), including 
follow-up for OS determination.
The study may be stopped if, in the judgment of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings. In addition, the study may be terminated 
at individual centres if study procedures are not being performed according to ICH GCP or if 
the recruitment rate does not allow for the study to be completed in the planned timeframe.
The end of the study is defined as the time of the final DCO for the full final analysis. Final 
analysis is planned to be performed approximately 
months after the last participant initiates 
study intervention. Based on data from Study DESTINY-Gastric01, this will allow the last 
participant sufficient opportunity to achieve a treatment response (estimated at 
months) 
and sufficient DoR follow-up for responders (estimated at 
months).
See Section 6.7 for details on participant management following the final DCO as well as 
following study completion.
5
STUDY POPULATION
The target population of primary interest in this study is participants in China with 
HER2-positive (IHC 3+ or IHC 2+/ISH + by central laboratory) advanced gastric or GEJ 
adenocarcinoma who have received at least 2 prior regimens including a fluoropyrimidine 
agent and a platinum agent. The study will enrol participants who have HER2-expressing 
(defined as IHC 3+ or IHC 2+) status, in which efficacy and safety will be evaluated as 
secondary endpoints.
For the purposes of eligibility, HER2 status should be determined at site based on a 
documented pathology result obtained from either a local laboratory or from a previous 
pathology report that has been confirmed by the investigator. In addition, HER2 status will be 
confirmed by central laboratory. If the result of HER2 testing by the central laboratory 
indicates that the participant is not HER2-expressing (IHC 3+ or IHC 2+), the participant may 
continue in the study and continue to receive study intervention. Prospective approval of 


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protocol deviations to recruitment and enrolment criteria, also known as protocol waivers or 
exemptions, is not permitted.
Participants who do not meet the eligibility criteria requirements are screen failures (see 
Section 5.4).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1. Male or female participant aged ≥18 years at the time of screening.
Type of Participant and Disease Characteristics
2. Pathologically documented locally advanced unresectable or metastatic gastric or GEJ 
adenocarcinoma.
3. Disease progression on or after ≥2 prior regimens for advanced/metastatic disease that 
included a fluoropyrimidine and a platinum:
(a) Progression within 6 months of prior adjuvant or neoadjuvant chemotherapy will 
count as rapid progression in the neoadjuvant/adjuvant setting and is thus equivalent 
to advanced/metastatic disease failing 1 regimen of therapy
(b) If prior combination therapy was discontinued due to an AE and then one of the 
combination agents was continued, this is considered to be 1 prior regimen, not 2
prior regimens
(c) A change in dosage form of the fluoropyrimidine (eg, intravenous to oral 
administration) without progression is considered to be 1 prior regimen, not 2 prior 
regimens. 
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 
5. Documentation of HER2 IHC 3+ or IHC 2+, regardless of ISH status, during screening. 
For the purposes of study eligibility, HER2 expression status should be determined at site 
based on a documented pathology result obtained from either a local laboratory or from a 
previous pathology report that has been confirmed by the investigator. If HER2 status has 
not been documented previously, a newly-acquired tumour sample must be provided for 
local assessment of HER2 status prior to enrolment if the primary tumour is accessible by 
endoscopy or if metastatic tissue can be biopsied. If a newly-acquired sample is not 
available, an archived sample is acceptable (based on the most recent archived tumour 
tissue sample).
6. Willing and able to provide an adequate newly-acquired tumour sample for confirmation 
of HER2 status by a central laboratory specified by the sponsor if the primary tumour is 
accessible by endoscopy or if metastatic tissue can be biopsied. If a newly-acquired 
sample is not available, an archived sample is acceptable (based on the most recent 


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archived tumour tissue sample). See Section 8.6.1 and the Laboratory Manual for further 
information.
7. At least 1 lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter (except lymph nodes, which must have short axis ≥15 mm) with CT or MRI and 
is suitable for accurate repeated measurements, as per RECIST 1.1.
8. Adequate organ and bone marrow function (as defined in Table 5) within 14 days prior to 
study enrolment. All parameters must meet the inclusion criteria and must be the most 
recent results available.
Table 5
Parameters for Adequate Organ and Bone Marrow Function
Adequate bone marrow function
Platelet count
≥100000/mm3
Platelet transfusion is not allowed within 7 days prior to the screening assessment
Haemoglobin
≥8.0 g/dL 
Red blood cell transfusion is not allowed within 7 days prior to the screening assessment. 
Participants requiring ongoing transfusions or growth factor support to maintain 
haemoglobin ≥8.0 g/dL are not eligible
Absolute neutrophil 
count
≥1500/mm3
Granulocyte-colony stimulating factor administration is not allowed within 7 days prior to 
screening assessment
Adequate hepatic function
ALT and AST
≤3 × ULN (or < 5 × ULN in participants with liver metastases)
Total bilirubin
≤1.5 × ULN if no liver metastases or < 3 × ULN in the presence of documented Gilbert’s 
syndrome (unconjugated hyperbilirubinaemia) or liver metastases at baseline
Serum albumin
≥2.5 g/dL
Adequate renal function
CrCL 
≥30 mL/min as determined by the Cockcroft Gault equation, using actual body weight:
Males:
CrCL = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
CrCL = 
Weight (kg) × (140 - Age)
× 0.85
(mL/min)
72 × serum creatinine (mg/dL)
Adequate blood clotting function
INR or PT and 
either PTT or aPTT
≤ 1.5 × ULN
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; CrCL = calculated creatinine clearance; INR = international normalised ratio; PT =
prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal.


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9. Left ventricular ejection fraction (LVEF) ≥
 by echocardiogram (ECHO) or 
multigated acquisition (MUGA) scan 28 days prior to enrolment.
10. Minimum life expectancy of 12 weeks.
11. Adequate treatment washout period prior to initiation of study intervention, as defined in 
Table 6.
Table 6
Adequate Treatment Washout Period
Treatment
Washout Period
Major surgery
≥ 4 weeks
Palliative radiotherapy
≥ 4 weeks for palliative radiotherapy with wide field of radiation or to 
more than 30% of the bone marrow or radiation therapy including 
palliative stereotactic radiation therapy to chest
≥2 weeks for palliative radiotherapy with a limited field of radiation 
or for whole brain radiation
Anti-Cancer chemotherapy 
[Immunotherapy (non-antibody based 
therapy)], retinoid therapy, hormonal 
therapy
≥ 3 weeks
Targeted agents and small molecules
≥2 weeks or 5 half-lives whichever is longer
Nitrosureas and mitomycin C
≥ 6 weeks
Antibody-based anticancer therapy 
≥ 4 weeks
Chloroquine and hydroxychloroquine
≥ 14 days
Cell-free and Concentrated Ascites 
Reinfusion Therapy (CART), 
peritoneal shunt or drainage of pleural 
effusion, ascites or pericardial effusion
≥2 weeks prior to screening assessment
Anticancer traditional Chinese 
medicines (ie, those with a label for the 
treatment of cancer)
≥ 14 days
Reproduction
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
12. Negative serum pregnancy test at screening for women of childbearing potential 
(WOCBP) who are sexually active with a non-sterilised male partner.
13. Female participants must be 1 year post-menopausal, surgically sterile, or using one highly 
effective form of birth control (a highly effective method of contraception is defined as 
one that can achieve a failure rate of less than 1% per year when used consistently and 
correctly; see Table 18). For women who are on hormone replacement therapy (HRT), 


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please refer to Appendix F. WOCBP who are sexually active with a non-sterilised male 
partner must agree to use one highly effective method of birth control. They should have 
been stable on their chosen method of birth control for a minimum of 3 months before 
entering the study until 7 months after the last dose of study intervention (see Appendix F, 
Table 18 for complete list of highly effective birth control methods). Complete 
heterosexual abstinence for the duration of the study and study intervention washout 
period is an acceptable contraceptive method if it is line with the participant’s usual 
lifestyle (consideration must be made to the duration of the clinical trial); however, 
periodic or occasional abstinence, the rhythm method, and the withdrawal method are not 
acceptable. Female participants must refrain from egg cell donation and breast-feeding
while on the study and for 7 months after the last dose of study intervention. Preservation 
of ova may be considered prior to enrollment in this study.Non-sterilised male partners of 
a WOCBP must use a male condom plus spermicide (condom alone in countries where 
spermicides are not approved) throughout this period. 
14. Male participants who intend to be sexually active with a female partner of childbearing 
potential must be surgically sterile or using an acceptable method of contraception (see 
Appendix F) from the time of screening throughout the total duration of the study and until 
4 months after the last dose of study intervention to prevent pregnancy in a partner. Male 
participants must not donate or bank sperm during this same time period. Not engaging in 
heterosexual activity (sexual abstinence) for the duration of the study and for the study 
intervention washout period is an acceptable practice if this is the preferred usual lifestyle 
of the participant; however, periodic or occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable methods of contraception.
Informed Consent
15. Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. As judged by the investigator, any evidence of diseases (such as severe or uncontrolled 
systemic diseases, including ongoing or active infection, uncontrolled hypertension, renal 
transplant and active bleeding diseases, serious chronic GI conditions associated with 
diarrhoea, which, in the investigator’s opinion, makes it undesirable for the participant to 
participate in the study or that would jeopardise compliance with the protocol.


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2. A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, 
or Cell-free and Concentrated Ascites Reinfusion Therapy (CART). Drainage and CART 
are not allowed within 2 weeks prior to screening assessment.
3.
History of another primary malignancy except for malignancy treated with curative intent 
with no known active disease within 3 years before the first dose of study intervention and 
of low potential risk for recurrence. Exceptions include basal cell carcinoma of the skin 
and squamous cell carcinoma of the skin that has undergone potentially curative therapy, 
adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other 
solid tumours curatively treated.
4. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to Grade ≤ 1 or baseline. Note: Subjects may be enrolled 
with chronic, stable Grade 2 toxicities (defined as no worsening to >Grade 2 for at least 3 
months prior to [randomization/enrollment/Cycle 1 Day 1] and managed with standard of 
care treatment) that the investigator deems related to previous anticancer therapy, such as:

Chemotherapy-induced neuropathy

Fatigue

Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies 
which may include:
a) Hypothyroidism/hyperthyroidism
b) Type 1 diabetes
c) Hyperglycaemia
d) Adrenal insufficiency
e) Adrenalitis
f)
Skin hypopigmentation (vitiligo)
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 whole brain 
radiotherapy and study enrolment/randomization.
6. Active primary immunodeficiency, known uncontrolled human immunodeficiency virus 
(HIV) infection or active hepatitis B or C infection. , or active hepatitis B or C infection. 
Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA. Participants should be tested for HIV prior to 
enrolment if required by local regulations or institutional review board (IRB)/independent 
ethics committee (IEC). 
7. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.


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8. Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines 
are not considered attenuated live vaccines) within 30 days prior to the first dose of study 
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.
9. 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 
participant’s participation in the clinical study or evaluation of the clinical study results.
10. Participants with a medical history of myocardial infarction (MI) within 6 months before 
enrolment, symptomatic CHF (NYHA Class II to IV), unstable angina pectoris, or a recent 
(< 6 months) cardiovascular event including stroke. Participants with troponin levels 
above the upper limit of normal (ULN) at screening (as defined by the manufacturer), and 
without any myocardial-related symptoms, should have a cardiological consultation before 
enrolment to rule out MI.
11. Investigator judgement of one or more of the following:
(a) Mean resting QT interval corrected by Fridericia’s formula (QTcF) interval > 470
msec (females) or > 450 msec (males) obtained from triplicate 12-lead ECGs taken at 
screening, where
QTcF =
QT
3✓RR
(b) History of QT prolongation associated with other medications that required 
discontinuation of that medication, or any current concomitant medication known to 
prolong the QT interval and cause Torsdes de Pointes
(c) Congenital long QT syndrome, family history of long QT syndrome, or unexplained 
sudden death under 40 years of age in first-degree relatives.
12. Lung criteria:
(a) History of (non-infectious) ILD/pneumonitis that required steroids, current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by 
imaging at screening
(b) Lung-specific intercurrent clinically significant illnesses including, but not limited to, 
any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of study 
enrolment, severe asthma, severe chronic obstructive pulmonary disease, restrictive 
lung disease, pleural effusion etc)
(c) Prior pneumonectomy(complete).
13. Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, 
Sjogren’s, sarcoidosis, etc), where there is documented, or a suspicion of pulmonary 


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involvement at the time of screening. Full details of the disorder should be recorded in the 
electronic Case Report Form (eCRF) for participants who are included in the study.
Prior/Concomitant Therapy
14. Prior exposure, without adequate treatment washout prior to enrolment for therapies 
detailed in Table 6.
15. Any concurrent anticancer treatment, Concurrent use of hormonal therapy for non-cancer 
related conditions (eg, HRT) is allowed. Washout periods for prior therapies are provided 
in Table 6.
16. Major surgical procedure (excluding placement of vascular access) or significant traumatic 
injury within 4 weeks of the first dose of study intervention or an anticipated need for 
major surgery during the study.
17. Palliative radiotherapy with a limited field of radiation within 2 weeks or with wide field 
of radiation or to more than 30% of the bone marrow within 4 weeks before the first dose 
of study intervention. Radiation therapy, including palliative stereotactic radiation therapy 
to chest ≥4 weeks. See Table 6.
Prior/Concurrent Clinical Study Experience
18. Previous treatment in the present study. 
19. Randomisation into a prior T-DXd study regardless of treatment assignment, or concurrent 
enrolment in another clinical study, unless it is an observational (non-interventional) 
clinical study or during the follow-up period of an interventional study.
20. Known allergy or hypersensitivity to study intervention or any of the study intervention 
excipients.
21. History of severe hypersensitivity reactions to other mAbs.
Other Exclusions
22. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
23. Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
24. Currently pregnant (confirmed with positive pregnancy test) or breastfeeding, or who are 
planning to become pregnant.
25. Subjects with past or resolved hepatitis B virus (HBV) infection or inactive chronic HBV 
infection are eligible only if they meet the following criteria and such patients should be 
closely monitored for HBV reactivation.  


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i.
HBsAg(-) (on or off anti-viral treatment), AND all of the following criteria:
a.
anti-HBc (+) (IgG or total Ig), 
b.
HBV viral DNA < 2,000 IU/mL,
c.
ALT ≤  ULN, 
d. Liver architecture normal (absence of any liver pathology including cirrhosis, 
fibrosis, and liver metastases), 
e.
Has access to a local Hepatitis B expert during and after the study, 
f.
Absence of HCV co-infection or history of HCV co-infection, 
g. Prophylactic anti-viral treatment starting at a minimum of 7 days before 
commencing study drug(s) is required if HBV viral DNA is detectable at 
baseline. 
ii.
HBsAg(+) AND all of the following criteria: 
h. Anti-HBc (+), 
i.
HBeAg(-),
j.
HBV viral DNA < 2,000 IU/mL,
k. ALT ≤ULN, 
l.
Liver architecture normal (absence of any pathology including cirrhosis, 
fibrosis or liver metastases)
m. No presence or family history of HCC or cirrhosis, no extrahepatic 
manifestations e.g. arthritis, polyarteritis nodosa, 
n. Has access to a local Hepatitis B expert during and after the study, 
o. Absence of HCV co-infection or history of HCV co-infection, 
p. Prophylactic anti-viral treatment starting at a minimum of 7 days before 
commencing study drug(s) is required. 
5.3
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:

Participants must follow the contraception requirements outlined in Appendix F.

Participants should not donate blood or blood components while participating in this 
study and through 40 (+ 7) days after the last dose of study intervention. 

Use of tobacco products, e-cigarettes and vaping is strongly discouraged but not 
prohibited. Participants should inform the investigator about any prior or current use of 
these products and details should be recorded in the eCRF.

Concomitant use of dietary supplements, medications not prescribed by the investigator, 
and alternative/complementary treatments is discouraged, but not prohibited.

Preservation of sperm should be considered prior to enrolment in this study.


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Restrictions relating to concomitant therapies are described in Appendix G 1.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
These participants should have the reason for study withdrawal recorded in the (eCRF) as 
“eligibility criteria not fulfilled” (ie, participant does not meet the required inclusion/exclusion 
criteria). This reason for study withdrawal is only valid for screen failures. The date of 
screening failure is defined as the date the site determined that the participant was ineligible.
Individuals who do not meet the eligibility criteria for participation in this study (screen 
failures) may be rescreened once with respect to HER2 status and once with respect to other 
screening procedures (see Section 1.3.1). 

Participants who are rescreened are required to sign a new ICF.

Rescreened participants should be assigned the same participant number (ie, E-code) as 
for the initial screening. 

Rescreening should be documented so that its effect on study results, if any, can be 
assessed. 

All assessments must be repeated for rescreening unless they are within 28 days of the 
participant being enrolled in the interactive response technology (IRT).
Participant enrolment is described in Section 6.3.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, placebo, 
or medical device intended to be administered to a study participant according to the CSP. 
6.1
Study Interventions Administered
6.1.1
Investigational Products
The investigational product in this study is T-DXd. Details of the study intervention are 
provided in Table 7. AstraZeneca will supply T-DXd. 
All participants included in the study will receive T-DXd 6.4 mg/kg as an IV infusion once 


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every 3 weeks, on Day 1 of each 3-week cycle. Participants may continue to receive study 
intervention until RECIST 1.1-defined PD, unacceptable toxicity, withdrawal of consent, or 
until any other criterion for discontinuation of study intervention is met (see Section 7.1). 
Continuation of study intervention beyond RECIST 1.1-defined PD is not permitted in this 
study. 
Participants may continue to receive T-DXd as long as they are continuing to show clinical 
benefit, as judged by the investigator and in the absence of discontinuation criteria.
Dose modifications are described in Section 6.6.
Table 7
Study Intervention: T-DXd
Arm Name
T-DXd arm
Intervention Name
T-DXd
Type 
Drug
Dose Presentation
Vial
Unit Dose Strength
Powder for concentrate for solution for infusion 100 mg/vial
Dosage Level
6.4 mg/kg
Route of Administration
IV infusion
Use
Experimental
IMP or NIMP
IMP
Sourcing
Provided centrally by sponsor
Packaging and Labelling
Study intervention will be provided in 100 mg vials in cartons. 
Each vial and carton will be labelled in accordance with Good 
Manufacturing Practice Annex 13 and per country requirements a
Former Name/Alias
DS8201a
a
Label text for T-DXd (DS8201a) will show “DS8201a” depending on the agreed product name used in the 
respective approved study master label document. All naming conventions for these compounds are correct 
during this transitional period.
IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal product; 
T-DXd = trastuzumab deruxtecan.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1. The investigator or designee (eg, pharmacist) must confirm appropriate temperature 
conditions have been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.
2. Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff.


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3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Reference Manual or other specified location.
6.2.1
T-DXd Preparation, Administration and Storage
T-DXd will be supplied as a 100 mg/vial lyophilised powder for concentrate for solution for 
infusion. Following reconstitution with sterile water for injection, the solution contains 
mg/mL T-DXd in 
mM histidine/histidine hydrochloride, 
mg/mL sucrose, 
 (w/v) 
polysorbate 80; it has a pH of 
. The post-reconstitution label-claim volume is 5 mL.
The reconstituted product is a clear to opalescent, colourless to yellow liquid, and practically 
free from visible particles. 
Preparation of T-DXd
The dose of T-DXd for administration must be prepared by the investigator’s or site’s 
designated study intervention manager using aseptic technique. Total time from needle 
puncture of the T-DXd vial to the start of administration must not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If the final product is stored at both refrigerated and ambient temperature, the total time must 
not exceed 24 hours.
Following preparation and during administration, the prepared IV bag must be covered by 
light protection cover.
Administration of T-DXd
It is recommended that participants receive prophylactic anti-emetic agents prior to infusion of 
T-DXd and on subsequent days. Anti-emetics such as 5-hydroxytryptamine 3 (5-HT3) 
antagonists or neurokinin 1 (NK1) receptor antagonists and/or steroids (eg, dexamethasone) 
should be considered and administered in accordance with the prescribing information or 
institutional guidelines. 
T-DXd will be administered using an IV bag containing 5% (w/v) Dextrose Injection infusion 
solution and delivered through an IV administration set with a 0.2- or 0.22-μm filter. The 
standard infusion time for T-DXd is approximately 90 (± 10) minutes for the first infusion. If 
the first infusion is well tolerated and the participant does not experience an IRR, the 


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minimum infusion time for subsequent cycles is 30 minutes. However, if there are 
interruptions during infusion, the total allowed time must not exceed 3 hours at room 
temperature. 
Do not co-administer other drugs through the same infusion line.
The participant’s weight at screening (baseline) will be used to calculate the initial dose of T-
DXd. If, during the course of treatment, the participant’s weight changes by ≥± 10%, the 
participant’s dose will be recalculated based on the participant’s updated weight. Thereafter, a 
dose recalculation will be required upon a ≥ ±10% change from the last updated weight. 
Refer to the Pharmacy Instructions for detailed information about preparation and 
administration of T-DXd.
Monitoring of T-DXd Administration
Participants will be monitored during and after infusion of T-DXd. Vital signs will be 
measured according to the SoA (Table 2).
Management of study intervention-related toxicities are described in Appendix K. As with any 
biological product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognise and treat anaphylaxis.
Storage of T-DXd
The investigator, or an appropriate delegate, will ensure that all study intervention is stored in 
a secured area, at appropriate temperatures and as specified on the label, and in accordance 
with applicable regulatory requirements. 

A calibrated temperature monitoring device will be used to record the temperature 
conditions in the drug storage facility. 

A temperature log will be used to record the temperature of the storage area. 

Temperature excursions outside the permissible range listed in the clinical supply 
packaging are to be reported to the Study Monitor upon detection. 

T-DXd vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. T-DXd must 
be kept in the original packaging until use to prevent prolonged light exposure.
6.3
Measures to Minimise Bias
Participant Enrolment
All participants will be centrally assigned to open-label study intervention using an IRT. 
Before the study is initiated, directions for the IRT will be provided to each site. The IRT will 


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provide the kit identification number to be allocated to the participant at each dispensing visit.
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening. At screening/baseline (Days -28 to -1), the investigators or suitably trained 
delegate will:

Obtain signed informed consent before any study-specific procedures are performed. If 
laboratory or imaging procedures were performed for alternate reasons prior to signing 
consent, these can be used for screening purposes with consent of the participant. All 
screening laboratory and imaging results must have been obtained within 28 days prior to 
the participant being enrolled in the study. 

Participants will be identified to the IRT per country regulations. Obtain a unique 7-digit 
enrolment number (E-code), through the IRT in the following format (ECCNNXXX: CC 
being the country code, NN being the centre number, and XXX being the participant 
enrolment code at the centre). This number is the participant’s unique identifier and is 
used to identify the participant on the eCRFs.

Determine participant eligibility (see Sections 5.1 and 5.2).

Following completion of all screening procedures and documentation of all baseline 
assessments, enrol eligible participant into the study and obtain a treatment assignment 
number. The treatment assignment number should be obtained from the IRT on the same 
day the participant’s eligibility is confirmed and they are enrolled in the study. The date 
of enrolment is defined as the date the participant is confirmed as eligible in the IRT.
If the participant is ineligible for inclusion in the study for any reason, the IRT should be 
accessed to terminate the participant in the system. The date of screening failure is defined as 
the date the site determined that the participant was ineligible.
Refer to Section 5.4 for details of rescreening procedures, where applicable.
Participants will begin study intervention on Day 1; every effort should be made to ensure 
study intervention is initiated within 3 days of enrolment. Participants must not be treated 
unless all eligibility criteria have been met. Clinical status should be checked prior to the first 
dose of study intervention.
Study intervention will be dispensed at the study visits summarised in SoA (Table 2). 
If a participant withdraws from the study, his/her enrolment code cannot be reused. Withdrawn 
participants will not be replaced.
Returned study intervention should not be re-dispensed to the participants.


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Methods for Assigning Treatment Groups
Not applicable. This is an open-label, single arm study and all participants will receive the 
same study intervention. Potential bias in data interpretation will be reduced through the 
following:

Efficacy: The primary endpoint, confirmed ORR, will be based on ICR.

Safety: An independent ILD Adjudication Committee will review and adjudicate on all 
cases of potential ILD/pneumonitis.
Procedures for Handling Incorrectly Enrolled Participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Participants who 
are enrolled but subsequently found not to meet all the eligibility criteria must not be started 
on study intervention and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is incorrectly started on study 
intervention, the investigator should inform the AstraZeneca study physician immediately, and 
a discussion should occur between the AstraZeneca study physician and the investigator 
regarding whether to continue or discontinue the participant from treatment. The AstraZeneca 
study physician must ensure all decisions are appropriately documented and that the potential 
benefit/risk profile remains positive for the participant.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
Deviations from the prescribed dosage regimen should be recorded in the eCRF.
The on-site Study Pharmacist is responsible for managing the study intervention from receipt 
by the study site until the destruction or return of all unused study intervention. 
6.5
Concomitant Therapy
Any concomitant treatment, procedure, or other medication considered necessary by the 
investigator for the participant’s safety and wellbeing (including over-the-counter or 
prescription medicines, vitamins, and/or herbal supplements) that the participant has received 
from the time of screening or receives during the study, including the 40-day (+ 7-day) 


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follow-up period following the last dose of study intervention, must be recorded in the eCRF 
along with:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency.
The study physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
If any concomitant therapy is administered due to a new or unresolved AE, it should be 
recorded.
Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.
Restricted, prohibited, and permitted concomitant medications/therapies are described in more 
detail in Appendix G 1.
Drug-drug Interactions
There is no information to date on drug-drug interactions with T-DXd, either preclinically or 
in participants. There may be a hypothetical interaction between T-DXd and
hydroxychloroquine and/or chloroquine and therefore concomitant treatment with 
hydroxychloroquine or chloroquine is not allowed during the study intervention.
6.5.1 Prohibited Concomitant Medications
T-DXd safety-specific restrictions are listed below (refer also to Appendix G 1):

Participants must be instructed not to take any medications, including over-the-counter 
products, without first consulting with the investigator.

Participants, if assigned treatment, should not receive live vaccine during the study and up 
to 30 days after the last dose of study intervention. Participants who have received live, 
attenuated vaccine within 30 days prior to the first dose of T-DXd will be excluded. 

The following medications are prohibited during the study. The sponsor must be notified 
if a participant receives any of these during the study

Any concurrent chemotherapy, anticancer study intervention or biological, 
radiotherapy (except palliative radiotherapy to areas other than chest, after 
consultation with the study physician) or hormonal therapy for cancer treatment, 
including anticancer traditional Chinese medicines (ie, those with a label for cancer 


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treatment). Concurrent use of hormones for noncancer-related conditions (eg, insulin 
for diabetes and HRT) is acceptable

T-DXd cannot be administered when the participant is taking immunosuppressive 
medications, including corticosteroids with the following exceptions:
o
short-term courses (< 2 weeks) of low to moderate dose (< 10 mg prednisolone 
per day or equivalent)
o
long-term, alternate-day treatment with short-acting preparations
o
maintenance physiological doses (replacement therapy)
o
administered topically (skin or eyes), by aerosol, or by intra-articular, bursal, or 
tendon injection 
o
treatment with corticosteroids to prevent or treat hypersensitivity reactions to 
radiographic contrast agents is allowed. A temporary period of steroid treatment 
will be allowed for different indications after discussion with the study physician 
(eg, chronic obstructive pulmonary disorder [COPD], radiation, nausea, etc) 
o
participants with bronchopulmonary disorders may use bronchodilators if only 
administered intermittently 
o
use of immunosuppressive medications for the management of study 
intervention-related AEs or in participants with contrast allergies is acceptable. 

Immunosuppressive medications also include drugs like methotrexate, azathioprine, 
and tumour necrosis factor-alpha blockers. 

Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the 
study intervention. If treatment with chloroquine or hydroxychloroquine is absolutely 
required for COVID-19, study intervention must be interrupted. If chloroquine or 
hydroxychloroquine is administered, a washout period of at least 14 days is required 
before restarting study intervention.
6.5.2 Other Protocol Restrictions or Supportive Treatments
Other CSP-mandated restrictions or supportive treatments are listed below (see also Appendix
G 1):

Based on the currently available clinical safety data, it is recommended that participants 
receive prophylactic anti-emetic agents prior to infusion of T-DXd and on subsequent 
days. Anti-emetics such as 5-HT3 antagonists or NK1 receptor antagonists and/or steroids 
(eg, dexamethasone) should be considered and administered in accordance with the 
prescribing information or institutional guidelines.

Concomitant use of dietary supplements, medications not prescribed by the investigator, 
and alternative/complementary treatments is discouraged, but not prohibited. 


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
Prophylactic or supportive treatment of study intervention-induced AEs will otherwise be 
as per investigator’s discretion and institutional guidelines.
Permitted/Rescue Therapies: 

Based on the currently available clinical safety data, it is recommended that patients 
receive prophylactic anti-emetic agents prior to infusion of T-DXd and on subsequent 
days.

Use of immunosuppressive medications for the management of IMP-related AEs or in 
patients with contrast allergies is acceptable.

Patients with Hepatitis B infection eligible for study participation should commence anti-
viral therapy (if not already ongoing) prior to or at the time of starting steroids equivalent 
to > 20 mg prednisolone and likely to continue for ≥ 4 weeks. Anti-viral therapy must be 
managed in consultation with a local Hepatitis B expert. 
6.6
Dose Modification
In case a dose reduction is necessary, the study intervention will be administered in 
accordance with Table 8 and the guidance in Table 23 (Appendix K).
Table 8
Dose Reduction Levels of T-DXd
Starting Dose
Dose Level -1
Dose Level -2
6.4 mg/kg
5.4 mg/kg
4.4 mg/kg
Once the dose of T-DXd has been reduced because of toxicity, all subsequent cycles should be 
administered at that lower dose level unless further dose reduction is required (Table 8). More 
than 2 dose reductions are not allowed, and the study intervention will be discontinued if 
further toxicity that meets the requirement for dose reduction occurs.
Dose delays are permitted for T-DXd treatment and the dosing interval for the next T-DXd 
cycle may be shortened, as clinically feasible, to gradually align with the schedule of tumour 
efficacy assessment. Two consecutive doses must be administered at least 
 apart.  
Every effort should be made to limit study drug delay, however, in circumstances, such as of 
adverse event management or medical intervention, the study drug can be held up to 
 
(
) from the last T-DXd dose. During this time scheduled CT/MRI scans should 
continue as per protocol, and patients should fulfil all of the following criteria:

Study drug may be resumed with confirmation of continued benefit per RECIST 1.1. 
Scans should be performed at the frequency defined per protocol, while the drug is 
being held


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o
At minimum 1 restaging scan must be done within 6 weeks prior to restarting the 
study drug 

IP(s) is/are restarted within the guidance of the TMGs for T-DXd and any combination 
agents, if appropriate

No prohibited concomitant medications have been administered since the last dose of 
T-DXd
Treatment cycles for a participant for whom T-DXd dosing is temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last T-DXd dose.
In addition, investigators may consider dose reductions or discontinuations of T-DXd 
according to the participant’s condition and after discussion with the study physician or 
designee. For management of dose delays due to T-DXd related events, the TMGs 
(Appendix K) should be followed, as applicable.
In summary, if a participant experiences a clinically significant and/or unacceptable toxicity, 
dosing will be interrupted or permanently discontinued depending on the severity of the 
toxicity, and supportive therapy administered as required.
On improvement of an AE for which T-DXd was temporarily interrupted, T-DXd may be 
restarted at the same dose at the discretion of the investigator. If a further episode of the same 
AE subsequently requires dose interruption, or if a different AE subsequently requires dose 
interruption, T-DXd may be restarted at a one dose level reduction on improvement of the AE 
or discontinued if the participant is receiving the lowest protocol-specified dose level 
(Appendix K). 
Appropriate and optimal treatment of the toxicity is assumed prior to considering dose 
modifications. Prior to discontinuation of study intervention due to toxicities, please consult 
with the sponsor study physician.
All dose modifications (interruption, re-initiation, reduction and/or discontinuation) should be 
based on the worst preceding toxicity (National Cancer Institute Common Terminology 
Criteria for Adverse Events [NCI CTCAE v5.0]). Specific criteria for interruption, re-
initiation, dose reduction and/or discontinuation of T-DXd are listed in Appendix K, which is 
applicable only to treatment-emergent adverse events (TEAEs) that are assessed as related to 
use of T-DXd by the investigator(s). For non-drug related TEAEs, follow standard clinical 
practice. Appropriate clinical experts should be consulted as deemed necessary.
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Refer 
to Appendix H for additional information on dose modification for suspected or confirmed 
COVID-19 infection for participants treated with T-DXd.


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ILD/Pneumonitis Management Guidance 
Please refer to the Guidance for Management of Participants with Drug-induced 
ILD/Pneumonitis summary flow chart in Appendix J for information on the management of 
participants with drug-induced ILD/pneumonitis. All potential ILD/pneumonitis cases should 
be reported within 24 hours; including both serious and non-serious potential 
ILD/pneumonitis cases (potential ILD/pneumonitis is defined in the current Site Manual List 
of Common Terminology Criteria for Adverse Events [MedDRA] Preferred Terms).
ILD/pneumonitis should be ruled out if a participant develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such as dyspnoea, cough, or fever. If 
the AE is confirmed to have an aetiology other than ILD/pneumonitis, follow the management 
guidance outlined in Appendix K.
If the AE is suspected to be ILD/pneumonitis, treatment with study intervention should be 
interrupted pending further evaluations. Evaluations should include those outlined in 
Section 8.2.5.2.1. As soon as ILD/pneumonitis is suspected, corticosteroid treatment should be 
started promptly as per clinical treatment guidelines.
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in 
Appendix J and Appendix K. All events of ILD/pneumonitis regardless of severity or 
seriousness will be followed until resolution including after study intervention 
discontinuation.
To ensure adequate and relevant evaluation, systematic additional data collection will be 
conducted for all cases that will be brought for evaluation. This additional data collection will 
cover a more in-depth relevant medical history (eg, smoking, radiation, COPD, and other 
chronic lung conditions), diagnostic evaluation, treatment and outcome of the event. This data 
collection will be triggered for AEs reported using selected MedDRA Preferred Terms.
LVEF Decrease Management Guidance 

Left ventricular ejection fraction will be measured by either ECHO or MUGA scan. All 
ECHOs/MUGAs will be evaluated by the investigator or delegated physician for 
monitoring cardiac function.

Troponin-T (preferably high-sensitivity troponin-T) will be measured locally at screening 
and at end of treatment, and as needed based on participant-reported cardiac signs or 
symptoms suggesting CHF, MI, or other causes of cardiac myocyte necrosis. If ECG is 
abnormal, follow institutional guidelines.

Refer to Sections 8.2.3 (ECGs and troponin testing) and 8.2.5.1 (ECHO/MUGA 
acquisition scans) for details of investigations of cardiac function.


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
Refer to Appendix K for information on the management of cardiac toxicities related to 
the study intervention. 
Refer to Table 8 for protocol-specified dose reductions of T-DXd and to Appendix K for 
further information.
6.7
Intervention after the End of the Study
As described in Section 4.4, the study will remain open until all participants have discontinued 
study intervention and completed their last expected visit/contact.
Participants who continue to receive benefit from their assigned study intervention at the 
scheduled DCO for the final analysis and final database lock may continue to receive study 
intervention for as long as they and their physician feel they are gaining clinical benefit. 
Where participants continue to receive study intervention following the scheduled DCO for 
final analysis, it is recommended that participants continue the scheduled site visits (see 
Section 1.3).
For all study participants, investigators should continue to monitor and document data in the 
source notes after the scheduled DCO for the final analysis and final database lock. Depending 
on the results of the analysis, a decision may be made to continue further data collection for a 
longer period with the intent to analyse long-term OS and safety data to fulfil any other 
potential Health Authority requirements. Any additional long-term analysis may be further 
clarified through an addendum to the main Statistical Analysis Plan (SAP), which will be 
developed before the final DCO. Data will be collected until any of following conditions are 
met:

Remaining participants in the study (including those who have discontinued study 
intervention) have discontinued the study, OR

Remaining participants have been transferred into a roll-over study, OR

If the sponsor decides to stop data collection, participants who are receiving study 
intervention at this time and deriving clinical benefit from their assigned study 
intervention will be allowed to continue treatment and only SAEs will be collected.
After the final DCO for this study, AstraZeneca will continue to supply T-DXd to participants 
who received T-DXd until meeting any discontinuation criteria as defined in Section 7.1. 
Where possible, if commercial supply of T-DXd is available in the local market, then this 
route should be used. 
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, participants currently receiving treatment with T-DXd may be 
transitioned to such a study, and the current study would reach its end. The roll-over or safety 


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extension study would ensure treatment continuation with visits and assessments per its 
protocol. Any participant who would be proposed to move to such a study would be asked to 
sign a new ICF. OS data collected in the roll-over study may be combined with OS data from 
this study and evaluated as a combined dataset.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. If study intervention is permanently discontinued, the participant will
remain in the study to be evaluated for safety and survival follow-up. The investigator should 
instruct the participant to contact the site before or at the time if study intervention is stopped. 
A participant who decides to discontinue study intervention will always be asked about the 
reason(s) and the presence of any AEs. The reason for discontinuation should be documented 
in the source document and the appropriate section of the eCRF.
Participants who have permanently discontinued from further study intervention will need to 
be discontinued from the IRT.
Individual participants may be discontinued from study intervention in the following 
situations: 

RECIST 1.1-defined radiological progression as assessed by the investigator (refer to 
Section 8.1.1 and Appendix E). 

Investigator determination that the participant is no longer benefiting from study 
intervention.

An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing. 

Any AE that meets criteria for discontinuation defined in the dose modification guidelines 
for management of study intervention-related toxicities (see Section 6.6).

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment. A participant who discontinues treatment is normally 
expected to continue to participate in the study (eg, for safety and survival follow-up) 
unless they specifically withdraw their consent to all further participation in any study 
procedures and assessments (see Section 7.2).

Severe non-compliance with the CSP as judged by the investigator or AstraZeneca.

Pregnancy or intent to become pregnant. Refer to Section 8.3.14 for information on 
pregnancy and to Appendix F for contraception requirements.

Initiation of subsequent anticancer therapy, including another investigational agent.


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Note that discontinuation from study intervention is NOT the same as withdrawal from the 
study.
Refer to the SoA for details of data to be collected at the time of study intervention 
discontinuation (ie, the end of treatment visit) and follow-up, and for any further evaluations 
that need to be completed.
7.1.1
Follow-up of Participants Post Discontinuation of Study Intervention
All participants who discontinue the study intervention will be followed up for safety 
assessments 40 (+ 7) days after their last dose of study intervention. Additional assessments to 
be performed at the time of the 40-day safety follow-up are detailed in the SoA (Table 3). For 
participants with ILD/pneumonitis and reactivation of Hepatitis B infection, safety follow-up 
will continue until the resolution of ILD/pneumonitis or reactivation of Hepatitis B infection.
Participants who have discontinued study intervention for any reason prior to objective 
progression per RECIST 1.1 as determined by the investigator, regardless of whether or not 
they have commenced subsequent anticancer therapy, will be followed up with tumour 
assessments as indicated in the SoA (Table 3) until RECIST 1.1-defined radiological PD or 
death regardless of whether or not the participant started a subsequent anticancer therapy, 
unless they have withdrawn all consent to study-related assessments.
7.1.2
Follow-up for Survival
Participants will be followed up for survival status as indicated in the SoA (Table 3) until 
death, withdrawal of consent, or the end of the study. Survival information may be obtained 
via telephone contact with the participant or the participant’s family, or by contact with the 
participant’s current physician. Additional assessments to be performed at the time of survival 
follow-up are detailed in the SoA (Table 3).
Note: Survival calls will be made following the date of DCO for the final analysis (these 
contacts should generally occur within 7 days of the DCO). If participants are confirmed to be 
alive or if the date of death is after the DCO date, these participants will be censored at the 
date of DCO.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options to ensure the collection of endpoints and 
safety information including new AEs and any ongoing AEs and concomitant medications 


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(eg, telephone contact at 40 [+ 7] days after discontinuation of study intervention, a 
contact with a relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, an Early Study Intervention 
Discontinuation visit should be conducted, as shown in the SoA (Table 2). See SoA for 
data to be collected at the time of study withdrawal and follow-up (Table 3) and for any 
further evaluations that need to be completed. 
-
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If the participant requests 
withdrawal of consent for use of samples, destruction of any samples taken and not tested 
should be carried out in line with what was stated in the informed consent and local 
regulation. The investigator must document the decision on use of existing samples in the 
site study records and inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and no contact has been established by the time the study is completed (see 
Section 4.4), such that there is insufficient information to determine the participant’s status at 
that time.
Participants who decline to continue participation in the study, including telephone contact, 
should be documented as “withdrawal of consent” rather than “lost to follow-up.” 
Investigators should document attempts to re-establish contact with missing participants 
throughout the study period. If contact with a missing participant is re-established, the 
participant should not be considered lost to follow-up and evaluations should resume 
according to the protocol.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 


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if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have been 
lost to follow-up from the study.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant during survival follow-up within legal and ethical boundaries for all 
participants, including those who did not get study intervention. Public sources may be 
searched for vital status information. If vital status is determined as deceased, this will be 
documented and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
In order to support efficacy endpoints of PFS and OS, the survival status of all participants in 
the Full Analysis and the Safety Analysis Sets should be re-checked, including participants 
who withdrew consent or are classified as “lost to follow-up.”

Lost to follow-up – Site personnel should check hospital records and a publicly available 
death registry (if available), as well as checking with the participants’ current physician, 
to obtain a current survival status.

In the event that the participant has actively withdrawn consent to the processing of their 
personal data, the survival status of the participant can be obtained by site personnel from 
publicly available death registries (if available) where it is possible to do so under 
applicable local laws to obtain a current survival status.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing (including permitted visit windows) are summarised in the 
SoA (Section 1.3). Data collection following study analysis until the end of the study is 
described below. 

Protocol waivers or exemptions are not allowed.

The investigator is responsible for ensuring the accuracy, completeness, and timeliness of 
data recorded on the eCRFs and for the provision of responses to data queries. The 
investigator will sign the completed eCRFs and a copy of the completed eCRFs will be 
archived at site.


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
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA 
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

If a participant has an unscheduled assessment or visit, eg, as a result of an AE, all 
relevant data must be collected on the eCRF.

If a participant undergoes unscheduled imaging, eg, to investigate clinical 
signs/symptoms of progression and is found not to have progressed, every attempt should 
be made to perform the subsequent imaging at the next regularly scheduled visit.
Data Collection Following Study Analysis until the End of the Study
Following the DCO for the final analysis, all participants who remain in the study will 
continue the scheduled survival follow-up site visits indicated in the SoA (Table 3). Refer to 
Section 6.7 for further details. In addition, any AEs of ILD/pneumonitis will be followed-up 
until resolution. For other safety reporting requirements after final analysis, see 
Section 8.3.12.
8.1
Efficacy Assessments
8.1.1
Imaging Tumour Assessments
Tumour assessments use images from CT (preferred) or MRI, with IV contrast, of the chest, 
abdomen, and pelvis (including the entire liver and both adrenal glands), collected during 
screening/baseline and at regular (follow-up) intervals (every 6 weeks [± 7 days]) during study 
intervention. Any other areas of disease involvement should also be imaged at screening based 
on known metastasis sites or signs and symptoms of the individual participant. Scans (CT or 
MRI) of the chest, abdomen, and pelvis are mandatory. Brain CT or MRI is required only in 
cases of pre-existing brain metastases or symptoms. The imaging modality used for baseline 
tumour assessment should be kept the same consistently at each subsequent follow-up 
assessment throughout the study, if possible. It is important to follow the tumour assessment 
schedule as closely as possible (refer to the SoA, Section 1.3) relative to first dose. 


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Screening/baseline imaging should be performed no more than 28 days before enrolment 
(confirmation of participant eligibility) and ideally should be performed as close as possible to 
and prior to the start of study intervention. Treatment continues until RECIST 1.1-defined PD, 
unacceptable toxicity, withdrawal of consent, or any other criterion for discontinuation of 
study intervention is met. Scanning/tumour assessments continue throughout treatment until 
RECIST 1.1-defined radiological progression by investigator’s assessment. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent 
assessments at the next scheduled visit. 
The RECIST 1.1 assessments of baseline images identify target lesions (TLs; defined as 
measurable) and non-target lesions (NTLs). On-study images are evaluated for TLs and NTLs 
chosen at baseline, and for new lesions (NLs) when they appear. This allows determination of 
follow-up TL response, NTL lesion response, the presence of unequivocal NLs, and overall 
time point responses (CR, PR, SD, PD, or not evaluable [NE]).
8.1.2
Central Reading of Scans 
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed imaging Contract Research Organisation (iCRO) for quality control, 
storage, and for ICR. Digital copies of all original scans should be stored at the investigator 
site as source documents. Electronic image transfer from the sites to the iCRO is strongly 
encouraged. An ICR of images will be performed at the discretion of AstraZeneca. Results of 
these independent reviews will not be communicated to investigators, and results of 
investigator tumour assessments will not be shared with the central reviewers.
Further details of the ICR will be documented in an Independent Review Charter.
8.1.3
Overall Survival
Assessments for survival will be conducted every 3 months ± 14 days following objective PD 
or discontinuation of study intervention. Survival information may be obtained via telephone 
contact with the participant, participant’s family, by contact with the participant’s current 
physician, or local death registries as described in Sections 7.1.2 and 7.3.
8.1.4
Clinical Outcome Assessments
Not applicable.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).


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8.2.1
Physical Examinations
A complete or targeted physical examination will be completed as indicated in the SoA 
(Section 1.3).

Complete physical examination will include assessments of the following; general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and 
extremities), urogenital, dermatological, GI, endocrine, haematological/lymphatic, and 
neurological systems. 

Targeted physical examinations are to be used by the investigator on the basis of clinical 
observations and symptomatology.
Physical examination, as well as assessment of height (screening only) and weight, will be 
performed at timelines as specified in the SoA; investigators should pay special attention to 
clinical signs related to previous serious illnesses, and to new or worsening abnormalities that 
may qualify as AEs. Refer to Section 8.3.5 for details.
8.2.2
Vital Signs
The following vital signs will be evaluated at the time points indicated in the SoA 
(Section 1.3).

Body temperature

Pulse rate

Respiratory rate

Systolic and diastolic blood pressure.
Pulse oximetry (SpO2) is described in Section 8.2.5.2.
Blood pressure and pulse measurements will be assessed with the participant in the seated or 
supine position using a completely automated device. Manual techniques will be used only if 
an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the participant in a quiet setting without distractions (eg, television, cell phones).
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded 
on the eCRF.


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All measurements scheduled to be taken before infusion on Day 1 of a treatment cycle may be 
taken up to 3 days prior to administration of study intervention.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. 
In the event of an AE of IRR, the corresponding vital signs values should be entered into the 
eCRF.
8.2.3
Electrocardiograms
Triplicate ECGs will be performed at screening and before infusion on C1D1. Subsequent 
ECGs will be performed in triplicate in close succession only if abnormalities are noted. 
Single 12-lead ECGs will be performed at the times specified in the SoA after the participant 
has been resting semi-supine for at least 5 minutes and recorded while the participant remains 
in that position using an ECG machine that automatically calculates heart rate and measures 
PR, RR, QRS, QT, and QTcF intervals. Refer to the TMGs in Appendix K for management of
prolonged average QTc > 500 ms or > 60 ms change from baseline. 
All ECGs should be assessed by the investigator as to whether they are clinically significantly 
abnormal. Any clinically significant abnormalities detected require triplicate ECG results. At 
each time point at which triplicate ECG are required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. Where required, the full set of triplicate 
ECGs should be completed within 5 minutes.
During treatment cycles, ECGs may be taken up to 3 days prior to administration of study 
intervention.
Troponin (preferably high-sensitivity troponin-T) will be collected at time points specified in 
the SoA (Section 1.3), including whenever a participant reports signs or symptoms suggesting 
CHF, MI, or other causes of myocyte necrosis:

Participants with troponin levels above the ULN at screening (as defined by the 
manufacturer), and without any MI related symptoms, should have a cardiological 
consultation before enrolment to rule out MI.

If troponin levels are above the ULN but below the level of MI defined by the 
manufacturer (CTCAE Grade 1), at baseline, no repeat testing is required.

Only Grade 3 troponin needs to be repeated.

If ECG is abnormal, follow institutional guidelines.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5.


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Whenever ECGs, vital signs, and blood draws are scheduled for the same nominal time, ECG 
assessments should occur first, then vital signs assessments, and then blood draws. The timing 
of the first 2 assessments should be such that it allows the blood draw (eg, PK blood sample) 
to occur at the timepoints indicated in the SoA. 
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation,
and urinalysis will be taken at the visits indicated in the SoA (Section 1.3).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The analysis of clinical chemistry and haematology samples, and urinalysis will be performed 
at a local laboratory at or near the investigator site. Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site.
Other safety laboratory tests include assessment for pregnancy and hepatitis B and C serology 
and HIV antibody test. Pregnancy tests may be performed at site using a licensed test, subject 
to the following: 

A negative serum pregnancy test (with a sensitivity of at least 25 mIU/mL) must be 
available at screening (within 72 hours prior to enrolment) for all female participants of 
childbearing potential

A negative pregnancy test (serum or urine per institutional guidelines) must be available 
within 72 hours prior to each subsequent administration of study intervention and at the 
end of treatment visit for all female participants of childbearing potential.

A positive urine pregnancy test result must immediately be confirmed using a serum test.
The laboratory variables indicated in Table 9 will be measured.


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Table 9
Laboratory Safety Variables
Haematology/Haemostasis (Whole Blood)
Clinical Chemistry (Serum or Plasma)
Haemoglobin
Creatinine
Leukocyte count
Bilirubin, total
Leukocyte differential count (absolute count and 
percentage; neutrophils, lymphocytes, monocytes, 
eosinophils, basophils)
Alkaline phosphatase
Platelet count
AST
Total red blood cell count
ALT
Haematocrit
Albumin
Urinalysis
Potassium
Haemoglobin/Erythrocytes/Blood 
Calcium, total
Protein/Albumin 
Sodium
Glucose 
Creatine kinase
Coagulation 
Amylase
Coagulation variables (aPTT, PTT, and INR)
Gamma-glutamyl transferase
Pregnancy Test
Glucose (fasting)
Serum pregnancy test (with sensitivity of at least 
25 mIU/mL) at screening; serum or urine thereafter
Lactate dehydrogenase
Protein, total
Blood urea nitrogen or Urea 
Troponin a
Magnesium
Chloride
a
See Section 8.2.3 for details of requirements for troponin testing.
ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; INR = international normalised ratio; PTT = partial thromboplastin time.
Creatinine clearance should be determined according to the Cockcroft Gault equation, using 
actual body weight to confirm adequate renal function within 14 days prior to study 
enrolment.
Males:
CrCL = 
Weight (kg) × (140 - Age)
(mL/min)
72 × serum creatinine (mg/dL)
Females:
CrCL = 
Weight (kg) × (140 - Age) × 0.85
(mL/min)
72 × serum creatinine (mg/dL)
The investigator should assess the available results with regard to clinically relevant 


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abnormalities in documentation. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated (preferably within 24 to 48 hours) and recorded on the 
eCRF. Situations in which laboratory safety results should be reported as AEs are described in 
Section 8.3.5.
All participants with Grade 3 or 4 laboratory values at the time of completion or 
discontinuation from study intervention must be followed and have further tests performed 
until the laboratory values have returned to Grade 1 or 2, unless these values are not likely to 
improve because of the underlying disease.
NB. In case a participant shows an AST or ALT ≥3 × ULN together with total bilirubin (TBL) 
≥2 × ULN, refer to Appendix D “Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law” (HL), for further instructions. 
8.2.5
Other Safety Assessments
8.2.5.1
Echocardiogram/Multigated Acquisition Scan 
An ECHO or MUGA scan to assess LVEF will be performed at the visits shown in SoA 
(Section 1.3). The modality of the cardiac function assessments must be consistent for a given 
participant (ie, if ECHO is used at screening for a given participant, then ECHO should also 
be used for subsequent scans for that participant). The participants should also be examined 
using the same machine and operator whenever possible, and quantitative measurements 
should be taken (ie, accurate to 1% and not estimated to 5%). All ECHOs/MUGAs will be 
evaluated by the investigator or delegated physician for monitoring cardiac function.
If a participant has had an ECHO or MUGA performed within 4 weeks prior to treatment 
discontinuation, the discontinuation visit ECHO/MUGA scan is not required unless clinically 
indicated. If a participant has any clinically significant decrease in LVEF (greater than 
percentage points to below
), there should be follow-up within 4 weeks until 
resolution.
Situations in which ECHO or MUGA results should be reported as AEs are described in 
Section 8.3.5.
8.2.5.2
Pulmonary Assessments
Pulse oximetry (SpO2) should be evaluated by the investigator or the delegate physician at 
each study visit.
On Day 1 of each treatment cycle, SpO2 should be evaluated by the investigator or the 
delegate physician prior to and at the end of the infusion of study intervention.
Pulmonary function tests should include basic (required) spirometry at a minimum, with 
optional additional components as detailed in Table 10.


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Table 10
Spirometry Components
Required spirometry components
Optional spirometry components
FVC
Peak expiratory flow
FVC % predicted
DLCO
FEV1
FEV6
FEV1 % predicted
Total lung capacity
FEV1/FVC %
Residual volume
DLCO = diffusion capacity of the lungs for carbon monoxide; FEV = forced expiratory volume; FEV1 = FEV in 
1 second; FEV6 = FEV in 6 seconds; FVC = forced vital capacity.
Diffusion capacity of the lungs (DLCO) will be performed/encouraged if feasible, but is 
strongly encouraged for participants with prior severe and/or clinically significant pulmonary 
disorders. In event of suspected ILD/pneumonitis, refer to Section 8.2.5.2.1 for additional 
pulmonary assessments.
High-resolution computed tomography (HRCT) of the chest is required at screening and if 
ILD/pneumonitis is suspected. Chest CT and/or chest HRCT scans will be reviewed separately 
for safety for the presence of ILD/pneumonitis prior to administration of the next scheduled 
dose of T-DXd. If both a non-contrast chest HRCT scan for assessment of ILD/pneumonitis 
and a diagnostic IV contrast enhanced chest CT scan for tumour response assessment (as part 
of chest-abdomen-pelvis imaging) are to be acquired in the same imaging session, HRCT 
should be performed first.
8.2.5.2.1
ILD/Pneumonitis Investigation
If new or worsening pulmonary symptoms (eg, dyspnoea, cough, or fever) or radiological 
abnormality suggestive of ILD/pneumonitis are observed, study intervention should be 
interrupted and a full investigation is required as described in the T-DXd TMGs 
(Appendix K). Evaluations should include:

Signs and symptoms (cough, shortness of breath, and pyrexia, etc) 

Detailed past medical history, including concomitant medications

Physical examination, including auscultation of lung field

Arterial blood gases if clinically indicated 

Pulmonary function tests (Section 8.2.5.2) and pulse oximetry (SpO2) 

Bronchoscopy and bronchoalveolar lavage, as clinically indicated and feasible

HRCT 

Pulmonologist consultation (infectious disease consultation as clinically indicated)

One blood sample collection for PK as soon as ILD/pneumonitis is suspected, if feasible

Other tests could be considered, as needed.


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The results of the full diagnostic workup (including HRCT, blood and sputum culture, 
haematological parameters, etc) will be captured in the eCRF. It is strongly recommended to 
perform a full diagnostic workup to exclude alternative causes such as lymphangitic 
carcinomatosis, infection, allergy, cardiogenic oedema, or pulmonary haemorrhage. In the 
presence of confirmatory HRCT scans where other causes of respiratory symptoms have been 
excluded, a diagnosis of ILD/pneumonitis should be considered and the TMGs should be 
followed. Troponin measurements will be performed to rule out cardiac aetiology.
The following assessments should be performed, if feasible, to enhance the investigation and 
diagnosis of potential cases of ILD/pneumonitis. The results of these assessment will be 
collected.

Other items
When ILD/pneumonitis is suspected during study intervention, the following markers
should be measured where possible:
o
ILD/pneumonitis markers (Krebs von den Lungen-6 [KL-6] and surfactant 
protein D [(SP-D]) and β-D-glucan
o
Tumour markers: particular tumour markers related to disease progression

Additional clinical chemistry: C-reactive protein, lactate dehydrogenase.
8.2.5.3
ECOG Performance Status
ECOG performance status will be assessed at the times specified in the SoA (Section 1.3) 
using the following:
0
Fully active; able to carry out all usual activities without restrictions.
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (eg, light housework or office work).
2
Ambulatory and capable of self-care, but unable to carry out any work activities; up 
and about more than 50% of waking hours.
3
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair.
5
Dead.
Any significant change from baseline or screening must be reported as an AE.


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8.2.5.4
Ophthalmological Assessments
Ophthalmological assessments will be performed as specified in the SoA (Section 1.3) and 
will include visual acuity testing, slit lamp examination, and fundoscopy.
8.2.5.5
Safety assessment for Eligible HBV infection only

Eligible patients enrolled with inactive or resolved Hepatitis B infection will be 
monitored for reactivation. 

In patients enrolled with HBsAg(-) at baseline, reactivation is defined as: 
(1) reverse HBsAg seroconversion occurs (reappearance of HBsAg positivity)
(2)HBV DNA > 2 log (100 x ) baseline, or HBV DNA becomes detectable, if 
undetectable at baseline 
(3)Reactivation may occur with or without a hepatitis flare, reasonably defined as an ALT 
increase to ≥3 times the baseline level and >100 U/L. 

In patients with HBsAg(+) at baseline, reactivation will be defined as: 
1) HBV DNA > 2log (100 x) baseline or becomes detectable, if undetectable at baseline,  
(2)With or without a hepatitis flare (ALT increase to ≥3 times the baseline level and >100 
U/L). 
If HBV reactivation is confirmed, interrupt T-DXd therapy, and if not already on anti-viral 
therapy, commence prompt treatment with anti-virals following consultation with the local 
Hepatitis B expert and in accordance with local practice (administration of a potent 
nucleos(t)ide analogue with a high barrier to resistance i.e. entecavir, tenofovir disoproxil or 
tenofovir alafenamide is recommended). A decision to re-start T-DXd therapy should consider 
any potential interactions between T-DXd and therapies for HBV reactivation, and should be 
made in consultation with the AstraZeneca Study Physician and the supervising local Hepatitis 
B expert.  Antivirals should be continued for at least 12 months after last dose of study 
treatment.
8.3
Adverse Events and Serious Adverse Events
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, recording, and 
reporting events that meet the definition of an AE.


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8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected from the time of signature of the ICF throughout 
the treatment period and including the safety follow-up period (which is 40 + 7 days after the 
discontinuation of study intervention). Additionally, for ILD/pneumonitis or reactivation of 
Hepatitis B, safety follow-up will be continued until resolution of ILD/pneumonitis or 
Hepatitis B reactivation. If an event that starts after the defined safety follow-up period is 
considered to be due to a late onset toxicity to study intervention, including reactivation of 
Hepatitis B infection, then it should be reported as an AE or SAE as applicable. Collection and 
reporting of AEs and SAEs after the final DCO is described in Section 8.3.12.
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor.
A TEAE is defined as an AE that occurs, having been absent before the first dose of study 
intervention, or has worsened in severity or seriousness after the initiating the study 
intervention until 40 (+7) days after last dose of the study intervention. SAEs with an onset or 
worsening more than 40 (+7) days after the last dose of study intervention, if considered 
related to the study intervention, are also TEAEs.
The following types of events should be reported by the investigator in eCRF electronic data 
capture (EDC) AE page(s) in the clinical study database within 24 hours of becoming aware 
for the purposes of reporting in the global safety database:

SAEs

All potential ILD/pneumonitis cases should be reported within 24 hours; including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD/pneumonitis is 
described in the Event Adjudication Site Manual).

All reactivation of Hepatitis B case (both serious and non-serious) should be reported 
within 24 hours. 

Hepatic events (both serious and non-serious) which meet the potential Hy’s Law (PHL) 
criteria defined as an elevated (ALT or AST) ≥ 3 × ULN and an elevated TBL ≥2 × ULN 
that may occur either at different time points or simultaneously during the study. A 
targeted questionnaire is built within the eCRF to collect relevant additional information 
for these potential cases. See Section 8.3.6.

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 a 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 participant. 


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
Overdose is always serious. By definition an overdose is medically important, which 
meets the seriousness criterion of important medical event. An overdose can occur 
with or without an AE. AEs can either be serious or non-serious. Details of the 
overdose including T-DXd dosage, clinical course, associated AEs, and outcome must 
be captured in the Narrative form of the eCRF within the EDC. See Section 8.4.
Disease progression/worsening of GC/GEJ adenocarcinoma will not be recorded as an AE on 
the Adverse Event eCRF. See Section 8.3.7.
Death due to disease progression should be recorded on the Death eCRF.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF.
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:

AE (verbatim)

The date the AE started and stopped

Initial CTCAE grade, plus any changes in CTCAE grade

Whether the AE is serious or not (Appendix B)

Investigator causality rating against the study intervention (yes or no)

Action taken with regard to study intervention

AE caused participant’s withdrawal from study (yes or no)

Administration of treatment for the AE

Outcome.
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

Seriousness criteria

Date of hospitalisation

Date of discharge

Probable cause of death


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
Date of death

Autopsy performed

Causality assessment in relation to study procedures

Causality assessment to other medication.
The grading scales found in the NCI CTCAE will be utilised for all events with an assigned 
CTCAE grading. For those events without assigned CTCAE grades, the recommendation in 
the CTCAE criteria that converts mild, moderate, and severe events into CTCAE grades 
should be used. A copy of the CTCAE can be downloaded from the Cancer Therapy 
Evaluation Program website (http://ctep.cancer.gov).
8.3.3 Causality Collection
The investigator should assess causal relationship between study intervention and each AE, 
and answer “yes” or “no” to the question “Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?”
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure, the causal 
relationship is implied as “yes”.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider or reported in response to 
the open question from the study site staff: “Have you had any health problems since the 
previous visit/since you were last asked?”, or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) to recording a list of signs and symptoms. However, if a diagnosis is known and 
there are other signs or symptoms that are not generally part of the diagnosis, the diagnosis 
and each sign or symptom will be recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests, vital signs, physical examinations, ECGs, 
and ECHO/MUGA scans will be summarised in the Clinical Study Report (CSR). 
Deterioration as compared with baseline in protocol-mandated laboratory values or vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the study intervention, or are considered to be clinically 
relevant as judged by the investigator (which may include but not be limited to consideration 
as to whether treatment or non-planned visits were required or other action was taken with the 


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study intervention, eg, dose adjustment or study intervention interruption).
If deterioration in a laboratory value or vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory result, 
or vital sign will be considered as additional information. Wherever possible the reporting 
investigator uses the clinical, rather than the laboratory term (eg, anaemia versus low 
haemoglobin value). Any diagnosis of the undesirable clinical outcome of ‘Left ventricular 
dysfunction’, a valid or qualifying reduction of LVEF (as measured by MUGA or ECHO) 
should be confirmed and included in the AE report. In the absence of clinical signs or 
symptoms, clinically relevant deteriorations in non-mandated parameters should be reported 
as AEs.
Deterioration of a laboratory value, which is unequivocally due to PD, should not be reported 
as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. Please refer to Appendix D for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
8.3.7 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the study intervention is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new, or progression of existing metastasis to the primary cancer under study 
should be considered as PD and not an AE. Events, which are unequivocally due to PD, 
should not be reported as an AE during the study.
8.3.8 Disease Under Study
Symptoms of disease under study are those that might be expected to occur as a direct result 
of GC/GEJ adenocarcinoma. Events which are unequivocally due to disease under study 
should not be reported as an AE during the study unless they meet SAE criteria or lead to 
discontinuation of the study intervention.
8.3.9
New Cancers
The development of a new cancer should be regarded as an AE and will generally meet at least 


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one of the serious criteria (ie, an SAE). New primary cancers are those that are not the primary 
reason for the administration of study intervention and have been identified after the 
participant’s inclusion in this study. They do not include metastases of the original cancer.
8.3.10
Deaths
All deaths that occur during the study intervention period, or within the protocol-defined 
follow-up period after the administration of the last dose of study intervention, must be 
reported as follows:

Death clearly resulting from PD should be documented in the eCRF in the Statement of 
Death page. It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, the 
AE causing the death must be reported as an SAE within 24 hours. It should also be 
documented in the Statement of Death page in the eCRF. The report should contain a 
comment regarding the co-involvement of PD, if appropriate, and should assign the main 
and contributory causes of death.

Any death with an unknown cause should always be reported as an SAE and documented 
in the Statement of Death page in the eCRF, but every effort should be made to determine 
a cause of death. A post-mortem may be helpful in the assessment of the cause of death, 
and if performed, a copy of the post-mortem results should be forwarded to AstraZeneca 
Patient Safety or its representative within the usual time frames.
Deaths occurring after the protocol-defined follow-up period after the administration of the 
last dose of study intervention should be documented in the Statement of Death page. If the 
death occurred as a result of an event that started after the defined follow-up period and the 
event is considered to be due to a late-onset toxicity to study intervention, it should also be 
reported as an SAE.
8.3.11
Adverse Events of Special Interest
An AESI is an event of scientific and medical interest specific to the further understanding of 
the safety profile of T-DXd, and requires close monitoring and rapid communication by the 
investigators to AstraZeneca. An AESI can be serious or non-serious. All AESIs will be 
recorded in the eCRF using a recognised medical term or diagnosis that accurately reflects the 
event. Serious AESIs will be recorded and reported as per Section 8.3.13.
AESI will be assessed by the investigator for severity, relationship to the study intervention, 
possible aetiologies, and whether the event meets criteria for an SAE and therefore requires 
immediate notification to AstraZeneca. If an AESI evolves into a condition that meets the 
regulatory definition of “serious,” it will be reported on the SAE Report Form.


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Based on the available pre-clinical and clinical data, review of the cumulative literature, 
reported toxicities for the same class of agents, and biological plausibility, the following 
events are considered to be AESIs: 
Interstitial Lung Disease/Pneumonitis
ILD is considered an important identified risk based on a comprehensive cumulative review of 
potential ILD/pneumonitis cases by the independent ILD Adjudication Committee, the 
available safety data from the clinical development programme, available data from recent 
epidemiology/literature, biological plausibility, and safety information from drugs of similar 
class. ILD event adjudication is a retrospective review and will not impact any safety 
decisions for participants. Refer to the current T-DXd IB for a summary of preliminary clinical 
study data.
LVEF Decrease
Left ventricular ejection fraction decrease in association with T-DXd is considered to be an 
important potential risk based on the available pre-clinical data, literature, and available safety 
information for drugs of a similar class. Refer to the current T-DXd IB for a summary of 
preliminary clinical trial data.
Refer to Sections 8.2.3 (ECGs and troponin testing) and 8.2.5.1 (ECHO/MUGA acquisition 
scans) for details of investigations of cardiac function. 
Additional relevant information regarding the AESIs ILD/pneumonitis, and LVEF decrease, 
for the trastuzumab deruxtecan clinical program regardless of seriousness is to be collected 
through the specific section of the eCRF. 
8.3.12
Safety Data to be Collected Following Final Study Data Cutoff
Where participants continue to receive study intervention following the final DCO, it is 
recommended that participants continue the scheduled site visits and investigators should 
continue to monitor and document data in the source notes. Thus, AEs and SAEs will continue 
to be collected, but only SAEs will be reported. In addition, it is recommended that 
investigators continue to monitor the participant’s safety laboratory results during treatment 
with T-DXd in order to manage AEs, consistent with the dose modification guidelines for 
management of study intervention-related toxicities (see Section 6.6). All data after the final 
DCO and database closure will be recorded in the participant’s notes but, with the exception 
of SAEs, will not otherwise be reported for the purposes of this study. Refer to Section 6.7 for 
further information.
All SAEs that occur in participants still receiving T-DXd (or within the 40 + 7 days follow-up 
period after the last dose of T-DXd) after the final DCO must be reported as detailed in 
Section 8.3.13. 


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8.3.13
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study 
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day ie, immediately but no later than 24 hours of when he or she becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, the investigator or other study site staff reports a SAE to 
the appropriate AstraZeneca representative by telephone followed by completion of a paper 
SAE form. The AstraZeneca representative will advise the investigator/study site staff how to 
proceed.
For further guidance on the definition of a SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness for T-DXd is the current IB.
8.3.14
Pregnancy
All pregnancies and outcomes of pregnancy with conception dates following the first date of 
study intervention, including pregnancy in the partner of male participants, should be reported 
to AstraZeneca.
8.3.14.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, the study intervention should 
be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 


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handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs during the study the investigator or other site personnel should inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.13) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy.
8.3.14.2
Paternal Exposure 
Non-sterilised male participants who intend to be sexually active with a female partner of 
childbearing potential should refrain from fathering a child or donating or banking sperm for 
the duration of the study (from the time of screening) and for 4 months after the last dose of 
study intervention. 
Pregnancy of the participant’s partner is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring from the date of the first dose of study intervention 
until 4 months after the last dose of study intervention should be followed up and documented 
in the medical record and provided to the AstraZeneca Patient Safety data entry site. Consent 
from the partner must be obtained before the information is collected and reported to 
AstraZeneca.
Where a report of pregnancy is received, prior to obtaining information about the pregnancy, 
the investigator must obtain the consent of the participant’s partner. The local study team 
should adopt the Master Pregnant Partner Form in line with local procedures/requirements and 
submit it to the relevant Regulatory Authority/IRBs/IECs prior to use.
8.3.15
Medication Error
If a medication error occurs in the course of the study, the investigator or other site personnel 
should inform the appropriate AstraZeneca representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure all 


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relevant information is completed within 1 (Initial Fatal/Life-threatening or follow-up 
Fatal/Life-threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.13), and within 30 days for all other 
medication errors.
Medication errors are defined in Appendix B.
8.4
Overdose
Use of T-DXd in doses exceeding that specified in the CSP is considered to be an overdose. 
There is currently no specific treatment in the event of overdose of T-DXd, and possible 
symptoms of overdose are not established.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel should inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours after he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.13) and within 30 days 
for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection, handling, storage and shipping of biological samples will be 
provided in the study-specific laboratory manual. Samples should be stored in a secure storage 
space with adequate measures to protect confidentiality. 
Samples collected in China will be stored and disposed of according to local laws and 
regulations. PK and anti-drug antibody (ADA) samples collected in China will be destroyed 
after finalisation of the Bioanalytical Report or completion of the CSR.
For further details on Handling of Human Biological Samples, see Appendix C.
8.5.1
Pharmacokinetics

Serum samples will be collected for measurement of serum concentrations of T-DXd, 
total anti-HER2 antibody, and MAAA-1181a as specified in the SoA and Appendix H. 


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
Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor, for example, for safety reasons. 
The timing of sampling may be altered during the course of the study based on newly 
available data (eg, to obtain data closer to the time of peak or trough matrix 
concentrations) to ensure appropriate monitoring. 

Serum samples will be used to analyse the PK of T-DXd, total anti-HER2 antibody, and 
MAAA-1181a. Samples collected for analyses of T-DXd, total anti-HER2 antibody, and 
MAAA-1181a concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in serum will be assayed by bioanalytical test 
sites operated by or on behalf of AstraZeneca, using an appropriately validated bioanalytical 
method. Full details of the analytical method used will be described in a separate Bioanalytical 
Report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADAs against T-DXd and neutralising ADAs in serum
will be collected per the SoA (Section 1.3). Samples will be assayed by bioanalytical test sites 
operated by or on behalf of AstraZeneca, using an appropriately validated bioanalytical 
method. Full details of the methods used will be described in a separate report.
ADA samples may also be further tested for characterisation of the ADA response. Please also 
refer to Appendix H.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Central Biomarker Analysis
Participant consent to the study includes participation in the mandatory biomarker assessment 
components of the study. FFPE tumour slides are mandatory in order to confirm HER2 status 
and will be collected from all enrolled participants as outlined below and in the SoA 
(Section 1.3).
FFPE tumour tissue slides must be provided for each enrolled participant after enrolment and 
prior to first dose of study intervention, in order to confirm HER2 status by central laboratory. 
It can be either:


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
A newly acquired tumour sample if the primary tumour is accessible by endoscopy or if 
metastatic tissue can be biopsied, or

The most recent archived tumour tissue sample, if a newly-acquired sample is not 
available.
If a tumour biopsy was performed at screening in order to determine participant’s HER2 status 
locally during screening, the same biopsy will be provided to the central laboratory for 
confirmation of HER2 status. If the participant’s HER2 status has not been documented 
locally, the newly-acquired biopsy obtained from an accessible tumour should be used to 
confirm HER2 status locally, and used to confirm HER2 status by central laboratory. 
For all FFPE tumour specimens, freshly-cut, unstained, serial tumour slides of sufficient 
quality to allow for assessment of HER2 status should be submitted. Please note:

The mandatory screening tumour biopsy must not be taken from a previously irradiated 
lesion.

Tumour lesions used for newly-acquired biopsies should not be the same lesions used as 
RECIST 1.1 target lesions, unless there are no other lesions suitable for biopsy and in this 
instance only core needle (not excisional/incisional) biopsy is allowed. 
To meet regulatory requirement, samples collected and testing data generated may be used to 
support companion diagnostic development and registration for the disease.
FFPE tumour slides collected for central HER2 confirmatory testing will be destroyed or 
repatriated maximally 5 years after study intervention is approved for marketing in China. To 
meet regulatory requirement, sections of the tumor may be retained that allow this for 
potential companion diagnostic filing as requested by the NMPA.
The histological images taken by the central laboratory may be used for computer-aided 
analysis to explore clinical response-associated biomarkers.
For further details on Handling of Human Biological Samples, including storage and 
destruction, refer to Appendix C and the Laboratory Manual. Details of tumour sampling 
requirements are provided in the Laboratory Manual.
9
STATISTICAL CONSIDERATIONS
Statistical analyses will be performed by AstraZeneca or its representatives. 
A comprehensive SAP will be prepared prior to enrolment of the first participant in the study.


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9.1
Statistical Hypotheses
This is a single-arm, Phase II open-label study in which all participants will receive the same 
study intervention. The primary objective of the study is to evaluate the efficacy of T-DXd 
6.4 mg/kg by assessing the confirmed ORR by ICR in participants with HER2-positive 
(defined as IHC 3+ and IHC 2+/ISH +) advanced gastric or GEJ adenocarcinoma who have 
received at least 2 prior treatment regimens including a fluoropyrimidine and a platinum 
agent. The secondary objective is to evaluate the efficacy of T-DXd 6.4 mg/kg by assessing 
the confirmed ORR by ICR in participants with HER2-expressing (defined as IHC 3+ and 
IHC 2+) advanced gastric or GEJ adenocarcinoma who have received at least 2 prior 
treatment regimens including a fluoropyrimidine and a platinum agent.
The primary endpoint of the study, confirmed ORR by ICR, is defined as the proportion (%) 
of participants with confirmed CR or confirmed PR as assessed by ICR per RECIST 1.1.
Although participant eligibility with respect to HER2-positive status will be determined 
locally, the primary analysis will be performed on participants whose HER2-positive status is 
confirmed by central laboratory.
In view of the open-label, single-arm study design, no formal statistical hypothesis will be 
tested and, unless otherwise specified, study data will be presented using descriptive statistics. 
However, to ensure strong control of type 1 error amongst the primary and secondary ORR 
endpoints in the HER2-positive and HER2-expressing populations, a gated approach will be 
applied to the analysis of ORR in the HER2-expressing population. The analysis of ORR in 
the HER2-expressing population will only be assessed for success if the analysis of ORR in 
the HER2-positive population is deemed successful. See Section 9.4.5 for details. Efficacy 
demonstrated in confirmed ORR by ICR per RECIST 1.1 is considered an early signal for 
clinical benefit. 
9.2
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.3
Populations for Analyses
Analysis populations are defined in Table 11 for analyses to support the primary objective in  
HER2 positive population ( HER2 Positive FAS,  HER2-Positive RES) and to support the 
secondary objectives in HER2-expressing population (HER2-expressing FAS,  HER2-
expressing RES).
Table 11
Populations for Analysis 
Population/Analysis Set
Description
ITT Analysis Set
All participants who signed the informed consent form and were enrolled in 
the study
HER2- Positive FAS 
All enrolled participants with HER2 status confirmed as IHC 3+ or 
IHC 2+/ISH + by central laboratory 
HER2-expressingFAS
All enrolled participants with HER2 status confirmed as IHC 3+ or IHC 2+ 
by central laboratory
HER2- Positive RES
All enrolled participants with HER2 status confirmed as IHC 3+ or 
IHC 2+/ISH + by central laboratory who received at least 1 dose of study 
intervention and had measurable disease at baseline by ICR
HER2-expressing RES
All enrolled participants with HER2 status confirmed as IHC 3+ or IHC 2+ 
by central laboratory who received at least 1 dose of study intervention and 
had measurable disease at baseline by ICR
Safety Analysis Set (SAF)
All enrolled participants who received at least 1 dose of study intervention
PK Analysis Set
All enrolled participants who received at least 1 dose of study intervention 
and had at least 1 post-dose measurable serum concentration of T-DXd
T-DXd ADA Evaluable Set
All participants in the Safety Analysis Set with a non-missing baseline ADA 
T-DXd result and at least 1 post-baseline ADA T-DXd result
ADA = anti-drug antibody; FAS = full analysis set; HER2 = human epidermal growth factor receptor 2; 
ICR = independent central review; IHC = immunohistochemistry; ISH = in situ hybridisation; ITT = intent to 
treat; PK = pharmacokinetic; RES = response evaluable set; T-DXd = trastuzumab deruxtecan.


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9.4
Statistical Analyses
9.4.1
General Considerations
The SAP will be finalised prior to enrolment of the first participant in the study and will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. Table 12 provides a summary of 
key endpoints and corresponding analysis populations.
The DCO for the primary analysis will occur approximately 
 after the last participant 
has initiated study intervention. At this time, 
 
 data will also be summarised.
The DCO for the full final analysis will occur approximately 
months after the last 
participant has initiated study intervention. Given the median time to response 
 
and the median duration of response 
 among participants with confirmed CR or 
PR in the T-DXd 
, this provides sufficient time 
for participants to reach response and sufficient DoR follow-up for responders. The full final 
analysis will report the analyses of all primary and secondary endpoints, including updated 


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Table 12
Summary of Outcome Variables and Analysis Populations
Outcome variable
Populations
Primary Efficacy Variable in HER2 Positive Population
•
Confirmed ORR by ICR per RECIST 1.1
Primary analysis: 
HER2 Positive FAS
Supplementary 
analysis: HER2 
Positive RES
Secondary Efficacy Variables in  HER2 Positive Population
•
Confirmed ORR by investigator assessment per RECIST 1.1
•
PFS, DoR, DCR, and tumour size change by ICR and by investigator assessment 
per RECIST 1.1
•
OS
HER2 Positive FAS
Secondary Efficacy Variables in HER2-expressing Population
•
Confirmed ORR by ICR per RECIST 1.1
•
Confirmed ORR by investigator per RECIST 1.1
•
PFS, DoR, DCR, and tumour size change by ICR and by investigator assessment 
per RECIST 1.1
•
OS
Primary analysis: 
HER2-expressing 
FAS
Supplementary 
analysis: HER2-
expressing RES
Baseline and Other Variables 
•
Demography, baseline, and disease characteristics
•
Important deviations
•
Medical/surgical history
•
Previous and subsequent anticancer therapy
•
Concomitant medications/procedures
Primary analysis:  
HER2-Positive FAS
Supplementary 
analysis: ITT 
Analysis Set
Pharmacokinetics 
•
Pharmacokinetics data
PK Analysis Set
Immunogenicity 
•
Anti-drug antibodies
T-DXd ADA 
Evaluable Set
Safety 
•
Exposure to study intervention
•
Safety data
Safety Analysis Set
ADA = anti-drug antibody; DCR = disease control rate; DoR = duration of response; FAS = full analysis set; 
ICR = independent central review; ITT = intent to treat; ORR = objective response rate; OS = overall survival; 
PFS = progression-free survival; PK = pharmacokinetic; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumours version 1.1; RES = response evaluable set; T-DXd = trastuzumab deruxtecan.


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9.4.2
Efficacy
9.4.2.1
Calculation or Derivation of Tumour Response Variable
Independent Central Review
An ICR of radiological scans will be performed on all participants. 
All images will be collected centrally. The imaging scans will be reviewed by 2 independent 
radiologists using RECIST 1.1 and will be adjudicated, if required. For each participant, the 
ICR will define the overall visit response data (CR, PR, SD, PD, or NE) and the relevant scan 
dates for each time point (ie, for visits where response or progression is/is not identified). If a 
participant has had a tumour assessment that cannot be evaluated, then the participant will be 
assigned a visit response of NE (unless there is evidence of progression, in which case the 
response will be assigned as PD). Efficacy endpoints (ORR, PFS, DoR, and DCR) by ICR will 
then be derived from the scan dates and overall visit responses. 
Further details of the ICR will be documented in an Independent Review Charter.
Investigator Assessments per RECIST 1.1
All RECIST assessments, whether scheduled or unscheduled, will be included in the 
calculations. This is also regardless of whether a participant discontinues study intervention or 
receives another anticancer therapy. 
At each visit, participants will be programmatically assigned a RECIST 1.1 visit response of 
CR, PR, SD, PD, or NE depending on the status of their disease compared with baseline and 
previous assessments. Baseline will be assessed within the 28 days prior to study enrolment.
Refer to Appendix E for definitions of CR, PR, SD, PD, and NE.
9.4.2.2
Primary Endpoint: Confirmed ORR by ICR per RECIST 1.1
The primary endpoint of the study is confirmed ORR by ICR according to RECIST 1.1. 
Confirmed ORR (per RECIST 1.1 by ICR) is defined as the percentage of participants with a 
confirmed response of CR or PR. Data obtained up until progression or the last evaluable 
assessment with the absence of progression will be included in the assessment of ORR. 
Participants who discontinue study intervention without progression, receive a subsequent 
anticancer therapy, and then respond will not be included as responders in the calculation of 
ORR. 
A confirmed response of CR or PR means that a response of CR or PR is recorded at 1 visit 
and confirmed by repeat imaging not less than 4 weeks after the response was first observed, 
with no evidence of progression between the initial and CR/PR confirmation visits.


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Confirmed Best Objective Response by ICR
Best objective response (BOR) is a participant’s best response during their participation in the 
study, but prior to starting any subsequent anticancer therapy, up until RECIST 1.1-defined 
progression or the last evaluable assessment in the absence of RECIST 1.1-defined 
progression.
Categorisation of BOR will be based on RECIST 1.1 by ICR using the following response 
categories: (confirmed) CR, (confirmed) PR, SD, PD, and NE; unconfirmed CR/PR will be 
included in SD.
Analyses of Primary Endpoint
The primary analysis of the primary endpoint will be based on the HER2 Positive FAS. ORR 
will be estimated with 2-sided 95% exact CI. Summaries will be produced presenting the 
number and percentage of participants with a confirmed tumor response. Confirmed BOR will 
be summarized descriptively by n (%) for each category (confirmed CR, confirmed PR, SD, 
PD, and NE).
Supplementary Analysis
Supplementary analysis of the primary endpoint will be performed in the HER2 Positive RES
using the same methods as described above. 
Sensitivity Analysis
Details of any sensitivity analyses to be conducted for the primary endpoint will be described 
in the SAP, as appropriate.
Subgroup Analysis
Details of any subgroup analyses to be conducted for the primary endpoint will be specified in 
the SAP.
9.4.2.3
Secondary Endpoints in HER2 Positive Population
9.4.2.3.1
Objective Response Rate by Investigator Assessment
The secondary efficacy endpoint of ORR is defined as the proportion of participants who have 
a confirmed CR or PR, as determined by the investigator at local site per RECIST 1.1.
Confirmed Best Objective Response by Investigator Assessment
BOR is calculated based on the overall visit responses per RECIST 1.1 using investigator 
assessments. BOR is a participant’s best response during their participation in the study, but 
prior to starting any subsequent anticancer therapy, up until RECIST 1.1-defined progression 
or the last evaluable assessment in the absence of RECIST 1.1-defined progression.


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Categorisation of BOR will be based on RECIST 1.1 by investigator assessment using the 
following response categories: (confirmed) CR, (confirmed) PR, SD, PD, and NE; 
unconfirmed CR/PR will be included in SD.
Refer to Appendix E for guidance on the evaluation of tumor response per RECIST 1.1.
BOR will be determined programmatically based on RECIST 1.1 using all investigator 
assessments up until the first progression event per RECIST 1.1 as determined by the 
investigator. For participants whose first progression event is death, BOR will be calculated 
based on all evaluable RECIST 1.1 assessments prior to death.
For participants who die with no evaluable RECIST 1.1 assessments, if death occurs ≤91 days 
(ie, 2 * (6 weeks) + 1 week) after the first dose of study intervention, then BOR will be 
assigned to the PD category. For participants who die with no evaluable RECIST assessments, 
if the death occurs > 91 days (ie, 2 * (6 weeks) + 1 week) after the date of the first dose of 
study intervention, BOR will be assigned to the NE category.
Analysis Methods
Investigator assessed ORR will be summarized using the same methods as those specified for 
ORR by ICR for the HER2 Positive FAS (see Section 9.4.2.2).
9.4.2.3.2
Progression-free Survival
Progression-free Survival by ICR
PFS by ICR is defined as the time from enrolment until the date of confirmed PD per 
RECIST 1.1 as assessed by ICR or death (by any cause in the absence of progression) (ie, date 
of event or censoring – date of the first dose of study intervention + 1). The analysis will 
include all participants regardless of whether the participant withdraws from study 
intervention, receives another anticancer therapy, or clinically progresses prior to RECIST 1.1 
progression. The date of progression will be determined based on the earliest of the scan dates 
of the component that triggered the progression. Participants who have not progressed or died 
at the time of analysis will be censored at the time of the latest date of assessment from their 
last evaluable RECIST 1.1 assessment. However, if the participant progresses or dies after 2 
or more consecutive missed visits, the participant will be censored at the time of the latest 
evaluable RECIST 1.1 assessment prior to the 2 missed visits. (Note: NE visit is not 
considered as missed visit).
If the participant has no evaluable visits or does not have baseline data, they will be censored 
at Day 1, unless they die within 2 visits of baseline, ie, ≤91 days (2 * (6 weeks) + 1 week) 
allowing for a late assessment within the visit window).


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Progression-free Survival by Investigator Assessment
PFS by investigator assessment is defined as the time from enrolment until the date of 
confirmed PD per RECIST 1.1 as assessed by the investigator or death (by any cause in the 
absence of progression) (ie, date of event or censoring – date of the first dose of study 
intervention + 1).
Data will be handled as described above for PFS by ICR.
Analysis Methods
PFS will be summarised for the HER2 Positive FAS. A Kaplan-Meier plot of PFS will be 
presented. The estimate of median PFS and corresponding 95% CI using the 
Brookmeyer-Crowley method with log-log transformation will be reported (Brookmeyer and 
Crowley 1982, Klein et al 1997). Summaries of the number and percentage of participants 
experiencing a PFS event and the type of event (RECIST 1.1 PD or death) will be provided. 
The proportion of participants alive and progression-free at 3-monthly intervals from the first 
dose of study intervention will be summarized.
9.4.2.3.3
Overall Survival
OS is defined as the time from the date of enrolment until death due to any cause. Any 
participant not known to have died at the time of analysis will be censored based on the last 
recorded date on which the participant was known to be alive. 
Analysis Methods
OS will be analyzed for the HER2 Positive FAS. 
A Kaplan Meier plot of OS will be presented. Summaries of the number and percentage of 
participants with an OS event will be provided along with the estimate of median OS and 
corresponding 95% CI using the Brookmeyer-Crowley method with log-log transformation 
(Brookmeyer and Crowley 1982, Klein et al 1997). The proportion of participants alive at 
3-monthly intervals from the first dose of study intervention will be summarised.
9.4.2.3.4
Duration of Response
Duration of Response by ICR
For participants who achieve a confirmed CR/PR per RECIST 1.1 by ICR, DoR is defined as 
the time from the date of first documented response until the date of documented progression 
(using RECIST 1.1 by ICR) or death in the absence of disease progression. The time of the 
initial response will be defined as the latest of the dates contributing towards the first visit 
response of CR or PR. The end of response should coincide with the date of progression or 
death from any cause used for the PFS endpoint. If a participant does not progress following a 
response, then their DoR will be the PFS censoring time (ie, DoR = date of PFS event or 
censoring - date of first response + 1).


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Duration of Response by Investigator Assessment
For participants who achieve a confirmed CR/PR per RECIST 1.1 by investigator assessment, 
DoR is defined as the time from the date of first documented response until the date of 
documented progression (using RECIST 1.1 by investigator assessment) or death in the 
absence of disease progression.
Data will be handled as described above for DoR by ICR.
Analysis Methods
DoR will be analysed for the HER2 Positive FAS.
A Kaplan Meier plot of DoR will be presented. The estimate of median DoR and 
corresponding 95% CI using the Brookmeyer-Crowley method with log-log transformation 
will be reported (Brookmeyer and Crowley 1982, Klein et al 1997).
9.4.2.3.5
Disease Control Rate
Disease Control Rate by ICR
The DCR by ICR at 6 weeks is defined as the percentage of participants who have a 
confirmed CR/PR or SD for at least 5 weeks (ie, 6 weeks - 1 week to allow for an early 
assessment within the assessment window) after the date of enrolment (without subsequent 
anticancer therapy) per RECIST 1.1 by ICR.
The DCR by ICR at 24 weeks is defined as the percentage of participants who have a 
confirmed CR/PR or SD for at least 23 weeks (ie, 24 weeks - 1 week to allow for an early 
assessment within the assessment window) after the date of enrolment (without subsequent 
anticancer therapy) per RECIST 1.1 by ICR. 
Disease Control Rate by Investigator Assessment
The DCR by investigator assessment at 6 weeks is defined as the percentage of participants 
who have a confirmed CR/PR or SD for at least 5 weeks (ie, 6 weeks - 1 week to allow for an 
early assessment within the assessment window) after the date of enrolment (without 
subsequent anticancer therapy) per RECIST 1.1 by investigator assessment.
The DCR by investigator assessment at 24 weeks is defined as the percentage of participants 
who have a confirmed CR/PR or SD for at least 23 weeks (ie, 24 weeks - 1 week to allow for 
an early assessment within the assessment window) after the date of enrolment (without 
subsequent anticancer therapy) per RECIST 1.1 by investigator assessment.
Analysis Methods
DCR will be summarised descriptively with the number and percentage of participants with a 
confirmed CR/PR or SD for the HER2-Positive FAS.


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9.4.2.4
Secondary Endpoints in HER2-expressing Population
Secondary efficacy endpoints in the HER2-expressing population including confirmed ORR, 
PFS, DoR, DCR, and tumour size change by ICR and by investigator assessment per RECIST 
1.1, and OS will be analysed in HER2-expressing RES as primary analysis population and 
HER2-expressing FAS as supplementary analysis population using corresponding methods 
specified in section 9.4.2.3 to support the secondary objective in the HER2- expressing 
population. Details of the planned analysis, including subgroup and sensitivity analysis will be 
specified in the statistical analysis plan. 
In order to ensure that family-wise type 1 error is controlled, the analysis of ORR in the 
HER2-expressing population will only be assessed for success if the analysis of ORR in the 
HER2-positive population is deemed successful, details see section 9.4.5.
9.4.3
Safety
Safety summaries will be provided using the Safety Analysis Set. Safety data will be presented 
using descriptive statistics unless otherwise specified. Summary statistics for continuous 
variables will include number of participants, mean, standard deviation, minimum, median, 
and maximum. Frequency tables and shift tables will include number and percentage of 
participants in the respective category. Unless otherwise stated, percentages will be calculated 
out of the population total.
Baseline
In general, the baseline value any parameter is the last non-missing value prior to 
administration of the first dose of study intervention. Details are described in the SAP.
Adverse Events
Adverse events will be coded using the most recent version of MedDRA that will be released 
for execution at AstraZeneca and NCI CTCAE v5.0.
Any TEAE occurring until 40 (+ 7) days after the last dose of the study intervention and prior 
to the start of a new anticancer treatment will be included in the AE summaries. Any other 
AEs will be flagged in the data listings, but not included in the summaries.
An overview of TEAEs will be provided: the number and percentage of participants with any 
TEAE, TEAEs with outcome of death, serious TEAEs, and TEAEs leading to discontinuation 
of study intervention, as well as TEAEs leading to study intervention dose interruptions, and 
AEs leading to study intervention dose reduction.
TEAEs will be presented by System Organ Class and/or Preferred Term covering number and 
percentage of participants reporting at least one event and number of events where 
appropriate. 


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Separate TEAE tables will be provided taking into consideration the relationship to study 
intervention as assessed by the investigator, the CTCAE grade, seriousness, death and events 
leading to discontinuation of study intervention as well as other action taken related to study 
intervention, AESIs, and other significant TEAEs (if applicable).
An additional table will be presented for the number and percentage of participants with most 
common TEAEs. Most common TEAEs will be defined in the SAP.
A TEAE listing will cover details for each individual TEAE.
Adverse events occurring prior to start of study intervention, TEAEs and post-treatment AEs 
will be presented separately.
Full details of TEAE analyses will be provided in the SAP.
Vital Signs
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline. 
Details of vital sign analyses will be provided in the SAP. 
ECGs
For each scheduled post-baseline visit, descriptive statistics for all ECG parameters will be 
presented for observed values and change from baseline. QTcF will be derived during creation 
of the reporting database using reported ECG values (RR and QT) using the following 
formula, where RR is in seconds:
QTcF =
QT
3✓RR
Details of ECG analyses will be provided in the SAP. 
Laboratory Parameters
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
haematology parameters will be presented for observed values and change from baseline. 
Elevation in liver parameters for assessment of HL will be evaluated and reported 
appropriately if potential cases are identified during the course of the study. Corrected calcium 
will be derived during creation of the reporting database using the following formula:
Corrected calcium (mmol/L) = total calcium (mmol/L) + ([40 – albumin (g/L)] × 0.02)


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A shift table for urinalysis will be presented with baseline assessment against the maximum 
on-study intervention category. 
Supportive laboratory listings will cover observed values and changes from baseline for each 
individual participant as well as abnormalities. 
Details of laboratory summaries will be provided in the SAP.
Other Safety Analyses
All other safety endpoints, eg, physical examination findings including ECOG performance 
status, elevated troponin levels, ECHO/MUGA, and ophthalmologic findings, will be listed. 
Further details will be provided in the SAP.
9.4.4
Other Analyses
9.4.4.1
Pharmacokinetics
Serum PK concentration data for T-DXd, total anti-HER2 antibody, and MAAA-1181a will be 
listed for each sampling time for each participant at each sampling point, and a summary will 
be provided for all participants in the PK Analysis Set. Descriptive statistics may be 
calculated.
Details of the PK analyses will be described in the SAP prior to enrolment of the first 
participant in the study.
The popPK analysis to evaluate the effect of intrinsic and extrinsic factors of T-DXd, and if 
appropriate, total anti-HER2 antibody and MAAA-1181a will be reported separately from the 
main CSR.
9.4.4.2
Immunogenicity Data 
Anti-drug antibody data will be summarized using the T-DXd ADA Evaluable Set. 
Immunogenicity results will be listed by participant, and a summary will be provided by the 
number and percentage of ADA-evaluable participants who develop detectable anti-T-DXd 
antibodies during the study. The immunogenicity titre and neutralising ADA data will be listed 
for samples confirmed positive for the presence of anti-T-DXd antibodies.
The effect of immunogenicity as well as the effect of its neutralising properties on PK, 
pharmacodynamics, efficacy, and safety will be evaluated, if the data allow. A detailed plan 
will be written by the AstraZeneca Clinical Pharmacology group or designee.
9.4.4.3
COVID-19
Summaries of data relating to participants diagnosed with COVID-19, and the impact of 
COVID-19 on study conduct (in particular missed visits, delayed or discontinued study 
intervention, and other protocol deviations) may be generated. More detail will be provided in 


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the SAP.
9.4.5
Methods for Multiplicity Control
 
 
 
.
The analysis of ORR in the 
 will only be assessed for success if 
the analysis of ORR in the 
is deemed successful. The success 
criterion for ORR endpoint in the 
 is defined as that the 
 
ORR of T-DXd 
 
 
The success criterion for ORR endpoint 
 
 is defined as that the 
 of 
 
 
 
9.5
Interim Analyses 
An interim analysis is not planned in this study.
9.6
Data Monitoring Committees
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators. 
An Independent Data Monitoring Committee is not considered necessary for this open-label, 
single-arm study.
9.6.1
ILD Adjudication Committee
An ILD Adjudication Committee and Charter will be established to review all cases of 
potential ILD/pneumonitis. To ensure adequate evaluation, relevant additional data from 
within the clinical database may be provided to the adjudication committee to fully 
characterise medical history (eg, smoking, radiation and pulmonary history), diagnostic 
evaluation, treatment, and outcome of the event. Further details can be found in the ILD 
Adjudication Charter.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organisation but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for Serious Adverse Events

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the [IB or state other documents] and will notify the IRB/IEC, 
if appropriate according to local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 


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information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 Code of Federal 
Regulations 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Unless previously specified, the biomarker data will have unknown clinical significance and 


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AstraZeneca will not provide biomarker assessment results to participants, their family 
members, any insurance company, any employer, a clinical study investigator, a general 
physician, or any other third party, unless required to do so by law; however, AstraZeneca may 
share data and biosamples with research partners, eg, Daiichi Sankyo. 
The participant’s samples will not be used for any purpose other than those described in the 
study protocol.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to investigators.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com, 
http://www.clinicaltrials.gov, and https://www.clinicaltrialsregister.eu/, as will the summary of 
the main study results when available. The clinical study and/or summary of main study 
results may also be available on www.chinadrugtrials.org.cn according to the regulations of 
China, the country in which the study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on the eCRF unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory authority inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organisations).


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
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years from the end of the study (as defined in 
the protocol) unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the clinical study agreement. 
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies).
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.


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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor’s procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. 
The investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence (other than progression of the 
malignancy under evaluation) in a participant or clinical study participant administered a 
study intervention and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (eg, an abnormal 
laboratory finding), symptom (for example nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the study 
intervention. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:

Results in death.

Is immediately life-threatening.

Requires in-participant hospitalisation or prolongation of existing hospitalisation. 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect.

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse events for malignant tumours reported during a study should generally be assessed 
as Serious AEs. If no other seriousness criteria apply, the “Important Medical Event” criterion 
should be used. In certain situations, however, medical judgment on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported 
as a Non-serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as Non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 


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removed via cone biopsy.
The above instruction applies only when the malignant tumour event in question is a new 
malignant tumour (ie, it is not the tumour for which entry into the study is a criterion and that 
is being treated by the study intervention under study and is not the development of new or 
progression of existing metastasis to the tumour under study). Malignant tumours that – as 
part of normal, if rare, progression – undergo transformation (eg, Richter’s transformation of 
B cell chronic lymphocytic leukaemia into diffuse large B cell lymphoma) should not be 
considered a new malignant tumour.
Life threatening
“Life-threatening” means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. “Life-threatening” does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important medical event or medical treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation


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
Development of drug dependency or drug abuse
Intensity rating scale:
The grading scales found in the revised NCI CTCAE latest version (v5.0) will be utilised for 
all events with an assigned CTCAE grading. For those events without assigned CTCAE 
grades, the recommendation in the CTCAE criteria that converts mild, moderate and severe 
events into CTCAE grades should be used. A copy of the CTCAE can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). The applicable 
version of CTCAE should be described clearly.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a “reasonable possibility” that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.


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In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of “related” is made if following a review of the relevant data, there is evidence for 
a “reasonable possibility” of a causal relationship for the individual case. The expression 
“reasonable possibility” of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as “not related”.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:

occurred.

was identified and intercepted before the participant received the drug.

did not occur, but circumstances were recognised that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion.

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant.

Drug not administered as indicated, for example, wrong route or wrong site of 
administration.

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet.


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
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature. 

Wrong participant received the medication (excluding IRT errors).

Wrong drug administered to participant (excluding IRT errors).
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT - including those which lead to one of the above 
listed events that would otherwise have been a medication error. 

Participant accidentally missed drug dose(s) eg, forgot to take medication.

Accidental overdose (will be captured as an overdose).

Participant failed to return unused medication or empty packaging.

Errors related to background and rescue medication, or SoC medication in open-label 
studies, even if an AstraZeneca product. 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each site keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent specifically to the subsequent use of donated biological 
samples, the samples will be disposed of/destroyed/repatriated, and the action documented. If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this 
research. The participant will be presented with the option to opt out of the subsequent use of 
the donated samples during the withdrawal process. If the participant decides to opt out, then 
the donated samples will be disposed of or repatriated. If the participant withdraws consent 
without opting out for the subsequent use of the donated samples, then the samples will be 
used as per protocol.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.


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
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
IATA (https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.
Category A pathogens are, for example, Ebola, Lassa fever virus. Infectious substances 
meeting these criteria which cause disease in humans or both in humans and animals must be 
assigned to UN 2814. Infectious substances which cause disease only in animals must be 
assigned to UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations.

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging. 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).


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
Biological samples transported in dry-ice require additional dangerous goods 
specification for the dry-ice content.


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Appendix D
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
D 1
Introduction
This appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
Specific guidance on managing liver abnormalities can be found in the TMGs (Appendix K
Table 23).
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including all local 
laboratory evaluations even if collected outside of the study visits. 
The investigator will also review AE data (eg, for AEs that may indicate elevations in liver 
biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
D 2
Definitions
Potential Hy’s Law Cases
Aspartate aminotransferase or ALT ≥3 × ULN together with TBL ≥2 × ULN at any point 
during the study following the start of study intervention irrespective of an increase in alkaline 
phosphatase.
Hy’s Law Cases
AST or ALT ≥3 × ULN together with TBL≥2 × ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, another drug. 


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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
D 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥3 × ULN.

AST ≥3 × ULN.

TBL ≥2 × ULN.
Local laboratories being used
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met will:

Notify the AstraZeneca representative

Determine whether the participant meets PHL criteria (see Section D 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory eCRF.
D 4
Follow-up
D 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria, the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
D 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria, the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
intervention (See Section D 6).

Notify the AstraZeneca representative who will then inform the central Study Team. 


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
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criterion “Important medical event” and causality assessment “yes/related” 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting study intervention, the investigator 
is not required to submit a PHL SAE unless there is a significant change# in the 
participant’s condition. 

The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data.

Subsequent to this contact the investigator will:
-
Monitor the participant until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long as 
medically indicated. Completes follow-up SAE Form as required.
-
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study physician.
-
Complete the 3 Liver eCRF Modules as information becomes available. 
#A “significant” change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty.
D 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study intervention, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date PHL criteria was met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:


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


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
If there is no significant change no action is required.

If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section D 4.2.
D 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on study intervention visit.
The requirement to conduct follow-up, review and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study eg, chronic or progressing malignant disease, severe infection or liver 
disease or did the participant meet PHL criteria prior to starting study intervention and at their 
first on-study intervention visit, as described in Section D 6 of this Appendix ?
If No: follow the process described in Section D 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’s condition
compared with when PHL criteria were previously met.

If there is no significant change no action is required.

If there is a significant change follow the process described in Section D 4.2 for reporting 
PHL as an SAE.
D 8
Laboratory Tests
The laboratory tests listed in Table 13 may be performed for central laboratories. In this study, 
a local laboratory will be used for safety tests and the Hy’s Law Laboratory Kit is not 
applicable for this study. 


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Table 13
Hy’s Law Laboratory Kit for Central Laboratories 
Additional standard chemistry and coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HCV DNA a
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM and IgG anti-CMV
IgM and IgG anti-HSV
IgM and IgG anti-EBV
Autoimmune hepatitis
Antinuclear antibody
Anti-liver/kidney microsomal antibody
Anti-smooth muscle antibody
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive.
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = gamma glutamyl 
transferase; HAV = hepatitis A virus; HBc = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; 
HCV = hepatitis C virus; HEV = hepatitis E virus; HSV = herpes simplex virus; IgG = immuno-globulin G; 
IgM = immunoglobulin M; INR = international normalised ratio; LDH = lactate dehydrogenase; 
RNA = ribonucleic acid.
D 9
References
Aithal et al 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 
2011;89(6):806-15.
FDA Guidance 2009
Food and Drug Administration. Guidance for industry: Drug-induced liver injury: 
premarketing clinical evaluation. July 2009. Available from: URL: 
https://www.fda.gov/downloads/guidances/UCM174090.pdf. Accessed 08 October 2019.


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Appendix E
Guidelines for Evaluation of Objective Tumour Response 
Using RECIST 1.1 Criteria (Response Evaluation Criteria in 
Solid Tumours)
Introduction
This appendix details the implementation of RECIST 1.1 guidelines (Eisenhauer et al 2009). 
Investigator assessments will use the RECIST 1.1 guidelines described in this appendix.
Imaging modalities and acquisition specifications for RECIST 1.1
A summary of the imaging modalities that can be used for tumour assessment of TLs, NTLs 
and NLs is provided in Table 14.
Table 14
Summary of Imaging Modalities for Tumour Assessment
Target Lesions 
Non-target Lesions
New Lesions
CT
MRI
CT
MRI
Plain X-ray
Chest X-ray
CT
MRI
Plain X-ray
Chest X-ray
Bone scan (Scintigraphy)
18F-fluoro-deoxyglucose-PET/CT
CT = computed tomography; PET/CT = positron emission tomography/CT; MRI = magnetic resonance imaging.
Computed Tomography and Magnetic Resonance Imaging 
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for tumour 
assessments (ie, for measurement of TLs, assessment of NTLs, and identification of NLs). It is 
essential that the same correct imaging modality, image acquisition parameters (eg, anatomic 
coverage, imaging sequences, etc), imaging facility, tumour assessor (eg, radiologist), and 
method of tumour assessment (eg, RECIST 1.1) are used consistently for each participant 
throughout the study. The use of the same scanner for serial scans is recommended, if 
possible. It is important to follow the image collection/tumour assessment schedule as closely 
as possible (refer to the SoA, Section 1.3), and this on-study imaging schedule MUST be 
followed regardless of any delays in dosing or missed imaging visits. If an unscheduled 
assessment is performed (eg, to investigate clinical signs/symptoms of progression) and the 
participant has not progressed, every attempt should be made to perform the subsequent scan 
acquisitions at the next scheduled imaging visit.
Due to its inherent rapid acquisition (seconds), CT is the imaging modality of choice. Body 
scans should be performed with breath-hold scanning techniques, if possible. Therefore, CT of 
the chest is recommended over MRI due to significant motion artefacts (eg, heart, major blood 


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vessels, breathing) associated with MRI. MRI has excellent contrast and spatial and temporal 
resolutions; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. The modality used at follow-up should be the same as 
was used at baseline, and the lesions should be measured/assessed on the same pulse 
sequence. In general, local oncology diagnostic imaging parameters are applied for scan 
acquisition. It is beyond the scope of this appendix to prescribe specific MRI pulse sequence 
parameters for all scanners, body parts, and diseases.
The most critical CT and MRI image acquisition parameters for optimal tumour evaluation are 
anatomic coverage, contrast administration, slice thickness, and reconstruction interval.
a. Anatomic coverage: Optimal anatomic coverage for most solid tumours is the 
chest-abdomen (-pelvis). Coverage should encompass all areas of known predilection for 
metastases in the disease under evaluation and should additionally investigate areas that may 
be involved based on signs and symptoms of individual participants. Because a lesion later 
identified in a body part not scanned at baseline would be considered as a NL representing 
PD, careful consideration should be given to the extent of imaging coverage at baseline and at 
subsequent follow-up time points. This will enable better consistency not only of tumour 
measurements but also identification of new disease.
Required anatomical regions to be imaged for assessment of tumour burden (TLs and/or 
NTLs) at baseline and follow-up visits vary according to the study, and these time points are 
specified in the SoA. Examples include the following:

IV contrast-enhanced CT of chest-abdomen (including the entire liver and both adrenal 
glands) (-pelvis).

Non-contrast CT of chest and IV contrast-enhanced abdomen (including the entire liver 
and both adrenal glands) (-pelvis).

IV contrast-enhanced CT or MRI of the head and neck.

IV contrast-enhanced MRI (preferred) or CT of the brain.
For chest-abdomen (-pelvis) imaging, the following are scanning options in decreasing order 
of preference, with additional options (2 to 4) for consideration when participants have 
sensitivity to IV contrast or have compromised renal function:
1. Chest-abdomen (-pelvis) CT with IV CT contrast (most preferred).
2. Chest CT without IV-contrast + abdomen (-pelvis) MRI with IV MRI contrast, if CT IV 
contrast (iodine based) is medically contraindicated at any time during the study.


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3. Chest-abdomen (-pelvis) CT without IV contrast, if both IV CT and MRI contrast are 
medically contraindicated or the participant has compromised renal function.
4. Chest-abdomen (-pelvis) MRI with IV MRI contrast, if CT cannot be performed at any 
time during the study.
b. IV contrast administration: Optimal visualisation and measurement of metastases in solid 
tumours require consistent administration (dose and rate) of IV contrast as well as timing of 
scanning. An adequate volume of a suitable contrast agent should be given so that the tumour 
lesions are demonstrated to best effect and a consistent method is used on subsequent 
examinations for any given participant. Oral contrast is recommended to help visualise and 
differentiate structures in the abdomen and pelvis.
c. Slice thickness and reconstruction interval: It is recommended that CT or MRI scans be 
acquired/reconstructed as contiguous (no gap) slices with ≤5 mm thickness throughout the 
entire anatomic region of interest for optimal lesion measurements. Exceptionally, particular 
institutions may perform medically acceptable scans at slice thicknesses > 5 mm. If this 
occurs, the minimum size of measurable lesions at baseline should be twice the slice thickness 
of the baseline scans.
For CT scans, all window settings should be included in the assessment, particularly in the 
thorax where lung and soft tissue windows should be considered. When measuring lesions, the 
TL should be measured on the same window setting for repeated examinations throughout the 
study.
Chest X-ray
Chest X-ray assessment will not be used for the assessment of TLs. Chest X-ray can, however, 
be used to assess NTLs and to identify the presence of NLs. However, there is preference that 
a higher resolution modality, such as CT, be used to confirm the presence of NLs.
Plain X-ray 
Plain X-ray may be used as a method of assessment for bone NTLs and to identify the 
presence of new bone lesions.
Isotopic bone scan 
Bone lesions identified on an isotopic bone scan at baseline and confirmed by CT, MRI, or 
X-ray at baseline should be recorded as NTLs and followed by the same method per baseline 
assessment (CT, MRI, or X-ray).
Isotopic bone scans may be used as a method of assessment to identify the presence of new 
bone lesions at follow-up visits. NLs may be recorded in case positive hot-spots appear on a 
bone scan that were not present on a previous bone scan; however, a newly observed 


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equivocal hot-spot on a bone scan that cannot be verified with correlative imaging (CT, MRI, 
or X-ray) of the same anatomical region shall not be the only trigger for a PD assessment at 
that time point.
18F-Fluoro-deoxyglucose-PET/CT
18F-fluoro-deoxyglucose positron emission tomography (PET)/CT scans may be used as a 
method for identifying new extrahepatic lesions (but not intrahepatic lesions) for RECIST 1.1 
assessments according to the following algorithm: NLs will be recorded where there is 
positive 18F-Fluoro-deoxyglucose uptake1 not present on baseline or prior 
18F-fluoro-deoxyglucose-PET scan or in a location corresponding to a NL on a companion 
CT/MRI collected close in time to the 18F-fluoro-deoxyglucose-PET scan. The PET portion of 
the PET/CT introduces additional data that may bias an investigator if it is not routinely or 
serially performed. Therefore, if there is no baseline or prior 18F-fluoro-deoxyglucose-PET 
scan available for comparison, and no evidence of NLs on companion CT/MRI scans, then 
follow-up CT/MRI assessments should continue as per the regular imaging schedule to verify 
the unequivocal presence of NLs.
At present, low-dose or attenuation correction CT portions of a combined 
18F-fluoro-deoxyglucose-PET/CT scan are of limited use in anatomically based efficacy 
assessments, and it is therefore suggested that they should not substitute for dedicated 
diagnostic contrast-enhanced CT scans for tumour measurements by RECIST 1.1. In 
exceptional situations, if a site can document that the CT performed, as part of a PET/CT 
examination, is of identical diagnostic quality (with IV contrast) to a dedicated diagnostic CT 
scan, then the CT portion of the PET/CT can be used for RECIST 1.1 tumour assessments. 
Caution that this is not recommended because the PET portion of the CT introduces additional 
(PET) data that may bias an investigator if it is not routinely or serially performed.
Ultrasound 
Ultrasound examination will not be used for RECIST 1.1 assessment of tumours as it is not a 
reproducible acquisition method (operator dependent), is subjective in interpretation, and may 
not provide an accurate assessment of the true tumour size. Tumours identified by ultrasound 
will need to be assessed by correlative CT or MRI anatomical scan.
Other tumour assessments
Clinical examination 
Clinical examination of skin/surface lesions (by visual inspection or manual palpation) will 
not be used for RECIST 1.1 assessments. Tumours identified by clinical examination will 
                                               
1
A positive 18F-fluoro-deoxyglucose-PET scan lesion should be reported only when an uptake (eg, standard uptake 
value) greater than twice that of the surrounding tissue or liver is observed.


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need to be assessed by correlative CT or MRI anatomical scans.
Endoscopy and laparoscopy 
Endoscopy and laparoscopy will not be used for tumour assessments as they are not validated 
in the context of tumour assessment.
Histology and cytology
Histology or tumour markers on tumour biopsy samples will not be used as part of the tumour 
response assessment as per RECIST 1.1.
Results of cytological examination for the neoplastic origin of any effusion (eg, ascites, 
pericardial effusion, and pleural effusion) that appears or worsens during the study will not be 
used as part of the tumour response assessment as per RECIST 1.1.
Furthermore, an overall assessment of CR (all other disease disappears/reverts to normal) 
would be changed to PR if an effusion remains present radiologically.
Measurability of tumour lesions at baseline
RECIST 1.1 measurable lesions at baseline
A tumour lesion that can be accurately measured at baseline as ≥10 mm in the longest 
diameter for non-nodal lesions or ≥15 mm in short axis2 diameter for lymph node lesions with 
IV contrast-enhanced CT or MRI and that is suitable for accurate repeated measurements. 
Please see additional RECIST 1.1 guidance below on measurability of intrahepatic 
hepatocellular carcinoma lesions and porta hepatis lymph nodes.
Non-measurable lesions at baseline

Truly non-measurable lesions include the following:
-
Bone lesions (see exception below for soft tissue component).
-
Leptomeningeal disease.
-
Ascites, pleural effusion, or pericardial effusion.
-
Inflammatory breast disease.
-
Lymphangitic involvement of skin or lung.

All other lesions, including small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥10 mm to < 15 mm short axis diameter at baseline).3
                                               
2
The short axis is defined as the longest in-plane axis perpendicular to the long axis.
3
Lymph nodes with < 10 mm short axis diameter are considered non-pathological and should not be recorded or 
followed as NTLs.


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
Previously irradiated lesions.4 However, a previously irradiated lesion that has shown 
objective progression and meets the other requirements for a measureable lesion may be 
considered as a TL if it is the only lesion available.

Brain metastasis.
Special considerations regarding lesion measurability at baseline

Bone lesions:
-
Bone scan, PET scan, or plain X-ray are not considered adequate imaging 
techniques to measure bone lesions; however, these techniques can be used to 
confirm the presence or disappearance of bone lesions.
-
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, can be considered measurable if the soft tissue component meets the 
definition of measurability.
-
Blastic lesions are considered non-measurable.

Cystic lesions thought to represent cystic metastases can be considered measurable 
lesions if they meet the criteria for measurability from a radiological point of view, but if 
non-cystic lesions are present in the same participant, these should be selected over cystic 
lesions as TLs.
RECIST 1.1 TL selection at baseline
A maximum of 5 measurable lesions, with a maximum of 2 lesions per organ (including 
lymph nodes collectively considered as a single organ), representative of all lesions involved 
should be identified as TLs at baseline. TLs should be selected on the basis of their size 
(longest diameter for non-nodal lesions or short axis diameter for nodal lesions), but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement, in which circumstance the next largest lesion that can be measured reproducibly 
should be selected.
Lymph nodes, in any location (local/regional and distant), are collectively considered as a 
single organ, with a maximum of 2 lymph nodes as TLs. A bilateral organ (eg, adrenal glands), 
a segmented organ (eg, liver), or a multilobed organ (eg, lung) is each considered as a single 
organ.
The site and location of each TL should be documented, as well as the longest axis diameter 
for non-nodal lesions (or short axis diameter for lymph nodes). All measurements should be 
                                               
4
Localised post-radiation changes that affect lesion size may occur. Therefore, lesions that have been previously 
irradiated are typically considered non-measurable and as NTL at baseline and followed up as part of the NTL 
assessment.


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recorded in millimetres. At baseline, the sum of the diameters for all TLs will be calculated 
and reported as the baseline sum of diameters. At follow-up visits, the sum of diameters for all 
TLs will be calculated and reported as the follow-up sum of diameters.
Special cases for TL assessment at baseline

For TLs measurable in 2 or 3 dimensions, always report the longest diameter. For 
pathological lymph nodes measurable in 2 or 3 dimensions, always report the short axis 
diameter.

When lymph nodes are coalesced and no longer separable in a conglomerate mass, the 
vector of the longest diameter should be used to determine the perpendicular vector for 
the maximal short axis diameter of the coalesced mass. Non-nodal lesions that coalesce 
should similarly be assessed by the longest axis diameter.

Tumour lesions selected for newly acquired screening biopsy should not be selected as 
TLs, unless imaging occurred at least approximately 2 weeks after biopsy, allowing time 
for healing.

If the CT/MRI slice thickness used is > 5 mm, the minimum size of measurable disease at 
baseline should be twice the slice thickness of the baseline scan.

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as a NL.
RECIST 1.1 NTL selection at baseline
All other lesions, including non-measurable lesions and surplus measurable lesions, not 
recorded as TLs should be identified as NTLs at baseline. Measurements of these lesions are 
not required, but the presence or absence of each should be noted throughout follow-up.
Evaluation of tumour response and progression
RECIST 1.1 TL assessment at follow-up
This section defines the criteria used to determine objective tumour visit response for 
RECIST 1.1-defined TLs. The imaging modality, location, and scan date of each TL identified 
previously at baseline should be documented at follow-up visits with the long axis diameter 
for non-nodal lesions or short axis diameter for lymph node lesions. All measurements should 
be recorded in millimetres. The sum of the diameters for all TLs at each follow-up visit will be 
compared with the baseline sum of diameters (for response or SD) or to the smallest prior 
(nadir) sum of diameters (for progression) (Table 15).
Special cases for TL assessment at follow-up:

If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.


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
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.

If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for 1 of the lesions and 0 mm recorded for the other lesion(s). If the merged TLs 
are non-nodal lesions, record the long axis diameter of the merged lesion. If pathologic 
lymph nodes coalesce and are no longer individually separable within a conglomerate 
mass, the vector of the longest diameter of the coalesced mass should be used to 
determine the perpendicular vector for the maximal short axis diameter.

If a TL is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned. If an accurate measure can be given, this should be 
recorded, even if it is below 5 mm.

If a TL cannot be measured accurately due to it being too large, provide an estimate of the 
size of the lesion.

When a TL has had any intervention (eg, definitive radiotherapy, embolisation, surgery, 
transarterial chemoembolisation, etc) during the study, the size of the TL should still be 
provided where possible and the intervention recorded in the RECIST 1.1 eCRF for the 
current imaging visit and all subsequent visits. If a TL has been completely removed 
(surgery) or disappears, the longest diameter should be recorded as 0 mm.
Table 15
RECIST 1.1 Evaluation of Target Lesions
CR
Disappearance of all TLs since baseline. Any pathological lymph nodes selected as TLs 
must have a reduction in short axis diameter to <10 mm.
PR
At least a 30% decrease in the sum of the diameters of TL, taking as reference the 
baseline sum of diameters.
SD
Neither sufficient decrease in the sum of diameters to qualify for PR nor sufficient 
increase to qualify for PD.
PD
At least a 20% increase in the sum of diameters of TLs, taking as reference the smallest 
previous sum of diameters (nadir). This includes the baseline sum if that is the smallest 
on study. In addition to the relative increase of 20%, the sum must demonstrate an 
absolute increase of at least 5 mm from nadir.
NE
Only relevant if any of the TLs at follow-up were not assessed or NE (eg, missing 
anatomy) or had a lesion intervention at this visit. Note: If the sum of diameters meets the 
PD criteria, PD overrides NE as a TL response.
Not applicable
Only relevant if no TLs present at baseline.
CR = complete response; NE = not evaluable; PD = progression of disease; PR = partial response; SD = stable 
disease; TL = target lesion.
RECIST 1.1 NTL assessment at follow-up
All other lesions (or sites of disease) not recorded as TLs should be identified as NTLs at 


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baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator (Table 16).
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 
the overall tumour burden has increased sufficiently to merit unequivocal progression by 
NTLs. A modest “increase” in the size of 1 or more NTLs is usually not sufficient to qualify 
for unequivocal progression status. The designation of overall progression solely on the basis 
of change in non-target disease in the face of SD or PD of target disease will therefore be 
extremely rare.
Table 16
RECIST 1.1 Evaluation of Non-target Lesions
CR
Disappearance of all NTLs since baseline. All lymph nodes must be non-pathological 
in size (<10 mm short axis).
Non-CR/non-PD
Persistence of 1 or more NTLs.
PD
Unequivocal progression of existing NTLs. Unequivocal progression may be due to 
an important progression in 1 lesion only or in several lesions. In all cases, the 
progression MUST be clinically significant for the physician to consider changing (or 
stopping) therapy.
NE
Only relevant when 1 or some of the NTLs were not assessed and, in the 
investigator’s opinion, they are not able to provide an evaluable overall NTL 
assessment at this visit.
Note: For participants without TLs at baseline, this is relevant if any of the NTLs 
were not assessed at this visit and the progression criteria have not been met.
Not applicable
Only relevant if no NTLs present at baseline.
CR = complete response; NE = not evaluable; NTL = non-target lesion; PD = progression of disease; TL = target 
lesion.
RECIST 1.1 NL identification at follow-up
Details, including the imaging modality, the date of scan, and the location of any NLs will also 
be recorded in the eCRF. The presence of 1 or more NLs is assessed as progression. The 
finding of a NL should be unequivocal, ie, not attributable to differences in scanning 
technique, change in imaging modality, or findings thought to represent something other than 
tumour. If a NL is equivocal, for example because of its small size, the treatment and tumour 
assessments should be continued until the previously (pre-existing) NL has been assessed as 
unequivocal at a follow-up visit, and then the progression date should be declared using the 
date of the initial scan when the NL first appeared.
A lesion identified at a follow-up assessment in an anatomical location that was not scanned at 
baseline is considered a NL and will indicate PD.


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RECIST 1.1 evaluation of overall visit response at follow-up
Derivation of overall visit response as a result of the combined assessment of TLs, NTLs, and 
NLs uses the algorithm shown in Table 17.
Table 17
RECIST 1.1 Overall Visit Response
Target Lesions
Non-Target Lesions
New Lesions
Overall Visit Response
CR
CR
No
CR
CR
NA
No
CR
CR
Non-CR/Non-PD 
No
PR
CR
NE
No 
PR
PR
Non-PD or NE or NA
No
PR
SD 
Non-PD or NE or NA
No
SD
NE
Non-PD or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Non-CR/Non-PD for overall response if only NTL (no TLs) are present at baseline.
Note: An overall assessment of CR (all other disease disappears/reverts to normal) would be changed to PR if 
ascites remains present radiologically.
CR = complete response; NA = not applicable (only relevant if there were no TLs or NTLs at baseline), NE = not 
evaluable; NTL = non-target lesion; PD = progression of disease; PR = partial response; SD = stable disease; 
TL = target lesion.
The following overall visit responses are possible depending on the extent of tumour disease 
at baseline:

For participants with TLs (at baseline): CR, PR, SD, PD, or NE.

For participants with NTLs only (at baseline): CR, Non-CR/Non-PD, PD, or NE.

For participants with no disease at baseline: no evidence of disease (available as an option 
in the eCRF), PD, or NE.
Central imaging
Images, including unscheduled visit scans, will be collected on an ongoing basis and sent to an 
AstraZeneca-appointed iCRO for quality control, storage, and for ICR. Digital copies of all 
original scans should be stored at the investigator site as source documents. Electronic image 
transfer from the sites to the iCRO is strongly encouraged. An ICR of images will be 
performed at the discretion of AstraZeneca. Results of these independent reviews will not be 
communicated to investigators, and results of investigator tumour assessments will not be 
shared with the central reviewers.


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The management of participants will be based in part upon the results of the tumour 
assessments conducted by the investigator. Further details of the ICR will be documented in 
an Independent Review Charter.
References
Eisenhauer et al 2009
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009;45(2):228-47.


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Appendix F
Contraception Requirements
Contraception requirements for this study are as follows.
F 1
Female Participants
Women not of childbearing potential are defined as those who are surgically sterile (ie, 
bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or who are 
post-menopausal.
Women will be considered post-menopausal if they have been amenorrhoeic for 12 months 
without an alternative medical cause. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
contraception methods outlined for WOCBP if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status 
prior to study enrolment. 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 dosage of HRT. 
Following confirmation of their post-menopausal status, participants can resume use of HRT 
during the study without use of a contraceptive method.
WOCBP who are not totally sexually abstinent (ie, refraining from heterosexual intercourse 
during the entire period of risk associated with study interventions) and intend to be sexually 
active with a non-sterilised male partner must use at least 1 highly effective method of 
contraception (Table 18). They should have been stable on their chosen method of birth 
control for a minimum of 3 months before entering the study and continue to use it throughout 
the total duration of the drug treatment and the drug washout period (7 months after the last 
dose of study intervention). 
Non-sterilised male partners of a WOCBP must use a male condom plus spermicide (condom 
alone in countries where spermicides are not approved) throughout this period. Cessation of 
birth control after this point should be discussed with a responsible physician. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. 
Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the 
participant. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study. 
Female participants should refrain from breast-feeding throughout this period.
Women must not donate, or retrieve for their own use, ova from the time of screening and 
throughout the study treatment period, and for at least 7 months after the final study 


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intervention administration. Female patients may wish to consider preservation of ova prior to 
enrolment in the study.
F 2
Male Participants with a Female Partner of Childbearing 
Potential
Non-sterilised male participants (including males sterilised by a method other than bilateral 
orchidectomy, eg, vasectomy) who intend to be sexually active with a female partner of 
childbearing potential must be using an acceptable method of contraception such as male 
condom plus spermicide (condom alone in countries where spermicides are not approved) 
from the time of screening throughout the total duration of the study and the drug washout 
period (4 months after the last dose of study intervention) to prevent pregnancy in a partner. 
Not engaging in sexual activity for the duration of the study and drug washout period is an 
acceptable practice. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. 
Male participants should refrain from sperm donation or banking throughout this period.
Consideration of preservation of sperm should be made prior to entering the study.
Vasectomised males are considered fertile and should still use a male condom plus spermicide 
as indicated above during the clinical study.
Even if the female partner is pregnant, male participants should still use a condom plus 
spermicide (where approved), as indicated above during the clinical study, if there is a concern 
about damaging the developing foetus from drug in ejaculate.
Female partners (of childbearing potential) of male participants must also use a highly 
effective method of contraception throughout this period (Table 18).
F 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as those that result in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 18. 
Note that some contraception methods are not considered highly effective (eg, male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or without 
spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal 
contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding 
Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral 
contraceptive pills).


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Table 18
Highly Effective Methods of Contraception (< 1% Failure Rate)
Non-hormonal Methods
Hormonal Methods
•
Total heterosexual abstinence (evaluate in 
relation to the duration of the clinical study and 
the preferred and usual lifestyle choice of the 
participant)
•
Vasectomised sexual partner (provided that 
partner is the sole sexual partner of the trial 
participant and that the vasectomised partner 
has received medical assessment of the surgical 
success)
•
Bilateral tubal occlusion
•
Intrauterine device (provided coils are 
copper-banded)
•
Combined (oestrogen 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 hormone-releasing system (IUS)


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Appendix G
Concomitant Medications
G 1
Restricted, Prohibited, and Permitted Concomitant 
Medications/Therapies
Restricted, prohibited, and permitted concomitant medications/therapies are described in 
Table 19, Table 20, and Table 21, respectively. Refer also to the dose modification guidelines 
for management of study intervention-related toxicities in Section 6.6. Participants must be 
instructed not to take any medications, including over-the-counter products, without first 
consulting with the investigator.
Table 19
Restricted Medications/Therapies
Medication/class of drug/therapy
Usage (including limits for duration permitted 
and special situations in which it is allowed)
Tobacco products, e-cigarettes and vaping
Use of tobacco products, e-cigarettes and vaping is 
strongly discouraged but not prohibited. 
Any prior or current use of these products should be 
recorded in the eCRF.
Haematopoietic growth factors
May be used for prophylaxis or treatment based on 
the clinical judgment of the investigator.
Dietary supplements, medications not prescribed by 
the investigator, and alternative/complementary 
treatments
Concomitant use is discouraged, but not prohibited.
Prophylactic or supportive treatment of study-drug 
induced AEs
As per investigator’s discretion and institutional 
guidelines
Hormonal therapy
For non-cancer-related conditions (eg, HRT) only
Corticosteroids and/or bisphosphonates
For the treatment of bone metastases and for the 
treatment of specific adverse drug reactions (refer to 
TMG, Table 23)
See Table 20 for restrictions on corticosteroids when 
used as immunosuppressants
AEs = adverse events; eCRF = electronic Case Report Form; HRT = hormone replacement therapy; 
TMG = toxicity management guidelines.
With the exception of the study intervention, T-DXd, the medications in Table 20 are 
considered exclusionary during the study. The sponsor must be notified if a participant 
receives any of these during the study.


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Table 20
Prohibited Medications/Therapies
Prohibited medication/class of drug/therapy
Usage
Chloroquine or hydroxychloroquine
Concomitant treatment with chloroquine or 
hydroxychloroquine is not allowed during the study 
treatment. If treatment with chloroquine or 
hydroxychloroquine treatment is absolutely required 
for COVID-19, study intervention must be interrupted. 
If chloroquine or hydroxychloroquine is administered, 
a washout period of at least 14 days is required before 
restarting study intervention (see Appendix H for 
further details).
Any concurrent chemotherapy, anticancer study 
intervention or biological, radiotherapy (except 
palliative radiotherapy to areas other than chest, 
after consultation with the sponsor study physician) 
or hormonal therapy for cancer treatment. 
Must not be given concomitantly while the participant 
is on study intervention.
Concurrent use of hormones for noncancer-related 
conditions (eg, insulin for diabetes and hormone 
replacement therapy) is acceptable.
Immunosuppressive medications, including 
corticosteroids
T-DXd cannot be administered when the participant is 
taking immunosuppressive medications, including 
corticosteroids with the exception of:
•
short-term courses (< 2 weeks) of low to 
moderate dose (<10mg prednisolone per day or 
equivalent)
•
long-term, alternate-day treatment with 
short-acting preparations; maintenance 
physiological doses (replacement therapy)
•
administered topically (skin or eyes), by aerosol, 
or by intra-articular, bursal, or tendon injection. 
Treatment with corticosteroids to prevent or treat 
hypersensitivity reactions to radiographic contrast 
agents is allowed. 
A temporary period of steroid treatment will be 
allowed for different indications after discussion with 
the sponsor study physician (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc). 
Participants with bronchopulmonary disorders who 
require intermittent use of bronchodilators (such as 
albuterol) will not be excluded from this study. 
Use of immunosuppressive medications for the 
management of study intervention-related AEs or in 
participants with contrast allergies is acceptable. 
Immunosuppressive medications also include drugs 
like methotrexate, azathioprine, and tumour necrosis 
factor-alpha blockers. 


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Table 20
Prohibited Medications/Therapies
Prohibited medication/class of drug/therapy
Usage
Live vaccine
Participants, if assigned study intervention, should not 
receive live vaccine during the study and up to 30 days 
after the last dose of study intervention. Participants 
who have received live, attenuated vaccine within
30 days prior to the first dose of T-DXd will be 
excluded
Herbal and natural remedies that may interfere with 
interpretation of study results
Must not be given concomitantly unless agreed by the 
sponsor
AE = adverse event; COVID-19 = coronavirus 2019-nCoV; T-DXd = trastuzumab deruxtecan.
Table 21
Supportive Medications/Therapies
Supportive medication/class of drug/therapy
Usage
Prophylactic anti-emetic agents
Recommended that participants receive prophylactic 
anti-emetic agents prior to infusion of T-DXd and on 
subsequent days. 
Antiemetics such as 5-HT3 receptor antagonists or 
NK1 receptor antagonists and/or steroids (eg, 
dexamethasone) should be considered and 
administered in accordance with the prescribing 
information or institutional guidelines.
Concomitant medications or treatments 
(eg, acetaminophen or diphenhydramine) deemed 
necessary to provide adequate AE management, 
except for those medications identified as 
“prohibited,” as listed above 
To be administered as prescribed by the investigator 
except for those medications identified as 
“prohibited,” as listed in Table 20
Best supportive care (including antibiotics, 
nutritional support, correction of metabolic disorders, 
optimal symptom control, and pain management 
[including palliative radiotherapy, etc]) except for 
those medications identified as “prohibited,” as listed 
above
Should be used, when necessary, for all participants 
except for those medications identified as 
“prohibited,” as listed in Table 20
Corticosteroids and/or bisphosphonates for the 
treatment of bone metastases and for the treatment of 
specific adverse drug reactions (refer to TMG, 
Table 23)
Permitted
Inactivated viruses, such as those in the influenza 
vaccine
Permitted
Required for management of other medical 
conditions
As required except for those identified as 
“prohibited,” as listed in Table 20
5-HT3 = 5-hydroxytryptamine 3; AE = adverse event; NK1 = neurokinin 1; T-DXd = trastuzumab deruxtecan; 
TMG = toxicity management guidelines.


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Appendix H
Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (COVID-19)
Benefit Risk Considerations for COVID-19
The emergence of the coronavirus 2019-nCoV (SARS-CoV-2 / COVID-19) presents a 
potential safety risk for patients. Several risk mitigation factors have been implemented in this 
study. Notably, the eligibility criteria will exclude participants with COVID-19 infections (see 
CSP Section 5.2).
Moreover, with the outbreak of COVID-19, there is the potential for increased use of 
chloroquine and hydroxychloroquine to treat severely symptomatic patients, or even for 
prophylactic use. Chloroquine and hydroxychloroquine have shown in vitro to substantially 
affect the pH of the lysosome, a key intracellular compartment involved in the trafficking and 
payload release of T-DXd. As it is unknown whether chloroquine/hydroxychloroquine may 
affect the safety and efficacy of T-DXd, to be eligible for this clinical trial, use of chloroquine 
and hydroxychloroquine treatment must be completed at least 14 days prior to the first dose of 
T-DXd (see CSP Section 5.1). During study intervention, chloroquine and hydroxychloroquine 
are considered prohibited concomitant medications. However, in case treatment with 
chloroquine or hydroxychloroquine treatment is absolutely required for COVID-19, study 
intervention must be interrupted. After chloroquine or hydroxychloroquine is administered for 
COVID-19, then a washout period of at least 14 days is required before restarting study 
intervention.
Lastly, due to the potential overlapping impact of T-DXd and COVID-19 on the lung, the 
sponsor has also provided in this appendix, a dose modification and management plan for 
participants with confirmed or suspected COVID-19 who are being treated with T-DXd.
With these measures in place, it is considered the anticipated potential benefits for the 
participants enrolled in this study outweigh the potential risks.
Inclusion Criteria

Has adequate treatment washout period prior to initiation of study intervention, defined 
as:

Chloroquine/hydroxychloroquine: ≥14 days
Prior and Concomitant Medications
Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the 
study intervention. If treatment with chloroquine or hydroxychloroquine is absolutely required 
for COVID-19, study intervention must be interrupted. If chloroquine or hydroxychloroquine 
is administered, then a washout period of at least 14 days is required before restarting study 
intervention.


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COVID-19 Assessment(s)
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. 
Serum samples will be used for COVID-19 testing from each participant who provides 
consent. Samples will be collected prior to the study intervention infusion, shipped to a central 
laboratory, and stored there until the tests become available.
Serum and PK sample collection, preparation, handling, storage, and shipping instructions are 
provided in the Study Laboratory Manual.
Dose modification criteria 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF. Dose 
modifications will be based on the worst CTCAE grade. All interruptions or modifications 
must be recorded on the AE and drug administration eCRFs. Please use CTCAE v5.0 general 
grading criteria to evaluate COVID-19. All dose modifications (discontinuation, interruptions 
or reductions) must be recorded on the AE and drug administration eCRFs.
Dose modification criteria for suspected or confirmed COVID-19
If COVID-19 infection is suspected, delay T-DXd and rule out COVID-19 per local guidance.

If COVID-19 is ruled out, follow dose modification and management guidelines as 
outlined in the CSP.

If COVID-19 is confirmed or diagnosis is suspected after evaluation, follow dose 
modification as outlined below and manage COVID-19 per local guidance until recovery 
of COVID-19. Recovery is defined as no signs/symptoms of COVID-19, at least 
1 negative RT-PCR test result5, and nearly or completely resolved chest CT findings. 
Then follow dose modifications in Table 22.
Table 22
COVID-19 Dose Modification Criteria
COVID-19 Worst Toxicity 
NCI-CTCAE Version 5.0 Grade 
(unless otherwise specified)
Schedule Modification for T-DXd
Grade 1
Resume T-DXd at the same dose a
Grade 2
Resume T-DXd at the same dose if chest CT findings are completely 
resolved a
Reduce by 1 dose level if chest CT findings are nearly resolved 
                                               
5 If PCR testing is not available, the participant must not have any sign/symptoms for at least 2 weeks, in addition 
to meeting the requirement for chest CT imaging.


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COVID-19 Worst Toxicity 
NCI-CTCAE Version 5.0 Grade 
(unless otherwise specified)
Schedule Modification for T-DXd
Grade 3
Reduce by 1 dose level if chest CT findings are completely resolved
Discontinue T-DXd if chest CT findings are not completely resolved
Grade 4
Discontinue T-DXd
a
Closely monitor signs/symptoms after resuming study intervention, initially with a phone call every 3 days 
for the first week, and then with a weekly phone call thereafter, for a total of 6 weeks.
CT = computed tomography; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for 
Adverse Events; COVID-19 = coronavirus 2019-nCoV; T-DX-d = trastuzumab deruxtecan.

In addition to the recommendations outlined in Table 22, investigators may consider dose 
modifications of T-DXd according to the participant’s condition and after discussion with 
the study physician or designee.

If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline.


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Appendix I
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with COVID-19 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
agreement from the sponsor.
Refer to the Study Instruction Manual for Mitigation Due to Civil Crisis, Natural Disaster, or 
Public Health Crisis for step-by-step guidance.
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Section 1.3. Local and regional regulations and/or guidelines regarding reconsent 
of study participants should be checked and followed. Reconsent may be verbal if allowed by 
local and regional guidelines (note, in the case of verbal reconsent the ICF should be signed at 
the participant’s next contact with the study site). Visiting the study sites for the sole purpose 
of obtaining reconsent should be avoided. 
Rescreening of Participants to Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with study 
intervention. If this delay is outside the screening window specified in Section 1.3, the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to rescreen a participant in addition to that 
detailed in Section 5.4. The procedures detailed in Section 1.3.1 must be undertaken to 
confirm eligibility. Rescreened participants should retain the same participant number as for 
the initial screening.


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Appendix J
Guidance for Management of Participants with Drug-induced 
ILD/Pneumonitis


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Appendix K
Toxicity Management Guidelines
Table 23
Toxicity Management Guidelines for T-DXd
Worst toxicity CTCAE v 5.0 Grade 
(unless otherwise specified)
Management guidelines for T-DXd
Infusion-related reaction
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 decreased
 
 
 
















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Appendix L
Abbreviations
Abbreviation or 
Special Term
Explanation
ADA(s)
anti-drug antibody(ies)
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BOR
best objective response
CART
cell-free and concentrated ascites reinfusion therapy
CHF
congestive heart failure
CI
confidence interval
COPD
chronic obstructive pulmonary disorder
COVID-19
coronavirus 2019-nCoV, also referred to as severe acute respiratory syndrome 
coronavirus 2
CR
complete response
CrCL
calculated creatinine clearance
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DAR
drug-antibody ratio 
DCO
data cutoff
DCR
disease control rate
DILI
drug-induced liver injury
DLCO
diffusion capacity of the lungs for carbon monoxide
DNA
deoxyribonucleic acid 
DoR
duration of response
DXd
MAAA-1181a (deruxtecan)
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
ED
early discontinuation
EDC
electronic data capture


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Abbreviation or 
Special Term
Explanation
EOT
end of treatment
ER
exposure-response
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEV
forced expiratory volume
FFPE
formalin-fixed and paraffin-embedded
GC
gastric cancer
GCP
Good Clinical Practice
GEJ
gastroesophageal junction
GI
gastrointestinal
HBV
Hepatitis B virus
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HL
Hy’s Law
HR
hazard ratio
HRCT
high-resolution computed tomography
HRT
hormone replacement therapy
5-HT3
5-hydroxytryptamine 3
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICR
Independent Central Review
iCRO
imaging Contract Research Organisation
IEC
Independent Ethics Committee
IHC
immunochemistry
ILD
interstitial lung disease
INR
international normalised ratio
IRB
Institutional Review Board
IRR
infusion-related reactions
IRT
interactive response technology
ISH
in situ hybridisation
ITT
Intent to treat
IV
intravenous


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Abbreviation or 
Special Term
Explanation
LVEF
left ventricular ejection fraction
MAAA-1162a
drug-linker, the complex of MAAA-1181a and a maleimide tetrapeptide linker
MAAA-1181a
the drug released from T-DXd, a derivative of exatecan, a topoisomerase I inhibitor
MAAL-9001
the intermediate of T-DXd, a recombinant humanised anti-HER2 IgG1 monoclonal 
antibody with the same amino acid sequence as trastuzumab
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
not evaluable
NK1
neurokinin 1
NL
new lesion
NMPA
National Medical Products Administration
NTL
non-target lesion
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PD
progression of disease/progressive disease
PET
positron emission tomography
PFS
progression-free survival
PHL
Potential Hy’s Law
PK
pharmacokinetic
popPK
population PK
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QTc
corrected QT interval
QTcF
QT interval corrected by Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumours, Version 1.1
RES
response evaluable set
RNA
ribonucleic acid
SAE
serious adverse event 


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Abbreviation or 
Special Term
Explanation
SAP
Statistical Analysis Plan
SD
stable disease
SFU
safety follow-up
SoA
Schedule of Activities
SoC
standard of care
SpO2
peripheral capillary oxygen saturation
TBL
total bilirubin
T-DM1
trastuzumab emtansine
TEAE
treatment emergent adverse event
TMG
toxicity management guideline
T-DXd
trastuzumab deruxtecan
TL
target lesion
ULN
upper limit of normal
WOCBP
women of childbearing potential
w/v
weight per volume


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11
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Statistical Analysis Plan
Study Code
D9676C00002
Edition Number
4.0
Date
12 July 2023
A Single-arm Study of Trastuzumab Deruxtecan (T-DXd) 
Monotherapy for Patients with HER2-expressing Locally 
Advanced or Metastatic Gastric or Gastroesophageal Junction 
(GEJ) Adenocarcinoma Who Have Received 2 or More Prior 
Regimens (DESTINY-Gastric06)


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS...................................................................................................... 2
LIST OF ABBREVIATIONS ............................................................................................... 5
AMENDMENT HISTORY................................................................................................... 8
1
STUDY DETAILS ........................................................................................... 10
1.1
Study objectives................................................................................................ 10
1.1.1
Primary objective.............................................................................................. 10
1.1.2
Secondary objectives ........................................................................................ 10
1.1.3
Safety objective ................................................................................................ 13
1.2
Study design ..................................................................................................... 13
1.3
Number of subjects........................................................................................... 14
2
ANALYSIS SETS ............................................................................................ 15
2.1
Definition of Analysis Sets ............................................................................... 15
2.1.1
Enrolled patients............................................................................................... 17
2.1.2
Intention to treat analysis set............................................................................. 17
2.1.3
HER2-Positive Full analysis set ........................................................................ 17
2.1.4
HER2-Expressing Full analysis set ................................................................... 17
2.1.5
HER2-Positive Response evaluable set ............................................................. 17
2.1.6
HER2-Expressing Response evaluable set......................................................... 17
2.1.7
Safety analysis set............................................................................................. 17
2.1.8
Pharmacokinetic analysis set............................................................................. 17
2.1.9
T-DXd ADA evaluable set................................................................................ 18
2.2
Protocol deviations ........................................................................................... 18
3
PRIMARY AND SECONDARY VARIABLES ............................................... 20
3.1
Derivation of RECIST Visit Responses............................................................. 20
3.1.1
Target lesions – site investigator data................................................................ 21
3.1.2
Non-target lesions and new lesions – site investigator data................................ 26
3.1.3
Overall visit response – site investigator data.................................................... 27
3.1.4
Independent review........................................................................................... 28
3.2
Efficacy Variables ............................................................................................ 29
3.2.1
Objective response rate (ORR).......................................................................... 29
3.2.1.1
Best objective response (BoR) .......................................................................... 30
3.2.2
Progression free survival (PFS)......................................................................... 30
3.2.3
Disease control rate (DCR) ............................................................................... 32
3.2.4
Duration of response (DoR).............................................................................. 32
3.2.5
Overall survival (OS)........................................................................................ 33
3.2.6
Change in TL tumour size................................................................................. 34
3.3
Safety Variables................................................................................................ 34


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3.3.1
Exposure and dose interruptions ....................................................................... 34
3.3.2
Dose intensity................................................................................................... 37
3.3.3
Adverse events.................................................................................................. 37
3.3.4
Physical examinations....................................................................................... 38
3.3.5
Vital signs......................................................................................................... 39
3.3.6
Electrocardiograms........................................................................................... 39
3.3.7
Elevated troponin levels.................................................................................... 40
3.3.8
Laboratory measurements ................................................................................. 40
3.3.9
Other safety assessments................................................................................... 41
3.3.9.1
Echocardiograms/multigated acquisition scans.................................................. 41
3.3.9.2
Pulmonary assessments..................................................................................... 41
3.3.9.3
ECOG performance status................................................................................. 42
3.3.9.4
Ophthalmologic assessments............................................................................. 42
3.3.9.5
ILD/Pneumonitis investigation.......................................................................... 42
3.3.9.6
Eligible HBV infection ..................................................................................... 43
3.3.10
General considerations for safety assessments................................................... 43
3.3.10.1
Time windows .................................................................................................. 43
3.3.10.2
Missing data ..................................................................................................... 44
3.4
Pharmacokinetic Variables................................................................................ 46
3.5
Immunogenicity Variables................................................................................ 46
3.6
Biomarker Variables......................................................................................... 47
3.7
Other variables.................................................................................................. 48
3.7.1
Prior and concomitant medications and procedures........................................... 48
4
ANALYSIS METHODS................................................................................... 49
4.1
General principles............................................................................................. 49
4.2
Analysis methods.............................................................................................. 50
4.2.1
Multiplicity....................................................................................................... 50
4.2.2
Objective response rate..................................................................................... 51
4.2.2.1
Best objective response..................................................................................... 52
4.2.3
Progression free survival................................................................................... 53
4.2.4
Disease control rate........................................................................................... 53
4.2.5
Duration of response......................................................................................... 54
4.2.6
Tumour size change.......................................................................................... 54
4.2.7
Overall survival ................................................................................................ 54
4.2.8
PK .................................................................................................................... 55
4.2.9
Immunogenicity................................................................................................ 56
4.2.10
Safety ............................................................................................................... 56
4.2.10.1
Adverse events.................................................................................................. 56
4.2.10.2
Exposure........................................................................................................... 60
4.2.10.3
Vital signs......................................................................................................... 60
4.2.10.4
ECGs................................................................................................................ 61
4.2.10.5
Laboratory measurements ................................................................................. 61
4.2.10.6
WHO/ECOG performance status ...................................................................... 63


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4.2.10.7
Pulmonary assessments..................................................................................... 63
4.2.10.8
Eligible HBV infection ..................................................................................... 63
4.2.10.9
Other safety assessments................................................................................... 63
4.2.11
Demographics and baseline characteristics........................................................ 63
4.2.12
Concomitant and other treatments..................................................................... 64
4.2.13
COVID-19........................................................................................................ 65
4.2.14
Data Cut-offs .................................................................................................... 66
5
INTERIM ANALYSES.................................................................................... 66
6
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 66
7
REFERENCES................................................................................................. 66
8
APPENDIX ...................................................................................................... 67
LIST OF TABLES
Table 1 Primary study objective and corresponding endpoint/variable................................. 10
Table 2 Secondary study objectives and corresponding endpoints/variables ........................ 10
Table 3 Safety study objective and corresponding endpoints/variables ................................ 13
Table 4 Summary of outcome variables and analysis sets.................................................... 15
Table 5 TL Visit Responses (RECIST 1.1).......................................................................... 22
Table 6 NTL Visit Responses.............................................................................................. 26
Table 7 Overall visit responses............................................................................................ 27
LIST OF FIGURES
Figure 1 Overview of study design...................................................................................... 14


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LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
ADA
Anti-drug antibodies
AE
Adverse event
AESI
Adverse event of special interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
BLQ
Below the limit of quantification
BoR
Best objective response
BP
Blood pressure
CHF
Congestive heart failure
CI
Confidence interval
COVID-19
Coronavirus 2019-nCoV, also referred to as severe acute respiratory syndrome
coronavirus 2
CR
Complete response
CrCl
Creatinine clearance
CRO
Contract research organisation
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DBL
Database lock
DCO
Data cut-off
DCR
Disease control rate
DLCO
Diffusing capacity of the lungs for carbon monoxide
DoR
Duration of response
d.p.
Decimal place
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form


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Abbreviation or special 
term
Explanation
EOT
End of treatment
FAS
Full analysis set
FEV1
Forced expiratory volume in 1 second
FEV6
Forced expiratory volume in 6 seconds
FiO2
Fraction of inspired oxygen
FVC
Forced vital capacity
GEJ
Gastroesophageal junction
HER2
Human epidermal growth factor receptor 2
HRCT
High resolution CT scan
ICF
Informed consent form
ICR
Independent central review
IHC
Immunohistochemistry 
ILD
Interstitial lung disease
ISH
In situ hybridisation
ITT
Intention to treat
IV
Intravenous
LD
Longest diameter
LLOQ
Lower limit of quantification
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MRI
Magnetic resonance imaging
MUGA
Multigated acquisition scan
NA
Not applicable
nAb
Neutralising ADAs
NC
Not calculable
NCI
National Cancer Institute
NE
Not evaluable
NED
No evidence of disease
NQ
Not quantifiable
NTL
Non-target lesion
NYHA
New York Heart Association
OAE
Other significant adverse events
ORR
Objective response rate


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Abbreviation or special 
term
Explanation
OS
Overall survival
PD
Progressive disease
PD plan
Protocol Deviation plan
PEF
Peak expiratory flow
PFS
Progression-free survival
PI
Principal investigator
PK
Pharmacokinetics
PR
Partial response
PS
Performance status
PT
Preferred term
QTc
Corrected QT interval
QTcF
QT interval corrected by Fridericia’s formula
RDI
Relative dose intensity
RECIST 1.1
Response Evaluation Criteria in Solid Tumours, Version 1.1
RES
Response evaluable set
SAE
Serious adverse events
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
Stable disease
SoA
Schedule of Activities
SOC
System organ class
Sp02
Pulse oximetry
T-DXd
Trastuzumab deruxtecan
TEAE
Treatment emergent adverse events
TL
Target lesion
TLC
Total lung capacity
ULN
Upper limit of normal
WHO-DD
World Health Organisation Drug Dictionary




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1
STUDY DETAILS
This statistical analysis plan (SAP) contains a more detailed description of the analyses in the 
clinical study protocol (CSP). This SAP is based on version 2.0 of the CSP.
1.1
Study objectives
1.1.1
Primary objective
The primary objective for this study and the corresponding endpoint/variable are shown in 
Table 1.
Table 1 Primary study objective and corresponding endpoint/variable
Objective
Endpoints/variables
To evaluate the efficacy of T-DXd by 
assessment of confirmed ORR by ICR in 
participants with HER2-positive advanced 
gastric or GEJ adenocarcinoma who have 
received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
Confirmed ORR, defined as the proportion of 
patients who have a confirmed CR or confirmed 
PR, as determined by ICR per RECIST 1.1.
GEJ Gastroesophageal Junction; HER2 Human epidermal growth factor receptor 2; ICR Independent central review; 
ORR Objective response rate; RECIST 1.1 Response Evaluation Criteria in Solid Tumours, Version 1.1; T-DXd Trastuzumab 
Deruxtecan.
1.1.2
Secondary objectives
The secondary objectives for this study and the corresponding endpoints/variables are shown 
in Table 2.
Table 2 Secondary study objectives and corresponding endpoints/variables
Objective
Endpoints/variables
To evaluate the efficacy of T-DXd by assessment 
of confirmed ORR by investigator in participants 
with HER2-positive advanced gastric or GEJ 
adenocarcinoma who have received at least 2 
prior regimens including a fluoropyrimidine agent 
and a platinum agent
Confirmed ORR, defined as the proportion of 
patients who have a confirmed CR or 
confirmed PR, as determined by the 
investigator per RECIST 1.1.
To evaluate the efficacy of T-DXd by assessment 
of PFS in participants with HER2-positive 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
PFS, defined as the time from date of 
enrolment until progression per RECIST 1.1 or 
death due to any cause, as assessed by ICR and 
by the investigator.


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Objective
Endpoints/variables
To evaluate the efficacy of T-DXd by assessment 
of DCR in participants with HER2-positive 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
DCR, defined as the percentage of patients 
who have a confirmed CR/PR or SD (without 
subsequent anticancer therapy), as assessed by 
ICR and by the investigator.
To evaluate the efficacy of T-DXd by assessment 
of DoR in participants with HER2-positive 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
DoR, defined as the time from the date of first 
documented response until date of documented 
progression or death in the absence of 
progression, as assessed by ICR and by the 
investigator.
To evaluate the efficacy of T-DXd by assessment 
of OS in participants with HER2-positive 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
OS, defined as the time from date of enrolment 
until the date of death due to any cause.
To evaluate efficacy of T-DXd by assessment of 
tumour size change in participants with 
HER2-positive advanced gastric or GEJ 
adenocarcinoma who have received at least 2 
prior regimens including a fluoropyrimidine agent 
and a platinum agent 
Best percentage change from baseline in 
tumour size, based on the sum of diameters of 
target lesions, as assessed by ICR and by the 
investigator.
To evaluate the efficacy of T-DXd by assessment 
of confirmed ORR by ICR in participants with 
HER2-expressing advanced gastric or GEJ 
adenocarcinoma who have received at least 2 
prior regimens including a fluoropyrimidine agent 
and a platinum agent
Confirmed ORR, defined as the proportion of 
patients who have a confirmed CR or 
confirmed PR, as determined by ICR per 
RECIST 1.1.
To evaluate the efficacy of T-DXd by assessment 
of confirmed ORR by investigator in participants 
with HER2-expressing advanced gastric or GEJ 
adenocarcinoma who have received at least 2 
prior regimens including a fluoropyrimidine agent 
and a platinum agent
Confirmed ORR, defined as the proportion of 
patients who have a confirmed CR or 
confirmed PR, as determined by the 
investigator per RECIST 1.1.


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Objective
Endpoints/variables
To evaluate the efficacy of T-DXd by assessment 
of PFS in participants with HER2-expressing 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
PFS is defined as time from date of enrolment 
until progression per RECIST 1.1 or death due 
to any cause, as assessed by ICR and the 
investigator.
To evaluate the efficacy of T DXd by assessment 
of DCR in participants with HER2-expressing 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
DCR is defined as the percentage of 
participants who have a confirmed CR/PR or 
SD (without subsequent anticancer therapy) as 
assessed by ICR and the investigator.
To evaluate the efficacy of T DXd by assessment 
of DoR in participants with HER2-expressing 
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
DoR is defined as the time from the date of 
first documented response until date of 
documented progression or death in the 
absence of disease progression, as assessed by 
ICR and the investigator.
To evaluate the efficacy of T DXd by assessment 
of OS in participants with HER2-expressing  
advanced gastric or GEJ adenocarcinoma who 
have received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
OS is defined as time from date of enrolment 
until the date of death due to any cause.
To evaluate efficacy of T-DXd by assessment of 
tumour size change in participants with 
HER2-expressing advanced gastric or GEJ 
adenocarcinoma who have received at least 2 
prior regimens including a fluoropyrimidine agent 
and a platinum agent
Best percentage change from baseline in 
tumour size, based on the sum of diameters of 
target lesions, as assessed by ICR and by the 
investigator.
To assess the PK of T-DXd
Serum concentrations of T-DXd, total 
anti-HER2 antibody, and MAAA-1181a, and 
evaluation of appropriate PK parameters.
To investigate the immunogenicity of T-DXd
Presence of ADAs for T-DXd and Neutralising 
ADAs.
ADAs Anti-drug antibodies; DCR Disease control rate; DoR Duration of Response; GEJ Gastroesophageal Junction; 
HER2 Human epidermal growth factor receptor 2; ICR Independent central review; ORR Objective response rate; OS Overall 
survival; PFS Progression-free survival; PK Pharmacokinetics; RECIST 1.1 Response Evaluation Criteria in Solid Tumours, 
Version 1.1; T-DXd Trastuzumab Deruxtecan.


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1.1.3
Safety objective
The safety objective for this study and the corresponding endpoints/variables are shown in 
Table 3.
Table 3 Safety study objective and corresponding endpoints/variables
Objective
Endpoints/variables
To assess the safety and tolerability of T-DXd in 
participants with HER2-expressing advanced 
gastric or GEJ adenocarcinoma who have 
received at least 2 prior regimens including a 
fluoropyrimidine agent and a platinum agent
Assessed by the occurrence of AEs, clinical 
laboratory results, vital signs, physical 
examination findings, elevated troponin results, 
ECG and ECHO/MUGA results, ophthalmologic 
results and ADAs.
ADAs Anti-drug antibodies; AEs Adverse events; ECG Electrocardiogram; ECHO Echocardiogram; GEJ Gastroesophageal 
Junction; HER2 Human epidermal growth factor receptor 2; MUGA Multigated acquisition scan; T-DXd Trastuzumab 
Deruxtecan.
1.2
Study design
This is a Phase II, open-label, single-arm, multicentre study in China assessing the efficacy 
and safety of trastuzumab deruxtecan (T-DXd) in participants with human epidermal growth 
factor receptor 2-positive (HER2-positive), in addition to participants with HER2-expressing, 
advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received at 
least 2 prior regimens including a fluoropyrimidine agent and a platinum agent.
After signing the informed consent form (ICF), patients will begin screening procedures. 
Following completion of all screening procedures and documentation of all baseline 
assessments, eligible patients are enrolled in the study. Enrolled patients will be assigned to 
treatment with T-DXd monotherapy at a dose of 6.4 mg/kg administered intravenously (IV) 
every 3 weeks until Response Evaluation Criteria in Solid Tumours, Version 1.1 (RECIST 
1.1)-defined progressive disease (PD), unacceptable toxicity, withdrawal of consent, or any 
other criterion for discontinuation of study intervention is met.
An overview of the study design is shown in Figure 1.




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2
ANALYSIS SETS
2.1
Definition of Analysis Sets
A summary of the analysis sets used for each outcome variable is provided in Table 4.
Table 4 Summary of outcome variables and analysis sets
Outcome variable
Analysis set
Primary Efficacy – HER2-positive
  Confirmed ORR by ICR
Primary analysis: HER2-positive Full analysis set
Supplementary analysis: HER2-positive Response 
evaluable set
Secondary Efficacy – HER2-positive
  Confirmed ORR by investigator
  PFS by ICR
  DCR by ICR
  DoR* by ICR
  Tumour size change by ICR
  PFS by investigator
  DCR by investigator
  DoR* by investigator
  Tumour size change by investigator
  OS
Primary analysis: HER2-positive Full analysis set


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Outcome variable
Analysis set
Secondary Efficacy – HER2-expressing
  Confirmed ORR by ICR  
  Confirmed ORR by investigator
  PFS by ICR
  DCR by ICR
  DoR* by ICR
  Tumour size change by ICR
  PFS by investigator
  DCR by investigator
  DoR* by investigator
  Tumour size change by investigator
  OS
Primary analysis: HER2-expressing Full analysis 
set
Supplementary analysis for confirmed ORR by 
ICR: HER2-expressing Response evaluable 
analysis set
Study population/Demography
  Demography characteristics
Primary analysis: HER2-positive Full analysis set
Supplementary analysis: Intention to treat analysis 
set
  Baseline and disease characteristics
  Important deviations
  Medical/surgical history
  Previous anti-cancer therapy
  Concomitant medications/procedures
  Subsequent anti-cancer therapy
Safety data
  Exposure
Safety analysis set
  AEs
  Laboratory measurements
  Vital signs
  ECGs
PK data
PK analysis set
ADA data
T-DXd ADA evaluable set
*Patients who are evaluable for the analysis of DoR analysis are those who responded in the associated ORR analysis.
ADA Anti-drug antibody; AE Adverse event; DCR Disease control rate; DoR Duration of Response; 
ECG Electrocardiogram; HER2 Human epidermal growth factor receptor 2; ORR Objective response rate; OS Overall 
survival; PFS Progression-free survival; PK Pharmacokinetics; T-DXd Trastuzumab Deruxtecan.


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2.1.1
Enrolled patients
Enrolled patients will be defined as all subjects who sign the ICF, have an enrolment code and 
have a treatment assignment number.
2.1.2
Intention to treat analysis set
The intention to treat (ITT) analysis set will include all patients who signed the ICF and are 
enrolled in the study.
2.1.3
HER2-Positive Full analysis set 
The HER2-positive full analysis set (FAS) will include all enrolled patients with HER2 status 
confirmed as IHC 3+ or IHC 2+/ISH positive by central laboratory.
2.1.4
HER2-Expressing Full analysis set 
The HER2-expressing FAS will include all enrolled patients with HER2 status confirmed as 
IHC 3+ or IHC 2+ by central laboratory.
2.1.5
HER2-Positive Response evaluable set
The HER2-positive response evaluable set (RES) will include all enrolled patients with HER2 
status confirmed as IHC 3+ or IHC 2+/ISH positive by central laboratory who received at 
least 1 dose of study treatment and had measurable disease at baseline as assessed by ICR.
2.1.6
HER2-Expressing Response evaluable set
The HER-2 expressing RES will include all enrolled patients with HER2 status confirmed as 
IHC 3+ or IHC 2+ by central laboratory who received at least 1 dose of study treatment and 
had measurable disease at baseline as assessed by ICR.
2.1.7
Safety analysis set
The safety analysis set (SAF) will include all enrolled patients who received at least 1 dose of 
study treatment. Safety data will not be formally analysed but summarised using the SAF.
2.1.8
Pharmacokinetic analysis set
The pharmacokinetic (PK) analysis set will include all enrolled patients who received at least 
1 dose of study treatment and had at least 1 post-dose measurable serum concentration of 
T-DXd.


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2.1.9
T-DXd ADA evaluable set
The anti-drug antibodies (ADA) evaluable set will include all enrolled patients who received 
at least 1 dose of study treatment with a non-missing baseline ADA result and at least 1 non-
missing post-baseline ADA result.
2.2
Protocol deviations
The following general categories will be considered important protocol deviations and will be 
programmatically identified from the electronic Case Report Form (eCRF) data. These will be 
listed and discussed in the clinical study report (CSR) as appropriate. Additional details can be 
found in the Protocol Deviation plan (PD plan) V3.0:

Patients who deviate from key inclusion entry criteria per the CSP (Deviation 1):
o
Lack of provision of informed consent prior to study related procedures.
o
Inclusion criteria 2: Pathologically documented locally advanced unresectable 
or metastatic gastric or GEJ adenocarcinoma.
o
Inclusion criteria 3: Disease progression on or after ≥ 2 prior regimens for 
advanced/metastatic disease that included a fluoropyrimidine and a platinum.
o
Inclusion criteria 4: Eastern Cooperative Oncology Group (ECOG) 
performance status 0 or 1.
o
Inclusion criteria 5: Documentation of HER2 IHC 3+ or IHC 2+, regardless of 
ISH status, during screening.
o
Inclusion criteria 6: Able to provide a tumour sample for confirmation of 
HER2 status by a central laboratory.
o
Inclusion criteria 7: At least 1 lesion that can be accurately measured at 
baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must 
have short axis ≥ 15 mm) with computed tomography (CT) or magnetic 
resonance imaging (MRI) and is suitable for accurate repeated measurements, 
as per RECIST 1.1.
o
Inclusion criteria 11: Adequate treatment washout period prior to initiation of 
study intervention.


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
Patients who deviate from key exclusion entry criteria per the CSP (Deviation 2):
o
Exclusion criteria 4: Unresolved toxicities caused by previous anticancer 
therapy, defined as toxicities (excluding alopecia) not yet resolved to Grade ≤ 1 
or baseline.
o
Exclusion criteria 10: Participants with a medical history of myocardial 
infarction (MI) within 6 months before enrolment, symptomatic congestive 
heart failure (CHF) (New York Heart Association [NYHA] Class II to IV), 
unstable angina pectoris, or a recent (< 6 months) cardiovascular event 
including stroke.
o
Exclusion criteria 12: History of interstitial lung disease (ILD)/pneumonitis, or 
where suspected ILD/pneumonitis cannot be ruled out by imaging at screening, 
or other lung-specific clinically significant illnesses, or prior pneumonectomy.
o
Exclusion criteria 18: Previous treatment in the present study.
o
Exclusion criteria 19: Concurrent enrolment in another clinical study, unless it 
is an observational (non-interventional) study or during follow-up period of an 
interventional study.

Discontinuation criteria for study treatment met but patient not withdrawn from study 
treatment (Deviation 3).
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
Received prohibited concomitant medications (including other anti-cancer agents) 
(Deviation 6). Please refer to the CSP section 6.5.1 for those medications that are 
detailed as being ‘excluded’ from permitted use during the study. This will be used as 
a guiding principle for the physician review of all medications prior to database lock 
(DBL).

Study procedure deviations (Deviation 7)
o
Baseline RECIST scan > 28 days before enrolment.
o
No baseline RECIST 1.1 assessment on or before date of enrolment.
The important protocol deviations will be listed and summarised. The third category of 
Deviation 5 would lead to exclusion from the safety analysis set and the RES. None of the 
other deviations will lead to patients being excluded from the analysis sets described in 
Section 2.1 (with the exception of the PK analysis set, if the deviation is considered to impact 
upon PK). A per-protocol analysis excluding patients with specific important protocol 
deviations is not planned. However, a ‘deviation bias’ sensitivity analysis may be performed 
on the objective response rate endpoint, excluding patients with deviations that may affect the 
efficacy evaluation if the deviations happen in > 10% of patients.
Any other deviations from monitoring notes or reports will be reported in an appendix to the 
CSR.
3
PRIMARY AND SECONDARY VARIABLES
3.1
Derivation of RECIST Visit Responses
For all patients, the RECIST tumour response data will be used to determine each patient’s 
visit response according to RECIST version 1.1. It will also be used to determine if and when 
a patient has progressed in accordance with RECIST and their best objective response to study 
treatment. 
Baseline radiological tumour assessments are to be performed no more than 28 days before 
enrolment and ideally as close as possible to the start of study treatment. Tumour assessments 
are then performed every 6 weeks (± 1 week) following the start of study treatment until 
disease progression. If a patient discontinues study treatment prior to progression, then tumour 
assessments continue every 6 weeks (± 1 week) for the first 48 weeks after the date of first 
dose, then every 12 weeks (± 1 week) thereafter until disease progression.
If an unscheduled assessment is performed, and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule 


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is to be followed in order to minimise any unintentional bias caused by some patients being 
assessed at a different frequency than other patients.
From the investigator’s review of the imaging scans, the RECIST tumour response data will 
be used to determine each patient’s visit response according to RECIST version 1.1. At each 
visit, patients will be programmatically assigned a RECIST 1.1 visit response of complete 
response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), using 
the information from target lesions (TLs), non-target lesions (NTLs) and new lesions and 
depending on the status of their disease compared with baseline and previous assessments. If a 
patient has had a tumour assessment that cannot be evaluated then the patient will be assigned 
a visit response of not evaluable (NE), unless there is evidence of progression in which case 
the response will be assigned as PD.
Please refer to Sections 3.1.1, 3.1.2 and 3.1.3 for the definitions of CR, PR, SD and PD. 
RECIST outcomes (i.e. ORR, progression-free survival [PFS] etc.) will be calculated 
programmatically for the site investigator data (see Section 3.2) from the overall visit 
responses.
3.1.1
Target lesions – site investigator data
Measurable disease is defined as having at least one measurable lesion, which is ≥ 10 mm in 
the longest diameter (LD), (except lymph nodes which must have short axis ≥ 15 mm) with 
CT or MRI and which is suitable for accurate repeated measurements. A patient can have a 
maximum of five measurable lesions recorded at baseline with a maximum of two lesions per 
organ (representative of all lesions involved and suitable for accurate repeated measurement) 
and these are referred to as TLs. A previously irradiated lesion that has shown objective 
progression and meets the other requirements for a measurable lesion may be considered as a 
TL if it is the only lesion available. If more than one baseline scan is recorded then 
measurements from the one that is closest and prior to the first dose of study treatment will be 
used to define the baseline sum of TLs. 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.
All other lesions (or sites of disease) not recorded as TL should be identified as NTLs at 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits.
Note: For patients who do not have measurable disease at entry (i.e. no TLs) but have non-
measurable disease, evaluation of overall visit responses will be based on the overall NTL 
assessment and the absence/presence of new lesions (see Section 3.1.3 for further details). If a 


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patient does not have measurable disease at baseline then the TL visit response will be not 
applicable (NA). 
Table 5 TL Visit Responses (RECIST 1.1)
Visit Responses
Description
Complete response (CR)
Disappearance of all TLs. Any pathological lymph nodes selected 
as TLs must have a reduction in short axis to <10mm.
Partial response (PR)
At least a 30% decrease in the sum of diameters of TLs, taking as 
reference the baseline sum of diameters as long as criteria for PD 
are not met.
Progressive disease (PD)
A ≥ 20% increase in the sum of diameters of TLs and an absolute 
increase of ≥ 5mm, taking as reference the smallest sum of 
diameters since treatment started including the baseline sum of 
diameters.
Stable disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.
Not evaluable (NE)
Only relevant in certain situations (i.e. if any of the TLs were not 
assessed or not evaluable or had a lesion intervention at this visit; 
and scaling up could not be performed for lesions with 
interventions). Note: If the sum of diameters meets the progressive 
disease criteria, progressive disease overrides not evaluable as a 
TL response.
Not applicable (NA)
No TLs are recorded at baseline.
NTL Non-target lesion; TL Target lesion.
Rounding of TL data
For calculation of PD and PR for TLs, percentage changes from baseline and previous 
minimum should be rounded to one decimal place (d.p.) before assigning a TL response. For 
example, 19.95% should be rounded to 20.0% but 19.94% should be rounded to 19.9%.
Missing TL data
For a visit to be evaluable then all TL measurements should be recorded. However, a visit 
response of PD should still be assigned if any of the following occurred:

A new lesion is recorded

A NTL visit response of PD is recorded

The sum of TLs is sufficiently increased to result in a 20% increase, and an absolute 
increase of ≥ 5mm, from nadir even assuming the non-recorded TLs have disappeared


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Note: the nadir can only be taken from assessments where all the TLs had a LD 
recorded.
If there is at least one TL measurement missing and a visit response of PD cannot be assigned, 
the visit response is NE.
If all TL measurements are missing then the TL visit response is NE. Overall visit response 
will also be NE, unless there is a progression of non-TLs or new lesions, in which case the 
response will be PD.
Lymph nodes
For lymph nodes, if the size reduces to < 10mm then these are considered non-pathological. 
However, a size will still be given, and this size should still be used to determine the TL visit 
response as normal. In the special case where all lymph nodes are < 10mm and all other TLs 
are 0mm then although the sum may be > 0mm the calculation of TL response should be over-
written as a CR.
TL visit responses subsequent to CR
Only CR, PD or NE can follow a CR. If a CR has occurred then the following rules at the 
subsequent visits must be applied:

Step 1: If all lesions meet the CR criteria (i.e. 0mm or < 10mm for lymph nodes) then 
response will be set to CR irrespective of whether the criteria for PD of TL is also met 
i.e. if a lymph node LD increases by 20% but remains < 10mm. 

Step 2: If some lesion measurements are missing but all other lesions meet the CR 
criteria (i.e. 0mm or < 10mm for lymph nodes) then response will be set to NE 
irrespective of whether, when referencing the sum of TL diameters, the criteria for PD 
are also met. 

Step 3: If not all lesions meet the CR criteria (i.e. a pathological lymph node selected 
as TL has short axis ≥ 10mm and an absolute increase of ≥ 5mm taking as reference 
the smallest short axis for the same TL since treatment started including the baseline or 
the reappearance of previously disappeared lesion) or a new lesion appears, then 
response will be set to PD.

Step 4: If after steps 1 – 3 a response can still not be determined the response will be 
set to remain as CR.


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TL too big to measure
If a TL becomes too big to measure this should be indicated in the database and a size (‘x’) 
above which it cannot be accurately measured should be recorded. If using a value of x in the 
calculation of TL response would not give an overall visit response of PD, then this will be 
flagged and reviewed by the study team. It is expected that a visit response of PD will remain 
in the vast majority of cases. 
TL too small to measure
If a TL becomes too small to measure then this will be indicated as such on the case report 
form and a value of 5mm will be entered into the database and used in TL calculations. 
However, a smaller value may be used if the radiologist has not indicated ‘too small to 
measure’ on the case report form and has entered a smaller value that can be reliably 
measured. If a TL response of PD results (at a subsequent visit) then this will be reviewed by 
the study team.
Irradiated lesions/lesion intervention
Previously irradiated lesions (i.e. lesion irradiated prior to entry into the study) should be 
recorded as NTLs and should not form part of the TL assessment, unless they show objective 
progression, meet the other requirements for measurable lesion, and is the only lesion 
available.
Any TL (including lymph nodes), which has had intervention during the study (for example, 
irradiation / palliative surgery / embolisation), should be handled in the following way. Once a 
lesion has had intervention then it should be treated as having intervention for the remainder 
of the study noting that an intervention will most likely shrink the size of tumours:

Step 1: the diameters of the TLs (including the lesions that have had intervention) will 
be summed and the calculation will be performed in the usual manner. If the visit 
response is PD, this will remain as a valid response category. 

Step 2: If there was no evidence of progression after step 1, treat the lesion diameter 
(for those lesions with intervention) as missing and if ≤ 1/3 of the TLs have missing 
measurements then scale up as described in the ‘Scaling’ section below. If the scaling 
results in a visit response of PD then the patient would be assigned a TL response of 
PD.

Step 3: If, after both steps, PD has not been assigned, then, if appropriate (i.e. if ≤ 1/3 
of the TLs have missing measurements), the scaled sum of diameters calculated in step 
2 should be used, and PR or SD then assigned as the visit response. Patients with 


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intervention are evaluable for CR as long as all non-intervened lesions are 0 (or 
< 10mm for lymph nodes) and the lesions that have been subject to intervention have a 
value of 0 (or < 10mm for lymph nodes) recorded. If scaling up is not appropriate due 
to too few non-missing measurements then the visit response will be set as NE.
At subsequent visits, the above steps will be repeated to determine the TL and overall visit 
response. When calculating the previous minimum, lesions with intervention should be treated 
as missing and scaled up (as per step 2 above).
Scaling (applicable only for irradiated lesions/lesion intervention)
If > 1/3 of TL measurements are missing (because of intervention) then the TL response will 
be NE, unless the sum of diameters of non-missing TL would result in PD (i.e. if using a value 
of 0 for missing lesions, the sum of diameters has still increased by 20% or more compared to 
nadir and the sum of TLs has increased by ≥5mm from nadir). 
If ≤ 1/3 of the TL measurements are missing (because of intervention) then the results will be 
scaled up (based on the sizes at the nadir visit to give an estimated sum of diameters) and this 
will be used in calculations; this is equivalent to comparing the visit sum of diameters of the 
non-missing lesions to the nadir sum of diameters excluding the lesions with missing 
measurements.
Example of scaling
Lesion 5 is missing at the follow-up visit; the nadir TL sum including lesions 1-5 was 74mm.
The sum of lesions 1-4 at the follow-up is 68mm. The sum of the corresponding lesions at the 
nadir visit is 62mm.
Scale up as follows to give an estimated TL sum of 81mm:
68 x 74 / 62 = 81mm
CR will not be allowed as a TL response for visits where there is missing data. Only PR, SD 
or PD (or NE) could be assigned as the TL visit response in these cases. However, for visits 
with ≤ 1/3 lesion assessments not recorded, the scaled up sum of TLs diameters will be 
included when defining the nadir value for the assessment of progression.
Lesions that split in two
If a TL splits in two, then the LDs of the split lesions should be summed and reported as the 
LD for the lesion that split.


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Lesions that merge
If two TLs merge, then the LD of the merged lesion should be recorded for one of the TL 
sizes and the other TL size should be recorded as 0cm.
Change in method of assessment of TLs
CT and MRI are the only methods of assessment that can be used in this trial. If a change in 
method of assessment occurs between CT and MRI, this will be considered acceptable and no 
adjustment within the programming is needed.
If a change in method involves clinical examination (e.g. CT changes to clinical examination 
or vice versa), any affected lesions should be treated as missing. 
3.1.2
Non-target lesions and new lesions – site investigator data
At each visit, the investigator should record an overall assessment of the NTL response. This 
section provides the definitions of the criteria used to determine and record overall response 
for NTL at the investigational site at each visit.
NTL response will be derived based on the investigator’s overall assessment of NTLs as 
follows:
Table 6 NTL Visit Responses
NTL Non-target lesion; TL Target lesion.
Visit Responses
Description
Complete response (CR)
Disappearance of all NTLs present at baseline with all lymph 
nodes non-pathological in size (<10 mm short axis).
Progressive disease (PD)
Unequivocal progression of existing NTLs. Unequivocal 
progression may be due to an important progression in one lesion 
only or in several lesions. In all cases, the progression MUST be 
clinically significant for the physician to consider changing (or 
stopping) therapy.
Non-CR/Non-PD
Persistence of one or more NTLs with no evidence of progression.
Not evaluable (NE)
Only relevant when one or some of the NTLs were not assessed 
and, in the investigators opinion, they are not able to provide an 
evaluable overall NTL assessment at this visit. Note: For patients 
without TLs at baseline, this is relevant if any of the NTLs were 
not assessed at this visit and the progression criteria have not been 
met.
Not applicable (NA)
No NTLs are recorded at baseline.


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To achieve ‘unequivocal progression’ on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR in 
TLs, the overall tumour burden has increased sufficiently to merit a determination of disease 
progression. A modest ‘increase’ in the size of one or more NTLs is usually not sufficient to 
qualify for unequivocal progression status.
Details of any new lesions will also be recorded with the date of assessment. The presence of 
one or more new lesions is assessed as progression.
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.
The finding of a new lesion should be unequivocal: i.e. not attributable to differences in 
scanning technique, change in imaging modality or findings thought to represent something 
other than tumour.
New lesions will be identified via a Yes/No tick box. The absence and presence of new lesions 
at each visit should be listed alongside the TL and NTL visit responses.
A new lesion indicates progression so the overall visit response will be PD irrespective of the 
TL and NTL response.
If the question ‘Any new lesions since baseline’ has not been answered with Yes or No and 
the new lesion details are blank this is not evidence that no new lesions are present, but should 
not overtly affect the derivation.
Symptomatic progression is not a descriptor for progression of NTLs: it is a reason for 
stopping study therapy and will not be included in any assessment of NTLs.
Patients with ‘symptomatic progression’ requiring discontinuation of treatment without 
objective evidence of disease progression at that time should continue to undergo tumour 
assessments where possible until objective disease progression is observed.
3.1.3
Overall visit response – site investigator data
Table 7 defines how the previously defined TL and NTL visit responses will be combined 
with new lesion information to give an overall visit response.
Table 7 Overall visit responses
TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
CR or NA
No (or NE)
CR


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TARGET
NON-TARGET
NEW LESIONS
OVERALL VISIT 
RESPONSE
CR
Non-CR/Non-PD or NE
No (or NE)
PR
PR
Non-PD or NE or NA
No (or NE)
PR
SD
Non-PD or NE or NA
No (or NE)
SD
PD
Any
Any
PD
Any
PD
Any
PD
Any
Any
Yes
PD
NE
Non-PD or NE or NA
No (or NE)
NE
NA
CR
No (or NE)
CR
NA
Non-CR/Non-PD
No (or NE)
SD
NA
NE
No (or NE)
NE
CR Complete response; NA Not applicable; NE Not evaluable; PD Progressive disease; PR Partial response; SD Stable 
disease.
3.1.4
Independent review
A planned independent central review (ICR) of all radiological imaging data will be carried 
out using RECIST version 1.1. All radiological scans for all patients (including those at 
unscheduled visits, or outside visit windows) will be collected on an ongoing basis and sent to 
an AstraZeneca appointed Contract Research Organisation (CRO) for central analysis. The 
imaging scans will be reviewed by two independent radiologists using RECIST 1.1 and will 
be adjudicated, if required (i.e. two reviewers’ review the scans and adjudication is performed 
by a separate reviewer in case of a disagreement). For each patient, the ICR will define the 
overall visit response (i.e. the response obtained overall at each visit by assessing TLs, NTLs 
and new lesions) data and no programmatic derivation of visit response is necessary. (For 
patients with TLs at baseline: CR, PR, SD, PD, NE; for patients with NTLs only: CR, SD, PD, 
NE; for patients with no disease identified at baseline: PD, no evidence of disease [NED], 
NE). If a patient has had a tumour assessment that cannot be evaluated then the patient will be 
assigned a visit response of NE (unless there is evidence of progression in which case the 
response will be assigned as PD). RECIST assessments/scans contributing towards a 
particular visit may be performed on different dates and for the central review the date of 
progression for each reviewer will be provided based on the earliest of the scan dates of the 
component that triggered the progression. 
If adjudication is performed, the reviewer that the adjudicator agreed with will be selected as a 
single reviewer (note in the case of more than one review period, the latest adjudicator 
decision will be used). In the absence of adjudication, the records for all visits for a single 
reviewer will be used. The reviewer selected in the absence of adjudication will be the 


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reviewer who read the baseline scan first. The records from the single selected reviewer will 
be used to report all ICR RECIST information including dates of progression, visit response, 
censoring and changes in target lesion dimensions. Endpoints (of ORR, PFS, DoR, best 
percentage change in tumour size and DCR) will be derived programmatically from this 
information. 
Results of this independent review will not be communicated to investigators and the 
management of patients will be based solely upon the results of the RECIST 1.1 assessment 
conducted by the investigator.
An ICR of all patients will be performed prior to DBL, which will cover all of the scans up to 
the data cut-offs (DCOs).
Further details of the ICR will be documented in the ICR Charter.
3.2
Efficacy Variables
3.2.1
Objective response rate (ORR)
ORR is defined as the percentage of patients with a confirmed response of CR or PR. The 
primary endpoint is confirmed ORR as assessed by ICR per RECIST 1.1.
A secondary endpoint is confirmed ORR as assessed by the investigator.
A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit.
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Patients who discontinue treatment without 
progression, receive a subsequent anti-cancer therapy (note that for this analysis radiotherapy 
is not considered a subsequent anti-cancer therapy) and then respond will not be included as 
responders in the ORR (i.e. both visits contributing to a response must be prior to subsequent 
therapy for the patient to be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a responder. Similarly, if a patient has visit responses of 
CR, NE, CR, then, as long as the time between the 2 visits of CR is greater than 4 weeks, then 
a best response of CR will be assigned.


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3.2.1.1
Best objective response (BoR)
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST assessment described in Section 3.1.3. It is the best response a patient has had 
following first dose, but prior to starting any subsequent anti-cancer therapy, and up to and 
including RECIST progression or the last evaluable assessment in the absence of RECIST 
progression. Categorisation of BoR will be based on RECIST using the following response 
categories: confirmed CR, confirmed PR, SD, NED, PD and NE. Unconfirmed CR/PR will be 
included in SD. A BoR of NED applies only to those patients entering the study with no 
measurable disease at baseline. 
CR or PR must be confirmed. For determination of a best response of SD, the earliest of the 
dates contributing towards a particular overall visit assessment will be used. SD should be 
recorded at least 6 weeks minus 1 week, i.e. at least 35 days (to allow for an early assessment 
within the assessment window), after first dose of study treatment. For CR/PR, the initial 
overall visit assessment that showed a response will use the latest of the dates contributing 
towards a particular overall visit assessment.
BoR will be determined programmatically based on RECIST from the overall visit response 
using all ICR data up until the first progression event and prior to starting any subsequent 
anti-cancer therapy. It will also be determined programmatically based on RECIST using all 
site investigator data up until the first progression event and prior to starting any subsequent 
anti-cancer therapy. The denominators for each case will be consistent with those used in the 
ORR analysis.
For patients whose progression event is death, BoR will be calculated based upon all 
evaluable RECIST assessments prior to death.
For patients who die with no evaluable RECIST assessments, if the death occurs ≤ 13 weeks 
(i.e. 2*6 weeks + 1 week to allow for a late assessment within the assessment window) after 
first dose of study treatment, then BoR will be assigned to the progression (PD) category. For 
patients who die with no evaluable RECIST assessments, if the death occurs > 13 weeks after 
first dose of study treatment then BoR will be assigned to the NE category.
A patient will be classified as a responder if the RECIST criteria for a CR or PR are satisfied 
at any time following first dose, prior to RECIST progression and prior to starting any 
subsequent cancer therapy.
3.2.2
Progression free survival (PFS)
PFS is defined as the time from date of enrolment until the date of objective disease 
progression or death (by any cause in the absence of progression) regardless of whether the 


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patient withdraws from therapy or receives another anti-cancer therapy prior to progression 
(i.e. date of PFS event or censoring – date of enrolment + 1). PFS will be assessed using ICR 
assessments and using investigator assessments. Patients who have not progressed or died at 
the time of analysis will be censored at the time of the latest date of assessment from their last 
evaluable RECIST assessment. However, if the patient progresses or dies immediately after 
two or more consecutive missed visits, the patient will be censored at the time of the latest 
evaluable RECIST 1.1 assessment prior to the two missed visits (Note: NE visit is not 
considered as missed visit). 
Given the scheduled visit assessment scheme (i.e. every 6 weeks from the first dose of study 
treatment, changing to every 12 weeks after 48 weeks following date of first dose for patients 
who have discontinued study treatment prior to progression) the definition of two missed 
visits will be as follows:

For patients still on treatment or who discontinue due to progression or death:
o
If the previous RECIST assessment <= day 35 then two missing visits will 
equate to 13 weeks (2 x 6 weeks + 1 week for a late assessment)
o
If the previous RECIST assessment > day 35 then two missing visits will 
equate to 14 weeks (2 x 6 weeks + 1 week for an early assessment + 1 week for 
a late assessment)

For patients who discontinue treatment prior to progression or death:
o
If the previous RECIST assessment <= day 35 then two missing visits will 
equate to 13 weeks (2 x 6 weeks + 1 week for a late assessment)
o
If the previous RECIST assessment > day 35 and <= 287 (i.e. week 41) then 
two missing visits will equate to 14 weeks (2 x 6 weeks + 1 week for an early 
assessment + 1 week for a late assessment)
o
If the previous RECIST assessment > day 287 and <= 329 (i.e. week 47) then 
two missing visits will equate to 20 weeks (6 weeks + 12 weeks + 1 week for 
an early assessment + 1 week for a late assessment)
o
If the previous RECIST assessment > day 329 then two missing visits will 
equate to 26 weeks (2 x 12 weeks + 1 week for an early assessment + 1 week 
for a late assessment)


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If the patient has no evaluable visits or does not have baseline data they will be censored at 
Day 1 unless they die within two visits of baseline (12 weeks plus 1 week allowing for a late 
assessment within the visit window).
The PFS time will always be derived based on scan/assessment dates not visit dates.
RECIST assessments/scans contributing towards a particular visit may be performed on 
different dates. The following rules will be applied:

For ICR assessments, the date of progression will be determined based on the earliest
of the scan dates of the component that triggered the progression for the adjudicated 
reviewer selecting PD or of the reviewer who read baseline first if there is no 
adjudication for ICR data.

For investigational assessments, the date of progression will be determined based on 
the earliest of the dates of the component that triggered the progression.

For both ICR and investigational assessments, when censoring a patient for PFS the 
patient will be censored at the latest of the dates contributing to a particular overall 
visit assessment.
Note: for TLs only the latest scan date is recorded out of all scans performed at that 
assessment for the TLs and similarly for NTLs only the latest scan date is recorded out of all 
scans performed at that assessment for the NTLs.
3.2.3
Disease control rate (DCR)
Disease control rate (DCR) is defined as the percentage of patients with BoR of CR, PR or 
SD. See Section 3.2.1.1 for the BoR definition.
DCR at 12 weeks is defined as the percentage of patient with BoR of CR or PR, or SD for at 
least 11 weeks (i.e., 12 weeks – 1 week to allow for an early assessment within the assessment 
window) after the date of the first dose of study intervention (without subsequent anticancer 
therapy).
3.2.4
Duration of response (DoR)
DoR will be defined as the time from the date of first documented response (which is 
subsequently confirmed) until date of documented progression or death in the absence of 
disease progression (i.e. date of PFS event or censoring – date of first response + 1). The end 
of response should coincide with the date of progression or death from any cause used for the 


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PFS endpoint. The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit that was CR or PR that was subsequently confirmed.
If a patient does not progress following a response, then their DoR will use the PFS censoring 
time.
3.2.5
Overall survival (OS)
Overall survival (OS) is defined as the time from the date of enrolment until death due to any 
cause regardless of whether the patient withdraws from study treatment or receives another 
anti-cancer therapy (i.e. date of death or censoring – date of enrolment + 1). Any patient not 
known to have died at the time of analysis will be censored based on the last recorded date on 
which the patient was known to be alive.
Note: Survival calls will be made in the week following the date of the DCO for the final 
analysis, and if patients are confirmed to be alive or if the death date is post the DCO date 
these patients will be censored at the date of DCO. The status of ongoing, withdrawn (from 
the study) and “lost to follow-up” patients at the time of the final OS analysis should be 
obtained by the site personnel by checking the patient’s notes, hospital records, contacting the 
patient’s general practitioner and checking publicly-available death registries. In the event that 
the patient has actively withdrawn consent to the processing of their personal data, the vital 
status of the patient can be obtained by site personnel from publicly available resources where 
it is possible to do so under applicable local laws.
Note: For any OS analysis performed prior to the final OS analysis, in the absence of survival 
calls being made, it may be necessary to use all relevant CRF fields to determine the last 
recorded date on which the patient was known to be alive for those patients still on treatment 
(since the SURVIVE module is only completed for patients off treatment if a survival sweep 
is not performed). The last date for each individual patient is defined as the latest among the 
following dates recorded on the CRFs:

Adverse event (AE) start and stop dates

Admission and discharge dates of hospitalisation

Study treatment date

End of treatment date

Laboratory test dates

Date of vital signs


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
Disease assessment dates on RECIST CRF

Start and stop dates of alternative anticancer treatment

Date last known alive on survival status CRF

End of study date 
If a patient is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive +1 from the database and 
the death date using the available information provided:-
a.
For Missing day only – using the 1st of the month 
b.
For Missing day and Month – using the 1st of January
If there is evidence of death but the date is entirely missing, it will be treated as missing, i.e. 
censored at the last known alive date.
3.2.6
Change in TL tumour size
Tumour size is the sum of the longest diameters of the TLs. Baseline for RECIST is defined to 
be the last evaluable assessment prior to first dose. The percentage change in TL tumour size 
at each assessment will be obtained for each patient taking the difference between the sum of 
the TLs at a particular assessment (week X) and the sum of the target lesions at baseline 
divided by the sum of the TLs at baseline times 100 (i.e. (week X–- baseline) / baseline * 
100).
The absolute change and percentage change from baseline in the sum of tumour size at each 
assessment will be calculated. The best change in tumour size (i.e. depth of response) is the 
largest decrease from baseline or the smallest increase from baseline in the absence of a 
reduction and will include all assessments prior to the earliest of death in the absence of 
progression, any evidence of progression, the start of subsequent anti-cancer therapy or the 
last evaluable RECIST assessment if the patient has not died, progressed or started subsequent 
anti-cancer therapy.
Only patients with both baseline and post-baseline values will be included in the analysis. 
3.3
Safety Variables


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3.3.2
Dose intensity
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to the last day of dosing. RDI will be defined as follows:

RDI = 100% * d/D, where d is the actual cumulative dose delivered up to the actual 
last day of dosing and D is the intended cumulative dose up to the actual last day of 
dosing. D is the total dose that would be delivered, if there were no modification to 
dose or schedule. When accounting for the calculation of intended cumulative dose 2 
days should be added to the date of last dose to reflect the protocol allowed window 
for dosing.
When deriving actual dose administered the volume before and after infusion will also be 
considered:
Actual dose = actual dose per administration (initial or reduced dose level) * proportion of 
actual dose administrated, where the proportion of the actual dose administered will be 
calculated as (volume before infusion–- volume after infusion)/volume before infusion.
3.3.3
Adverse events
AEs and serious adverse events (SAEs) will be collected throughout the study, from date of 
informed consent throughout the treatment period and the safety follow-up period (until 40 
(+7) days after the last dose of study treatment). In the case of unresolved ILD/pneumonitis, 
Hepatitis B reactivation or events which are considered to be due to a late onset toxicity to 
study treatment, collection continues during Long-term Follow-up as specified in Table 3 of 
the CSP. Events will be defined as treatment emergent if they onset or worsen (by investigator 
report of a change in severity or seriousness), during the treatment period or safety follow-up 
as defined in the CSP. The Medical Dictionary for Regulatory Activities (MedDRA) (using 
the latest or current MedDRA version) will be used to code the AEs. AEs will be graded 
according to the National Cancer Institute Common Terminology Criteria for AEs (NCI 
CTCAE) (using CTCAE version 5).


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Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and ‘Discontinuation of Investigational Product 
due to Adverse Events’ (DAEs). Based on the expert’s judgement, significant adverse events 
of particular clinical importance may, after consultation with the Global Patient Safety 
Physician, be considered other significant adverse events (OAEs) and reported as such in the 
CSR. A similar review of laboratory/vital signs/ECG data will be performed for identification 
of OAEs.
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious) or significant 
additional treatment.
AEs of special interest
Some clinical concepts (including some selected individual preferred terms and higher-level 
terms) have been considered “AEs of special interest” (AESI) to the T-DXd program. AESIs 
represent pre-specified risks that are considered to be of importance to a clinical development 
program.
Based on the available pre-clinical and clinical data, review of the cumulative literature, 
reported toxicities for the same class of agents, and biological plausibility, ILD/pneumonitis 
and left ventricular ejection fraction (LVEF) decrease are considered to be AESIs.
Other categories may be added as necessary or existing terms may be merged. An 
AstraZeneca medically qualified expert after consultation with the Global Patient Safety 
Physician has reviewed the AEs of interest and identified which higher-level terms and which 
MedDRA preferred terms contribute to each AESI. Further reviews may take place prior to 
DBL to ensure any further terms not already included are captured within the categories.
3.3.4
Physical examinations
Physical examinations will be performed as described in Section 8.2.1 of the CSP. 
Abnormalities recorded prior to the first dose of study treatment will be recorded as part of the 
patient’s baseline signs. Abnormalities first recorded after first dose of study treatment will be 
recorded as AEs unless they fulfil any of the SAE criteria, are the reason for study treatment 
discontinuation, or are considered to be clinically relevant as judged by the investigator.


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3.3.5
Vital signs
The following vital signs will be measured as described in Section 8.2.2 of the CSP: Systolic 
and diastolic blood pressure (BP), pulse rate, temperature and respiratory rate. Body weight 
will also be recorded along with vital signs.
For the derivation of baseline and post-baseline visit values, the definitions and rules 
described in Section 3.3.10.1 for visit windows, and how to handle multiple records will be 
used.
3.3.6
Electrocardiograms
Resting 12-lead electrocardiograms (ECGs) will be recorded at screening, before Cycle 1 
infusion (within 3 days of administration), and then every 4 cycles, and at end of treatment 
(EOT) as described in Section 8.2.3 of the CSP. ECGs will be obtained in triplicate at 
screening, and subsequent ECGs will be performed in triplicate only if an abnormality is 
noted, otherwise single ECGs will be performed.
The following ECG variables will be collected: heart rate, RR interval, PR interval, QT 
interval, QT interval corrected for heart rate using Fridericia’s correction (QTcF interval), 
QRS duration, and an overall evaluation.
The overall evaluation of an ECG will either be “normal”, “abnormal” or “borderline”, with 
abnormalities categorised as either “clinically significant” or “not clinically significant”. In 
case of clinically significant ECG abnormalities, 2 additional ECGs will be obtained over a 
brief period (within 5 minutes) to confirm the finding. Where triplicate ECG results are taken, 
a single mean value for numeric parameters will be used, and the worst case of the three 
results will be used for the overall evaluation.
For the derivation of visit windows where baseline and post-baseline visits have triplicate 
ECGs, the date/time equal to the earliest date/time of the 3 results will be used.
Where QTcF is not collected, it will be calculated programmatically using the reported ECG 
values (RR and QT) as follows (where RR are in seconds):
𝑄𝑇𝑐𝐹=
𝑄𝑇
√𝑅𝑅

Alternatively, RR (or QT) can be programmatically derived if not collected but QTcF and QT 
(or RR, respectively) is collected. RR can be calculated as follows:


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𝑅𝑅=  𝑄𝑇
𝑄𝑇𝑐𝐹

The following relationship between RR and heart rate (with RR expressed in seconds and 
heart rate in bpm) will be used to derive programmatically the missing parameter in case only 
one of these variables is available:
𝑅𝑅=
60
Heart rate
3.3.7
Elevated troponin levels
Troponin will be collected at screening, when a patient reports signs or symptoms suggesting 
CHF, MI or other causes of myocyte necrosis, and at end of treatment (EOT). Further details 
regarding repeat testing are described in Section 8.2.3 of the CSP.
3.3.8
Laboratory measurements
Blood and urine samples for the determination of clinical chemistry, haematology, coagulation 
and urinalysis will be collected as described in Section 8.2.4 of the CSP.
For the derivation of baseline and post-baseline visit values, the rules described in 
Sections 4.1 and 3.3.10.1 of this document considering baseline, visit windows and how to 
handle multiple records will be used.
Change from baseline in haematology and clinical chemistry variables will be calculated for 
each post-dose visit. NCI CTCAE (version 5.0) grades will be defined at each visit according 
to the CTCAE grade criteria using project ranges, after conversion of lab result to 
corresponding project-wide preferred units. The following parameters have CTCAE grades 
defined for both high and low values: potassium, sodium, magnesium, glucose and corrected 
calcium so high and low CTCAE grades will be calculated.
Corrected calcium will be programmatically derived during the creation of the reporting
database using the following formula:
Corrected calcium (mmol/L) = Total calcium (mmol/L) + ([40-albumin (g/L)] x 0.02) 
Calculated creatinine clearance (CrCl) will be programmatically derived in the reporting 
database using the Cockcroft-Gault formula:
Creatinine clearance (mL/min) = ([140 – age at first dose] * weight (kg) [* 0.85 if patient is 
female]) / (72 * serum creatinine (mg/dL))


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Absolute values will be compared to the project reference range and classified as low (below 
range), normal (within range or on limits of range), and high (above range).
The maximum or minimum value (depending on the direction of an adverse effect) will be 
defined for each laboratory parameter as the maximum (or minimum) post-dose value at any 
time.
Local reference ranges will be used for the primary interpretation of laboratory data at the 
local laboratory. Project reference ranges will be used for reporting purposes.
The denominator used in laboratory abnormality summaries will include only evaluable 
patients (i.e., those who had sufficient data to have the possibility of an abnormality). For 
example:

If a CTCAE criterion involves a change from baseline, evaluable patients would have 
both a pre-dose and at least 1 post-dose value recorded.

If a CTCAE criterion does not consider changes from baseline, to be evaluable the 
patient need only have 1 post-dose value recorded.
3.3.9
Other safety assessments
3.3.9.1
Echocardiograms/multigated acquisition scans
Echocardiograms (ECHO)/multigated acquisition (MUGA) scans will be performed as 
described in Section 8.2.5.1 of the CSP. These will be used to assess the LVEF. The LVEF % 
and method details will also be reported. CTCAE (version 5.0) grades will be defined at each 
visit according to the CTCAE grade criteria. Change from baseline of LVEF % will be 
calculated. LVEF % measurements will be categorised as follows:

Change from baseline LVEF % values will be categorised as:

3.3.9.2
Pulmonary assessments
Pulse oximetry (SpO2) will be measured as described in Section 8.2.5.2 of the CSP.


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3.3.9.3
ECOG performance status
ECOG performance status (PS) will be assessed as described in Section 8.2.5.3 of the CSP as 
the following:
0.
Fully active; able to carry out all usual activities without restrictions.
1.
Restricted in strenuous activity, but ambulatory and able to carry out light work or 
work of a sedentary nature (e.g., light housework or office work).
2.
Ambulatory and capable of self-care, but unable to carry out any activities; up and 
about more than 50% of waking hours.
3.
Capable of only limited self-care; confined to bed or chair more than 50% of waking 
hours.
4.
Completely disabled; unable to carry out any self-care and totally confined to bed or 
chair.
5.
Dead.
Any significant change from baseline or screening will be reported as an AE.
3.3.9.4
Ophthalmologic assessments
Ophthalmologic assessments including visual acuity testing, slit lamp examination and 
fundoscopy will be performed at screening, EOT, and as clinically indicated.
3.3.9.5
ILD/Pneumonitis investigation
If ILD is suspected, additional assessments are performed as described in the CSP, including 
pulmonary function test and high resolution CT scan (HRCT).
For the pulmonary function test, the following parameters will be measured: diffusing 
capacity of the lungs for carbon monoxide (DLCO) (if feasible), SpO2, FiO2, whether the 
patient has received oxygen treatment, oxygen treatment start and stop dates and method 
provided, forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1% 
predicted, FVC % predicted, peak expiratory flow (PEF), forced expiratory volume in 6 
seconds (FEV6), total lung capacity (TLC), FEV1/FVC ratio.
An overview of the HRCT radiological findings will be collected at screening for all patients 
and if ILD/pneumonitis is suspected.


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3.3.9.6
Eligible HBV infection
Eligible patients enrolled with inactive or resolved Hepatitis B infection will be monitored for 
reactivation, where reactivation is as defined in Section 8.2.5.5 of the CSP.
If HBV reactivation is confirmed, T-DXd therapy must be interrupted and anti-viral therapy 
initiated following consultation with the local Hepatitis B expert and in accordance with local 
practice. 
3.3.10
General considerations for safety assessments
3.3.10.1
Time windows
Time windows will be defined for any presentations that summarise values by visit. The 
following conventions will apply:

The time windows will be exhaustive so that data recorded at any time point has the 
potential to be summarised. Inclusion within the time window will be based on the 
actual date and not the intended date of the visit.

All unscheduled visit data have the potential to be included in the summaries.

The window for the visits following baseline will be constructed in such a way that the 
upper limit of the interval falls half way between the two visits (the lower limit of the 
first post-baseline visit will be Day 2). If an even number of days exists between two 
consecutive visits then the upper limit will be taken as the earlier of the two middle 
days. For example, the visit windows for vital signs data are:
o
Cycle 1 Day 8, visit window 2 – 11.
o
Cycle 1 Day 15, visit window 12 – 18.
o
Cycle 2 Day 1, visit window 19 – 32.
o
Cycle 3 Day 1, visit window 33 – 53.
o
Cycle 4 Day 1, visit window 54 – 74.

Note, for safety data that are collected during the study both pre-infusion and 
post-infusion (e.g. vital signs), visit summaries following the first dose will present the 
pre-infusion and post-infusion timepoints separately. The pre-infusion timepoint will 
not be presented at Cycle 1 as any pre-infusion data at Cycle 1 are included in the 
derivation of baseline.

For summaries showing the maximum or minimum values, the maximum/minimum 
value recorded on treatment will be used (regardless of where it falls in an interval).

Listings should display all values contributing to a time point for a patient.


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
For visit based summaries, if there is more than one value per patient within a time 
window then the closest value to the scheduled visit date will be summarised, or the 
earlier, in the event the values are equidistant from the nominal visit date. The listings 
will highlight the value for the patient that contributed to the summary table, wherever 
feasible. Note: in summaries of extreme values all post baseline values collected are 
used including those collected at unscheduled visits regardless of whether or not the 
value is closest to the scheduled visit date.

For summaries at a patient level, all values will be included, regardless of whether they 
appear in a corresponding visit based summary, when deriving a patient level statistic 
such as a maximum.
3.3.10.2
Missing data
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e. below the lower limit of quantification [LLOQ]) or “> x” (i.e. above the 
upper limit of quantification) will be imputed as “x” in the calculation of summary statistics 
but will be displayed as “< x” or “> x” in the listings. Additionally, adverse events that have 
missing causality (after data querying) will be assumed to be related to study drug.
Furthermore, for missing diagnostic dates, if day and/or month are missing use 01 and/or Jan. 
If year is missing, put the complete date to missing.
AE and Medication Start/Stop Dates
The original incomplete or missing dates will be presented in the listing.

Adverse events: all AEs will be considered as treatment-emergent unless the opposite 
can be clearly stated. Imputation will be done only in the context of identifying 
treatment-emergent AEs.

Concomitant medications: all medications will be considered as concomitant unless 
the opposite can be clearly stated. Imputation will be done only in the context of 
identifying concomitant medications.
For missing AE and medications start dates, the following will be applied:
a.
Missing day – Impute the 1st of the month unless month is the same as month of 
the first dose of study drug then impute first dose date.
b. Missing day and month – Impute 1st January unless year is the same as first dose 
date then impute first dose date.


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c.
Completely missing – Impute first dose date unless the end date suggests it could 
have started prior to this in which case impute the 1st January of the same year as 
the end date.
For missing subsequent anti-cancer therapy start dates, the following rules will be applied:
a.
Missing day – If the month is the same as treatment end date, then impute to the 
day after treatment, otherwise 1st of the month.
b. Missing day and month – If year is the same as treatment end date, then impute to 
the day after treatment, otherwise 1st January of the same year as anti-cancer 
therapy date.
When imputing a start date, ensure that the new imputed date is sensible (i.e. is prior to the 
end date of the AE or medication).
For missing AE and medication end dates, the following will be applied:
a.
Missing day – Impute the last day of the month unless month is the same as 
month of last dose of study treatment then impute last dose date
b. Missing day and month – Impute 31st December unless year is the same as last 
dose then impute last dose date.
c.
Completely missing:
o
AE: since there is no ongoing flag recorded in CRF, then assume that AE 
is still present (i.e., do not impute a date).
o
Medication: if the ongoing flag is missing then assume that medication is 
still being taken (i.e., do not impute a date). If the medication has stopped 
and start date of medication is prior to first dose date then impute the first 
dose date, if the medication started on or after first dose date then impute 
a date that is after the last dose date.
When imputing a stop date, ensure that the new imputed date is sensible (i.e., is after the start 
date of the AE or medication). 
Patients with a partial date of birth (i.e. for those countries where year of birth only is given) 
will have the 1st of the month imputed if the day is missing, and 1st Jan imputed if the day and 
month is missing. 


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Flags will be retained in the database indicating where any programmatic imputation has been 
applied, and in such cases, any durations would not be calculated.
Date of Death
If a patient is known to have died where only a partial death date is available then the date of 
death will be imputed as the latest of the last date known to be alive +1 from the database and 
the death date using the available information provided:-
a.
For missing day only – using the 1st of the month
b. For missing day and month – using the 1st of January.
If there is evidence of death but the date is entirely missing, it will be treated as missing (i.e., 
the patient will be censored at the last known alive date).
3.4
Pharmacokinetic Variables
PK concentration data will be collected as per the CSP to assess the PK of T-DXd, total anti-
HER2 antibody, and MAAA-1181a. 
For PK concentration data below limit of quantification (BLQ) the following rules will apply:

If, at a given time point, 50% or less of the serum concentrations are not quantifiable 
(NQ), the geometric mean, geometric CV%, mean and SD will be calculated treating 
the NQ as the LLOQ.

If more than 50%, but not all, of the concentrations are NQ, the geometric mean, 
geometric CV%, mean, and SD will be reported as data not calculable (NC). The 
maximum value will be reported from the individual data, and the minimum and 
median will be set to NQ.

If all the concentrations are NQ, the geometric mean, mean, minimum, median and 
maximum will be reported as NQ, and the geometric CV% and SD as NC.
3.5
Immunogenicity Variables
Blood samples for determination of ADAs against T-DXd and neutralising ADAs (nAb) in 
serum will be collected per the Schedule of Activities (SoA) in the CSP. ADA results from 
each sample will be reported as either positive or negative. If the sample is positive, the ADA 
titre will be reported as well. In addition, the presence of neutralising ADA may be tested for 
all ADA-positive samples using a ligand-binding assay. The nAb results will be reported as 
positive or negative.


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The number of patients in the ADA analysis set who fulfil the following criteria will be 
determined. The percentage of patients in each of the categories listed below will be 
calculated, using the number of patients in the ADA evaluable set as the denominator.

ADA positive at any visit; the percentage of ADA-positive patients in the ADA 
analysis set is known as ADA prevalence. A patient is defined as being ADA positive 
if a positive ADA result is available at any time, including baseline and all post-
baseline measurements; otherwise ADA negative.

ADA positive post-baseline and positive at baseline.

ADA not detected post-baseline and positive at baseline.

Treatment-induced ADA, defined as ADA positive post-baseline and not detected at 
baseline.

Treatment-boosted ADA, defined as a baseline positive ADA titre that was boosted to 
a 2-fold or higher level (greater than the analytical variance of the assay) following 
drug administration.

Treatment-emergent ADA, defined as either treatment-induced or treatment-boosted 
ADA; the percentage of patients fulfilling this criterion in the ADA analysis set is 
known as ADA incidence.

Treatment-emergent ADA persistently positive, defined as treatment-emergent ADA+ 
patients having at least 2 post-baseline ADA positive measurements with at least 16 
weeks (112 days) between the first and last positive measurement, or an ADA positive 
result at the last available assessment.

Treatment-emergent ADA transiently positive, defined as treatment-emergent ADA+ 
patients having at least one post-baseline ADA positive measurement and not fulfilling 
the conditions for persistently positive.

nAb positive at any visit (baseline or post-baseline).
3.6
 


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3.7
Other variables
3.7.1
Prior and concomitant medications and procedures
All therapies (drug and non-drug), including herbal preparations, whether prescribed or over 
the-counter, that are used during the study will be recorded on the eCRF. Details include 
generic and/or brand names of the medications, World Health Organisation Drug Dictionary 
(WHO-DD) encoding (latest or current version), reason for use, route, dose, dosing frequency, 
and start and end dates.
Procedures performed during the study will be recorded on the eCRF and details include the 
procedure name, WHO-DD encoding (latest or current version), reason for the procedure, and 
start and end dates.
For the purpose of inclusion in prior and/or concomitant mediation or therapy summaries, 
missing start and stop dates for medications and procedures will be handled using the rules 
described in Section 3.3.10.2.
Prior medications, concomitant and post-treatment medications are defined based on imputed 
start and stop dates as follows:

Prior therapies are defined as those taken prior to study treatment with a stop date prior 
to the first dose of study treatment.

Concomitant therapies and procedures are defined as those with a stop date on or after 
the first dose date of study treatment (and could have started prior to or during 
treatment).

Post-treatment therapies are those with a start date after the last dose date of study 
treatment. 
Missing coding terms should be listed and summarised as "Not coded".


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4
ANALYSIS METHODS
4.1
General principles
Efficacy data will be summarised and analysed using both the HER2-positive and 
HER2-expressing FAS for the primary analyses, both the HER2-positive and the 
HER2-expressing RES for supplementary analyses, and both the HER2-positive and 
HER2-expressing FAS for PFS and OS sensitivity analyses, as specified in Table 4. Safety 
and treatment exposure data will be summarised based upon the SAF. Study population and 
demography data will be summarised based upon the HER2-positive FAS and the ITT 
analysis set as specified in Table 4. PK data will be analysed using the PK analysis set. ADAs 
will be summarised using the T-DXd ADA evaluable set. Study day will be relative to the date 
of first dose of study treatment, unless a patient discontinued prior to receiving treatment, in 
which case study day will be relative to date of enrolment.
The below mentioned general principles will be followed throughout the study:

Descriptive statistics will be used for all variables, as appropriate. Continuous 
variables will be summarised by the number of observations, mean, standard deviation, 
median, upper and lower quartiles, minimum, and maximum. For log-transformed data 
it is more appropriate to present geometric mean, CV, median, minimum and 
maximum. Categorical variables will be summarised by frequency counts and 
percentages for each category.

Unless otherwise stated, percentages will be calculated out of the population total.

For continuous data, the mean and median will be rounded to 1 additional decimal 
place compared to the original data. The standard deviation will be rounded to 2 
additional decimal places compared to the original data. Minimum and maximum will 
be displayed with the same accuracy as the original data.

For categorical data, percentages will be rounded to 1 decimal place.

The analyses will be descriptive, and no inferential analysis will be performed based 
on statistical tests.

SAS® version 9.4 or higher will be used for all analyses.
The last observation before the first dose of study treatment will be considered the baseline 
measurement. For assessments on the day of first dose where time is not captured, a nominal 


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pre-dose indicator, if available, will serve as sufficient evidence that the assessment occurred 
prior to first dose.
Assessments on the day of the first dose where neither time nor a nominal pre-dose indicator 
are captured will be considered prior to the first dose if such procedures are required by the 
CSP to be conducted before the first dose.
If two visits are equally eligible to assess status at baseline (e.g., screening and baseline 
assessments both on the same date with no time recorded), the average will be used as the 
baseline value. In the scenario where there are two assessments recorded on the same day, one 
with time recorded and the other without time recorded, the one with the time recorded would 
be selected as baseline.
Where safety data are summarised over time, time on study will be calculated in relation to 
date of first dose of study treatment.
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as (post-
baseline value – baseline value) / baseline value x 100. 
When calculating time to an event or duration, the default unit will be days unless otherwise 
specified. If an analysis requires days be converted to weeks, the time to event or duration will 
be divided by 7. If an analysis requires days be converted to months, the time to event or 
duration will be divided by (365.25/12).
4.2
Analysis methods
4.2.1
 
 
 
 
 
 
 


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4.2.2
Objective response rate
The ORR will be based on all scans regardless of whether they were scheduled or not. The 
primary endpoint, confirmed ORR as assessed by ICR based on the HER2-positive FAS, will 
be estimated and presented as the number (%) of patients along with the corresponding exact 
95% Clopper-Pearson CI. A summary will be produced that presents the number and 
percentage of patients with a confirmed tumour response (CR/PR).
As a supplementary analysis to the primary endpoint. the primary analysis for the primary 
endpoint will be repeated for confirmed ORR as assessed by ICR based on the HER2-positive 
RES.
For the secondary endpoint of ORR in the HER2-positive population, the primary analysis for 
the primary endpoint will be repeated using investigator assessments for patients in the 
HER2-positive FAS. 
For the secondary endpoint of ORR in the HER2-expressing population, the primary analysis 
for the primary endpoint will be repeated based on the HER2-expressing FAS, using both ICR 
and investigator assessments. The supplementary analysis for the primary endpoint will be 
repeated for this secondary endpoint based on the HER2-expressing RES using ICR 
assessments only.
Subgroup analysis
Subgroup analyses will be conducted for the primary endpoint, comparing ORR in the 
following subgroups of the HER2-positive FAS:

Lines of prior systemic therapy (2 versus 3 versus ≥ 4)

Age at enrolment (< 65 versus ≥ 65 years)

Sex (male versus female)

ECOG Performance status (0 versus 1)

HER2 status by central lab (IHC 3+ versus IHC 2+/ISH positive)

Primary tumour location (gastric versus GEJ)

Histological subtype (intestinal versus diffuse versus others)

Number of metastatic sites (< 2 versus ≥ 2)


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
Previous total gastrectomy (yes versus no)

Prior adjuvant/neoadjuvant therapy (yes versus no)

Prior treatment with irinotecan or other topoisomerase I inhibitors (yes versus no)

Prior treatment with taxane chemotherapy (yes versus no)

Prior treatment with checkpoint inhibitor or other immuno-oncology therapy (yes 
versus no)

Presence of liver metastasis at baseline (yes versus no)

Renal impairment at baseline (normal versus mild versus moderate)
o
Renal impairment status is determined by the baseline CrCl (calculated using 
the Cockcroft-Gault equation) (normal renal function: CrCl ≥90 mL/min versus 
mild renal impairment: CrCl ≥60, <90 mL/min versus moderate renal 
impairment: CrCl ≥30, <60 mL/min)
This subgroup analysis will also be conducted for the secondary endpoint comparing ORR in 
the HER2-expressing FAS, but the HER2 status by central lab will include IHC 2+/ISH – as 
an additional subgroup.
4.2.2.1
Best objective response
BoR will be summarised by number (%) for each category (confirmed CR, confirmed PR, SD, 
NED, PD and NE). The number (%) of patients with a single visit response (i.e., an 
unconfirmed response) will be presented. No formal statistical analyses are planned for BoR.
The BoR summaries will be presented for the ICR and investigator assessments for the 
HER2-positive FAS and the HER2-expressing FAS.
Concordance of BoR between ICR and investigator assessments will be summarised in a cross 
tabulation presenting the number (%) in each cell for the HER2-positive FAS only.
 
 


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4.2.3
Progression free survival
The treatment status at progression of patients at the time of analysis will be summarised. This 
will include the number (%) of patients who were on treatment at the time of progression, the 
number (%) of patients who discontinued study treatment prior to progression, the number 
(%) of patients who have not progressed and were on treatment or discontinued treatment. 
This will also provide a distribution of the number of days prior to progression for the patients 
who have discontinued treatment.
A Kaplan-Meier plot of PFS will be presented. A summary of the number and percentage of 
patients experiencing a PFS event and the type of event (RECIST 1.1 or death) will be 
provided along with the median PFS, upper and lower PFS quartiles, and corresponding 95% 
cIs, calculated using the Brookmeyer-Crowley method with log-log transformation 
(Brookmeyer & Crowley, 1982; Klein & Moeschberger, 1997).
The percentage of patients alive and progression-free at 3-monthly intervals from first dose 
(Kaplan-Meier estimates) will be presented along with 95% CI.
The duration of follow-up for censored patients will be presented (median, minimum and 
maximum) using time from date of enrolment to date of censoring. In addition, the number of 
days from last RECIST assessment (i.e. censoring date) to DCO will be summarised for 
censored patients.
The PFS summaries and plots will be presented for the ICR and investigator assessments for 
the HER2-positive FAS and the HER2-expressing FAS.
All of the collected RECIST 1.1 data will be listed for all enrolled patients. In addition, a 
summary of new lesions (i.e. sites of new lesions) will be produced.
4.2.4
Disease control rate
The DCR will be estimated and presented with the corresponding exact 95% Clopper-Pearson 
CI at each DCO, for both ICR and investigator assessments.
DCR at 12 weeks (as defined in Section 3.2.3) will also be summarised.
The number and percentage of patients meeting the definition of disease control will be 
presented for both the ICR and the investigator assessments.
These summaries for DCR will be presented for the HER2-positive FAS and the HER2-
expressing FAS.


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4.2.5
Duration of response
Kaplan-Meier plots of DoR will be presented. Median DoR will also be summarised 
calculated from the KM curve, and its corresponding 95% CI, calculated using the 
Brookmeyer-Crowley method with log-log transformation (Brookmeyer & Crowley, 1982; 
Klein & Moeschberger, 1997). Only patients who have a confirmed complete response or 
confirmed partial response will be included in this summary table. Swimmer plots that clearly 
show the profile of each patient who responds may also be produced.
Duration of response summaries will be presented for both the ICR and investigator 
assessments, for the HER2-positive FAS and the HER2-expressing FAS.
4.2.6
Tumour size change
The best change in TL tumour size from baseline (where best change in TL size is the 
maximum reduction from baseline or the minimum increase from baseline in the absence of a 
reduction) will also be summarised. The number and percentage of patients whose best 
percentage change data is imputed will also be presented.
Tumour size may also be presented graphically using waterfall plots, to present each patient’s 
best percentage change in TL tumour size as a separate bar, with the bars ordered from the 
largest increase to the largest decrease. Reference lines at the -30% and 20% change in TL 
tumour size level will be added to the plots, which corresponds with the definition of ‘partial 
response’ and ‘progressive disease’, respectively. All progressions will be marked with a ‘●’ 
or designated with patterns or colours for ORR categories. The scale in these plots will be 
fixed to be from -100 to 100 to avoid presenting extreme values. Values that are capped as a 
result of this restriction to the scale are marked with ‘#’. Values are ordered in descending 
order.
Additionally, a ‘spider’ plot will be produced. This depicts each patient’s percentage change 
in TL tumour size as a line over time and progression due to non-target and/or new lesions 
will be indicated. Reference lines at the -30% and 20% change in TL tumour size level will be 
added to the plots, which corresponds with the definition of ‘partial response’ and 
‘progressive disease’, respectively.
These summaries will be repeated for both the ICR and investigator assessments, for both the 
HER2-positive FAS and the HER2-expressing FAS.
4.2.7
Overall survival
A Kaplan-Meier plot will be presented for OS for the HER2-positive FAS. Summaries of the 
number and percentage of patients who have died, those still in survival follow-up, those lost 


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to follow-up and those who have withdrawn consent will be provided along with the median 
OS and corresponding 95% confidence interval, calculated using the Brookmeyer-Crowley 
method with log-log transformation (Brookmeyer & Crowley, 1982; Klein & Moeschberger, 
1997).
The percentage of patients alive at 3-monthly intervals (Kaplan-Meier estimates) will be 
presented along with 95% CI.
In addition, median duration of follow-up and range of follow-up (minimum – maximum) will 
be summarised where duration of follow-up is defined as time from enrolment to the date of 
death (i.e. overall survival) or to the date of censoring (date last known to be alive) for all 
patients and censored patients.
These summaries will be repeated for the HER2-expressing FAS.
4.2.8
PK
PK concentration data will be listed by patient and dosing day/time and will be tabulated using 
summary statistics for all patients in the PK analysis set.
Serum concentrations of T-DXd, total anti-HER2 antibody, and MAAA-1181a will be 
summarised by nominal sample time using standard summary statistics for PK concentrations 
geometric mean (calculated as exp [μ], where μ is the mean of the data on a logarithmic scale), 
geometric standard deviation (calculated as exp[standard deviation in log scale]), geometric 
coefficient of variation (calculated as 100 √ [exp(s2) - 1], where s is the standard deviation of 
the data on a log scale), arithmetic mean, standard deviation, minimum, median, maximum 
and n. All serum concentrations will be listed.
If the data are suitable, the relationship between PK exposure and efficacy/safety parameters 
may be investigated graphically or using an appropriate data modelling approach. The results 
of such an analysis, if conducted, will be reported in a separate report. The PK, 
pharmacodynamics, demographic, safety, and efficacy data collected in this study may also be 
combined with similar data from other studies and explored using population PK and/or 
PK-PD (pharmacokinetic-pharmacodynamic) methods.
Precision and Rounding Rules for Pharmacokinetic Data
For concentration data, the listings will be presented to the same number of significant figures 
as the data received from the bioanalytical laboratory. All descriptive statistics will be 
presented to 4 significant figures with the exception of the minimum and maximum which 


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will be presented to 3 significant figures, and n and n < LLOQ which will be presented as 
integers.
4.2.9
Immunogenicity
A summary of the number and percentage of patients who developed detectable ADA to 
T-DXd by ADA categories (see Section 3.5 for categories) will be presented based on the 
T-DXd ADA evaluable set.
Immunogenicity results of all patients in the SAF will be listed regardless of ADA evaluable 
status. ADA titre and neutralising antibody data will be listed for samples confirmed positive 
for the presence of T-DXd antibodies. AEs in ADA positive patients by ADA positive 
category will be listed.
The effect of ADA on PK, pharmacodynamics, efficacy, and safety will be evaluated, if the 
data allow.
4.2.10
Safety
Safety and tolerability data from all cycles of treatment will be combined. The SAF will be 
used for reporting of safety data. Safety summaries will be descriptive only. No formal 
statistical analyses will be performed on the safety variables.
4.2.10.1
Adverse events
All treatment emergent AEs (TEAEs) observed on or after the date of first dose until 40 (+ 7) 
days after the last dose of study treatment or until the initiation of the first subsequent anti-
cancer therapy following discontinuation of study treatment (whichever is earlier) and AEs 
with an onset prior to dosing that worsened in severity or seriousness during this period are 
included in the summaries. This will more accurately depict AEs attributable to study 
treatment only, as some AEs up to 40 (+7) days following discontinuation of the study 
treatment are likely to be attributable to subsequent therapy. Any other AEs will be flagged in 
the data listings but not included in the summaries. Any AE occurring before the first dose of 
study treatment which does not worsen during treatment, will be referred to as ‘pre-treatment’.
All AEs, both in terms of current MedDRA preferred term and CTCAE grade, will be 
summarised descriptively by count (n) and percentage (%).
Summary information (the number and percent of patients) by system organ class (SOC) 
and/or preferred term (PT) will be tabulated for:

All AEs


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
Most common AEs

All AEs possibly related to study treatment (*)

AEs by maximum reported CTCAE grade (*)

AEs with CTCAE grade 3 or higher (*)

AEs with CTCAE grade 3 or higher possibly related to study treatment

Most common AEs with CTCAE grade 3 or higher

AEs with outcome of death

AEs with outcome of death possibly related to study treatment

All SAEs (*)

All SAEs possibly related to study treatment

AEs leading to discontinuation of study treatment (*)

AEs leading to discontinuation of study treatment, possibly related to study treatment 

AEs leading to dose interruption of study treatment (*) 

AEs leading to dose interruption of study treatment, possibly related to study treatment

AEs leading to dose reduction of study treatment (*) 

AEs leading to dose reduction of study treatment, possibly related to study treatment

AEs leading to hospitalisation
An overview of AEs will be presented, including the number and percentage of patients in 
each of the categories above as well as the number and percentage of patients with dose 
modifications of study treatment (including discontinuation, interruption and/or reduction)
The MedDRA dictionary (latest or current version) will be used for coding.
Summary information (the number and percent of patients) by Grouped Term will be 
presented for those categories marked with (*) for the following Grouped Terms: abdominal 
pain, anemia, lymphopenia, neutropenia, thrombocytopenia, stomatitis, leukopenia, upper 


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respiratory tract infection, headache, rash, fatigue, transaminases increased, hypokalemia, 
musculoskeletal pain, skin hyperpigmentation, blood bilirubin increased and vision blurred. 
Note that this list may be modified after review of the data. An additional overview table will 
be presented, tabulating the number and percentages of patients who experience the AE 
alongside the worst outcome experienced (as a percentage of the number reporting that AE),
median time to onset and the duration of the first occurrence of that AE. Included in this table 
will be the Grouped Terms mentioned previously with the following selected preferred terms: 
constipation, decreased appetite, diarrhoea, febrile neutropenia, nausea and vomiting. 
For the AE tables of most common AEs, all events will be summarised by preferred term, by 
decreasing frequency. A cut-off may be applied after review of the data for the CSR. When 
applying a cut-off (e.g., 5%), the raw percentage should be compared to the cut-off, no 
rounding should be applied first (i.e., an AE with frequency 4.9% will not appear if the cut-off 
is 5%).
An additional AE summary will be presented for pre-treatment AEs and AEs which started 
more than 47 days after last dose of study treatment or after the start of subsequent anti-cancer 
therapy.
All reported AEs will be listed along with the date of onset (including study day), date of 
resolution (if AE is resolved), investigator’s assessment of CTCAE grade and relationship to 
study drug. If an AE has changes in CTCAE grade, the maximum value will be presented. A 
separate listing will be created for pre-treatment AEs.
Frequencies and percentages of patients reporting each PT will be presented (i.e. multiple 
events per patient will not be accounted for apart from on the episode level summaries which 
may be produced).
Adverse events of special interest
ILD/pneumonitis and LVEF decrease are considered to be AESIs (see Section 3.3.3 for 
details). AESI categories will be summarised separately unless otherwise specified. 
Potential ILD/pneumonitis (AESI-defined ILD cases identified based on MedDRA preferred 
terms) will be adjudicated by the ILD Adjudication Committee as follows:

Adjudicated as ILD/pneumonitis
o
Adjudicated as drug-related ILD/pneumonitis
o
Adjudicated as not drug-related pneumonitis


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
Adjudicated as not ILD/pneumonitis

Unable to adjudicate due to insufficient information
A summary of all potential ILD events that were submitted to the ILD adjudication committee 
for adjudication will be provided and categorised as above. Maximum CTCAE grade per 
adjudication committee will also be summarised for the events adjudicated as ILD 
(drug-related/not drug-related). For events unable to be adjudicated due to insufficient 
information, the maximum CTCAE grade per investigator assessment will be summarised.
Summaries of ILD/pneumonitis events will be primarily based on adjudicated drug-related 
ILD events from the ILD adjudication committee. For adjudicated ILD events, summaries of 
causality and CTCAE grading are as determined by the ILD Adjudication Committee.
For LVEF decrease, categories will be based on preferred terms provided by the patient safety 
team prior to database lock. All preferred terms provided by the patient safety team will be 
listed and the listing will identify those present in the study.
The number (%) of patients who have at least one AESI, at least one AESI causally related to 
study treatment, at least one AESI of grade 3 or higher, at least one serious AESI, at least one 
AESI with outcome of death, at least one AESI leading to discontinuation of study treatment, 
at least one AESI leading to drug interruption and at least one AESI leading to dose reduction 
will be presented.
A summary table of AESIs will be produced for each AESI category, sub-category (if 
applicable) and preferred term by maximum CTCAE grade.
Key patient information for each AESI occurrence will be listed.
Adverse events with confirmed/suspected COVID-19 infection 
Summary information (the number and percent of patients) by COVID-19 Preferred Terms
will be tabulated for all TEAEs with confirmed/suspected COVID-19 infection. An overview 
of TEAEs with confirmed/suspected COVID-19 infection will be presented, including the 
number and percentage of patients in each of the categories listed above. Key subject 
information for each and all AEs with confirmed/suspected COVID-19 infection will be listed.
Deaths
A summary of all deaths will be provided with the number and percentage of patients 
categorised as based on the ITT analysis set:


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
Total number of deaths (regardless of date of death)

Death related to disease under investigation only as determined by the investigator

SAE with outcome of death only
o
Sub-category: SAE with outcome of death only and onset date > 47 days 
following last dose of study treatment (*)

Death related to disease under investigation, as determined by the investigator, and AE 
with outcome of death
o
Sub-category: Primary cause of death due to AE.

Other deaths
This summary will be repeated for all deaths on treatment (considered within the period from 
first dose of study treatment to 47 days after the last dose of study treatment). The category 
marked (*) will not appear in this summary.
4.2.10.2
Exposure
Exposure will be listed and summarised for the SAF. The following summaries will be 
produced:

Total exposure

Actual exposure

Summary statistics (mean, standard deviation, median, quartiles, minimum and 
maximum) of RDI

Summary of dose infusion interruptions, reductions and cycle delays

Number of treatment cycles.
4.2.10.3
Vital signs
Summaries of vital signs data will include all data obtained until 47 days after the last dose of 
study treatment. Absolute values and change from baseline for diastolic and systolic BP, pulse 
rate, respiratory rate, temperature and body weight will be summarised at each visit. The 
denominator in vital signs data should only include those patients with recorded data.


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4.2.10.4
ECGs
ECG data obtained up until 47 days after the last dose of study treatment will be included in 
the summaries. Absolute values and change from baseline for ECG heart rate, PR interval, 
QRS duration, QT interval, and RR interval will be summarised at each visit.
Overall evaluation of ECG is collected in terms of normal or abnormal, and the relevance of 
the abnormality is termed as “clinically significant” or “not clinically significant”. ECG 
evaluations will be summarised using a shift table of baseline to worst evaluation on-treatment 
during the study.
4.2.10.5
Laboratory measurements
Laboratory data obtained up until 47 days following the last dose of study treatment or until 
the initiation of the first subsequent anti-cancer therapy following discontinuation of study 
treatment (whichever occurs first) will be included in the summary tables.
All laboratory data will be listed. Flags will be applied to values falling outside reference 
ranges.
Absolute values and change from baseline for all continuous haematology and clinical 
chemistry laboratory parameters will be summarised by visit.
Scatter plots (shift plots) of baseline to maximum/minimum value (as appropriate) on 
treatment may be produced for certain parameters if warranted after data review. 
Box-plots of absolute values by week, and box-plots of change from baseline by week, may be 
presented for certain parameters if warranted after data review.
Shift tables for laboratory values by worst CTCAE grade will be produced and for specific 
parameters separate shift tables indicating hyper- and hypo-directionality of change will be 
produced. The laboratory parameters for which CTCAE grade shift outputs will be produced 
are:

Haematology: Haemoglobin, platelet count, leukocytes (absolute count), differential 
leukocytes count (neutrophils, lymphocytes)

Clinical chemistry: serum creatinine, total bilirubin, albumin, alkaline phosphatase 
(ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), corrected 
calcium (Ca) (hypo- and hyper-), potassium (K) (hypo- and hyper-), sodium (Na) 
(hypo- and hyper-), magnesium (hypo- and hyper-) and glucose 

Coagulation: activated partial thromboplastin time (aPTT).


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For the parameters with no CTCAE grading that are listed in the CSP, shift tables from 
baseline to worst value on treatment will be provided if there are abnormal results. Additional 
summaries will include a shift table for categorical urinalysis parameters comparing baseline 
value to maximum value.
The denominator used in laboratory summaries of CTCAE grades will only include evaluable 
patients. If a CTCAE criterion involved a change from baseline, evaluable patients are those 
who have both a pre-dose and at least 1 post-dose value recorded. If a CTCAE criterion does 
not consider changes from baseline. Evaluable patients are those who have at least 1 post-dose 
value recorded.
Hy’s Law
The following summaries will include the number (%) of patients who have:

Elevated ALT, AST, and Total bilirubin during the study
o
ALT ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, and >20x upper limit of 
normal (ULN) during the study.
o
AST ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, and >20x ULN during 
the study.
o
Total bilirubin >1.5 – ≤2x, >2x – ≤3x, >3x – ≤5x, >5x ULN during the study.
o
ALT or AST ≥3x – ≤5x, >5x – ≤8x, >8x – ≤10x, >10x – ≤20x, >20x ULN 
during the study.
o
Potential Hy’s Law: ALT or AST ≥3x ULN and total bilirubin ≥2x ULN 
during the study, irrespective of an increase in ALP: the onset date of ALT or 
AST elevation should be prior to or on the date of total bilirubin elevation.
Narratives may be provided in the CSR for patients who have ALT ≥3x ULN plus total 
bilirubin ≥2x ULN or AST ≥3x ULN plus total bilirubin ≥2x ULN at any visit.
Liver biochemistry test results over time for patients with elevated ALT (i.e. ≥3x ULN) or 
AST (i.e. ≥3x ULN), and elevated total bilirubin (i.e. ≥2x ULN) (at any time during treatment) 
will be plotted. Individual patient data where ALT or AST plus total bilirubin are elevated at 
any time will be listed also.
Plots of maximum post-baseline ALT and AST vs. maximum post-baseline total bilirubin, 
expressed as multiples of ULN, will also be produced with reference lines at 3×ULN for ALT 


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and AST, and 2×ULN for Total bilirubin. In each plot, total bilirubin will be in the vertical 
axis.
4.2.10.6
WHO/ECOG performance status
All WHO/ECOG performance status data will be listed. A shift table will be presented, from 
baseline to worst evaluation during treatment.
4.2.10.7
Pulmonary assessments
SpO2 will be summarised for each visit.
4.2.10.8
Eligible HBV infection
A summary of patients with Hepatitis B at baseline will be presented, as well as a summary of 
first on-study reactivation for patients with reactivation. Hepatitis B reactivation will also be 
listed, including time to principal investigator (PI) confirmation (including any repeating 
episodes [PI confirmations]), length of delay to treatment, duration on drug after restart, and 
RECIST assessments during the delay.
4.2.10.9
Other safety assessments
ECHO/MUGA scan results and ophthalmologic findings will be listed.
Summaries of data collected for suspected ILD/pneumonitis investigation may be presented in 
patient narratives.
A summary of baseline LVEF % will be presented, both continuous and categorical (see 
Section 3.3.9.1). 
 
 
 Absolute value and change from 
baseline for the minimum LVEF value post-baseline will be presented, both continuous and 
categorical (see Section 3.3.9.1).
4.2.11
Demographics and baseline characteristics
The following will be summarised and/or listed for all patients in the HER2-positive FAS and 
the ITT analysis set (as appropriate):

Patient disposition (including screening failures and reason for screening failure)

Important protocol deviations

Inclusion in analysis sets


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
Demographics (age, age group[<50, ≥ 50 - < 65, ≥ 65 - < 75 and ≥ 75 years], sex, race 
and ethnicity)

Patient characteristics at baseline (height, weight, weight group, BMI group)

Patient recruitment by centre

Previous disease-related treatment modalities

Prior systemic therapy lines

Disease characteristics at baseline (ECOG performance status, primary tumour 
location, histology type, tumour grade, AJCC stage, time from diagnosis to start of 
study treatment and overall disease classification)

Extent of disease at baseline

TNM classification at baseline

Disease related medical history (past and current)

Relevant surgical history

Post-discontinuation cancer therapy

Nicotine use, categorised (never, current, former)

Pulmonary function test at baseline

Pulmonary medical history

Baseline HER2 status (IHC/ISH) from local and central testing.

Sum of diameters at baseline based on ICR
The medications will be coded using the latest version of MedDRA.
4.2.12
Concomitant and other treatments
Information on any treatment within the four weeks prior to initiation of study drug and all 
concomitant treatments given up to 47 days after discontinuation of study treatment, or 
objective disease progression (whichever is later), with reasons for the treatment, will be 


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recorded in the eCRF. Thereafter, only subsequent regimens of anti-cancer therapy will be 
recorded in the eCRF.
Other anti-cancer therapies, investigational agents, and radiotherapy should not be given while 
the patient is on study drug.
Medications received prior to, concomitantly, or post-treatment will be coded using the 
AstraZeneca Drug Dictionary Anatomical Therapeutic Chemical (ATC) Classification codes. 
Concomitant medications will be summarised for the FAS, RES and ITT analysis set (as 
appropriate) by ATC classification codes.
The following summaries will be produced for the HER2-positive FAS and the ITT analysis 
set:

Summary of disallowed concomitant medications

Summary of allowed concomitant medications

Summary of post study treatment cancer therapies.
All concomitant and other treatment data will be listed.
4.2.13
COVID-19
Summaries of data relating to patients diagnosed with coronavirus 2019-nCoV (COVID-19), 
and the impact of COVID-19 on study conduct (in particular missed visits, delayed or 
discontinued study treatment, and other protocol deviations) may be generated, including:

Disposition (discontinued study treatment due to COVID-19 and withdrew study due 
to COVID-19) 

Deviations (overall deviations plus if due to COVID-19 and not due to COVID-19)

Summary of COVID-19 disruption (visit affected, drug affected, concomitant 
medication affected, or withdrew from study due to global/country situation)

Treatment impacted due to COVID-19 (number of cycles impacted, duration of 
impact).

Listing for patients affected by the COVID-19 pandemic.


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
Listing for patients with reported issues in the Clinical Trial Management System due 
to the COVID-19 pandemic.
Additional summaries and sensitivity analyses may be conducted to investigate the impact of 
COVID-19 on study endpoints. In these sensitivity analyses, any patient who had a death with 
primary or secondary cause as COVID-19 infection will be censored at their COVID-19 
infection death date. COVID-19 deaths will be identified by primary/secondary cause of 
death.
4.2.14
 
 
 
 
5
6
CHANGES OF ANALYSIS FROM PROTOCOL
Supplementary analyses based on the RES will only be presented for confirmed ORR by ICR, 
for both the HER2-positive RES and the HER2-expressing RES.
An additional analysis of best overall response will be conducted, including unconfirmed 
response (PR and CR) as a response. 
 
No sensitivity analyses will be performed for PFS or OS. 
SAEs which onset or worsen after the end of safety follow-up and are considered to be related 
to the study treatment will not be defined as treatment emergent AEs.
7
REFERENCES
Brookmeyer, R., & Crowley, J. A. (1982). Confidence Interval for the Median Survival Time. 
Biometrics, 38:29-41.


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Klein, J., & Moeschberger, M. (1997). Survival Analysis: Techniques for Censored and 
Truncated Data. New York: Springer-Verlag.
8
APPENDIX
Not applicable.