An Open-label, Single-arm, Phase 2 Study to Evaluate the Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) for Patients With HER2-mutant Metastatic NSCLC Who Have Disease Progression on or After at Least One-line of Treatment (DESTINY-Lung05)
Phase: PHASE2
Conditions: HER2-mutant Non-Small Cell Lung Cancer
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention
Trastuzumab deruxtecan 
(T-DXd, DS-8201a)
Study Code
D7811C00001
Version
2.0
Date
24 Feb 2022
An Open-label, Single-arm, Phase 2 Study to Evaluate the 
Efficacy and Safety of Trastuzumab Deruxtecan (T-DXd) for 
Patients with HER2-mutant Metastatic NSCLC who have Disease 
Progression on or after at Least One-line of Treatment 
(DESTINY-Lung05)
Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
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: D7811C00001
Amendment Number: 01
Study Intervention: Trastuzumab deruxtecan (T-DXd)
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 2
Short Title: Phase 2 study of the Efficacy and Safety of Trastuzumab Deruxtecan for Patients 
with HER2-mutant Metastatic NSCLC who have Disease Progression on or after at least 
One-line of Treatment
Acronym: DESTINY-Lung05
Study Physician Name and Contact Information will be provided separately
National Co-ordinating Investigator
Employed by
 
 (the “Principal Investigator”)
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 1 (Version 2.0)
24 Feb 2022
Original Protocol (Version 1.0)
13 July 2021
Amendment 1 (24 Feb 2022)
Overall Rationale for the Amendment:
 
 
 
 
Additional changes implemented in this protocol amendment relate to updates or clarification 
to eligibility criteria, study assessments and dosing. The rationale for each of these changes is 
provided in the table below.
Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
Section 1.1 Synopsis
Section 1.2 Schema
Section 1.3 Schedule 
of Activities Table 1
Section 4.1 Overall 
Design
Section 5.1 Inclusion 
Criteria
Section 8.1.3 
Mandatory Tumour 
Tissue Sample
Section 8.6.1 
Collection of 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial
CCI
CCI
CCI

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
Mandatory Samples 
for Biomarker 
Analysis
Appendix L List of 
Qualifying Activating 
HER2 exon 19 and 20 
Mutations
Section 1.1 Synopsis
Section 1.2 Schema
Section 4.1 Overall 
Design
Section 9 Statistical 
considerations
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial
Section 1.3 Schedule 
of Activities Table 1
Section 8.1.4 
 
 
Section 8.6.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Substantial
CCI
CCI
CCI
CCI
CCI
CCI

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
 
Section 1.3 Schedule 
of Activities
Section 6.6 Dose 
Modification
Appendix K Toxicity 
Management 
Guidelines
Deleted 49 day 
discontinuation criteria, 
updated as 126 days to 
be the time frame for 
discontinuation, the 
criteria for drug 
resuming is added 
To allow longer time 
frame for drug 
discontinuation and 
alignment with current 
project safety 
requirements
Substantial
Section 1.3 Schedule 
of Activities Table 1
Clarification of timing 
of the Haematology and 
Clinical Chemistry 
assessments in footnote 
“d”.
Alignment with current 
project safety 
requirements
Non-substantial
Section 1.3 Schedule 
of Activities Table 1
Deleted the “d” for 
WHO/ECOG PS
Clarification of the 
timing of WHO/ECOG 
assessment
Non-substantial
Section 1.3 Schedule 
of Activities Table 1 
Addition of required 
parameters of 
Coagulation test at 
screening, including 
addition of new 
footnote “f”
Alignment with current 
project safety 
requirements
Non-substantial
Section 1.3 Schedule 
of Activities Table 1 
Section 6.6 Dose 
Modification
Section 8.2.3 
Electrocardiograms
Addition of C1D1 
timepoint of triplicate 
ECG testing, 
clarification of the 
timepoint of 
ECHO/MUGA scan 
assessments
Alignment with current 
project safety 
requirements
Non-substantial
Section 1.3 Schedule 
of Activities Table 1
Clarification of PFT, 
HRCT and 
Ophthalmologic 
assessments,  including 
addition of new 
Alignment with current 
project safety 
requirements 
Non-substantial
CCI
CCI

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
footnotes “i”, “j” and 
“k”
Section 1.3 Schedule 
of Activities Table 1
Addition a note to 
clarify the brain scan at 
EoT for participants 
with brain metastases
Alignment with current 
project safety 
requirements
Non-substantial
Section 1.3 Schedule 
of Activities Table 1
Section 8.2.5.2 
Pulmonary 
Assessments
Amended to “DLCO is 
strongly encouraged”
Alignment with current 
project safety 
requirements
Non-substantial
Section 2.3.1.1 
Potential Risks of T-
Dxd
Deleted “asthenia” And 
“malaise” in other 
identified risks for T-
Dxd
Update to cover most 
Up to date safety 
information related to 
T-DXd 
Non-substantial
Section 2.3.1.1 
Potential Risks of T-
Dxd
Addition of participants 
with  severe renal 
impairment who has 
not been studied
Update to cover most 
up to date safety 
information related to 
T-DXd
Non-substantial
Section 5.1 Inclusion 
Criteria 2
Amended to state that 
participants must be 
≥18 years at the time of 
signing the ICF
Clarification of the 
timing of calculating 
age
Non-substantial
Section 5.1 Inclusion 
Criteria 5 and 6
Section 8.1.3 
Mandatory Tumour 
Tissue Sample
 
 
 
Non-substantial
Section 5.1 Inclusion 
Criteria 9
Addition of timing 
requirement of 
parameters tests
Alignment with current 
project safety 
requirements.
Non-substantial
Section 5.1 Inclusion 
Criteria 12
Deleted “such as 
5-fluorouracil-based 
agents, folinate agents, 
Alignment with current 
project requirements
Non-substantial
CCI
CCI

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
weekly paclitaxel”
Section 5.1 Inclusion 
Criteria 12
Clarification of CART 
and the washout period
Alignment with current 
project requirements
Non-substantial
Section 5.1 Inclusion 
Criteria 15
Clarification the 
starting timepoint of 
Refraining from 
fathering a child, or 
freezing or donating 
sperm
To align with current 
project level text and 
To provide clarity
Non-substantial
Section 5.2 Exclusion 
Criteria 2
Clarification of 
participants with CNS 
metastases must have 
previously completed 
local therapy
Alignment with context 
and clarification of the 
requirement of previous 
local therapy for 
participants with CNS 
metastases
Non-substantial
Section 5.2 Exclusion 
Criteria 11
Clarification of the 
eligibility of 
participants with past or 
resolved hepatitis B 
virus (HBV) infection
Alignment with current 
project requirements
Non-substantial
Section 5.2 Exclusion 
Criteria 11
Addition of one 
example of serologic 
evidence of viral 
infection
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 5.2 Exclusion 
Criteria 12
Clarification of 
“mRNA and replication 
deficient adenoviral 
vaccines are not 
considered attenuated 
live vaccines”
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 5.2 Exclusion 
Criteria 14
Clarification of chronic 
stable Grade 2 toxicity 
To align with current 
project level text and to 
provide clarity
Non-substantial

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
Section 5.3 Lifestyle 
Considerations
Addition of 
requirement of donate 
Or retrieve ova, 
breastfeeding for 
female patients
To align with current 
project level text and 
To provide clarity
Non-substantial
Section 6.2.1 T-DXd 
Preparation, 
Administration and 
Storage
Added that the 
preparation, handling, 
storage, and 
administration 
instructions for T-DXd 
will follow the IP 
handling instructions
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 6.2.1 T-DXd 
Preparation, 
Administration and 
Storage
Clarification of dose 
calculation method 
based on weight 
To align with current 
project level text and to 
provide clarity 
Non-substantial
Section 6.5.1 
Prohibited 
Concomitant 
Medications
Addition of one 
example of 
bronchodilators
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 6.6 Dose 
Modification
Clarification of 
potential 
ILD/pneumonitis 
review
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 7.1 
Discontinuation of 
Study Intervention
Clarified that subjective 
disease progression was 
one of the treatment 
discontinuation criteria
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 7.1 
Discontinuation of 
Study Intervention
Clarification of
definition of EoT and 
EoT assessment when 
EoT is > 40 days (+ 7 
days) after last 
treatment 
To align with current 
project level text and to 
provide clarity
Non-substantial

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
Section 7.1 
Discontinuation of 
Study Intervention
Clarification of
continuation on Study 
Intervention After 
CNS-only Progression
and added one new 
section 7.1.3
To align with current 
project level text and to 
provide clarity
Non-substantial
Section 8.2.3 
Electrocardiograms
Amended to 
supine/semi-recumbent 
position when 
conducting ECG test
Alignment with current 
project requirements
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments Table 10
Amended to “INR or 
PT and either PTT or 
aPTT” including add 
new footnote “c”
Alignment with current 
project requirements 
and context
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments Table 10
Deleted leukocyte 
count and serum 
creatinine
Duplicated
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments Table 10
Addition of Calcium 
and Urea
Addition of options to 
conduct required tests 
Non-substantial
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
Section 8.3 Adverse 
Events and Serious 
Adverse Events
Appendix D Actions 
Required in Cases of 
Increases in Liver 
Biochemistry and 
Evaluation of Hy’s 
Law
Appendix K Toxicity 
Management 
Guidelines
Amended to “TBL ≥2 
× ULN”
Alignment with current 
project requirements
Non-substantial

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
Section 8.6.1.1
Mandatory Tumour 
Tissue Samples
Based on the 
requirement of 
Laboratory Manual
Non-substantial
Section 8.6.1 
Collection of 
Mandatory Samples 
for Biomarker 
Analysis
Clarification of handing 
of human biological 
samples with addition 
of one new section 
8.6.1.3
Clarification of handing 
of human biological 
samples align with 
context
Non-substantial
Section 9.4.2.2.6
“If calculable” is 
added to the providing 
of estimate of median 
OS and corresponding 
95%CI.
Updated in cases if 
median OS and 
corresponding 95%CI 
is not calculable.
Non-substantial
Section 9.4.2.2.7
Analysis of CNS-PFS 
updated to use 
appropriate Descriptive 
statistics based on 
Kaplan-Meier estimates
To ensure appropriate 
descriptive statistics is 
reported if the CNS-
PFS events is relatively 
low.
Non-substantial
Section 9.6.1 ILD 
Adjudication 
Committee
Clarification of data 
collection will be 
triggered for adverse 
events reported based 
on a set of pre-defined 
list of PTs eligible for 
adjudication as 
described by the Event 
Adjudication Site 
Manual
Alignment with current 
project requirements 
and context
Non-substantial
Appendix E 
Guidelines for 
Evaluation of 
Objective Tumour 
Response Using 
RECIST 1.1 Criteria 
Deleted IV contrast-
enhanced CT or MRI of 
the head and neck
Alignment with current 
project requirements 
and context
Non-substantial
CCI

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
(Response Evaluation 
Criteria in Solid 
Tumours)
Appendix L
 
 
 
 
Duplicated
Non-substantial
Section 5.3 Lifestyle 
Considerations
Section 6.5.1 
Prohibited 
Concomitant 
Medications
Section 6.6 Dose 
Modification
Section 8.2 Safety 
Assessments
Section 8.3 Adverse 
Events and Serious 
Adverse Events
Section 8.6.1.1 
Screening Tumour 
Tissue Samples
Appendix D Actions 
Required in Cases of 
Increases in Liver 
Biochemistry and 
Evaluation of Hy’s 
Law 
Appendix E 
Guidelines for 
Evaluation of 
Objective Tumour 
Response Using 
RECIST 1.1 Criteria 
Minor editorial changes To align with current 
project level text and to 
provide clarity
Non-substantial
CCI
CCI

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Section # and Name
Description of Change Brief Rationale
Substantial/Non-
substantial
(Response Evaluation 
Criteria in Solid 
Tumours)
Appendix F 
Contraception 
Requirements
Appendix G 
Concomitant 
Medications
Appendix J Guidance 
for Management of 
Participants with Drug 
induced 
ILD/Pneumonitis
Appendix K Toxicity 
Management 
Guidelines
Appendix M 
Abbreviations
Appendix L list of 
Qualifying Activating 
HER2 exon 19 and 20 
Mutations Table 25

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS .................................................................................................... 13
LIST OF FIGURES ............................................................................................................ 16
LIST OF TABLES .............................................................................................................. 16
1
PROTOCOL SUMMARY ................................................................................ 18
1.1
Synopsis ........................................................................................................... 18
1.2
Schema............................................................................................................. 22
1.3
Schedule of Activities ....................................................................................... 23
2
INTRODUCTION............................................................................................ 32
2.1
Study Rationale ................................................................................................ 32
2.2
Background ...................................................................................................... 33
2.2.1
Background on HER2-mutant NSCLC.............................................................. 33
2.2.2
Relevance of HER2-mutant NSCLC ................................................................. 36
2.2.3
Therapies in mNSCLC and HER2-mutant mNSCLC ........................................ 36
2.3
Benefit/Risk Assessment................................................................................... 43
2.3.1
Risk Assessment ............................................................................................... 43
2.3.1.1
Potential Risks of T-DXd .................................................................................. 43
2.3.1.2
Potential Risks of HER2-targeted Agents.......................................................... 45
2.3.1.3
Potential Risks of Topoisomerase I Inhibitors.................................................... 46
2.3.2
Benefit Assessment........................................................................................... 46
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 46
3
OBJECTIVES AND ENDPOINTS................................................................... 48
4
STUDY DESIGN ............................................................................................. 50
4.1
Overall Design.................................................................................................. 50
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 50
4.2
Scientific Rationale for Study Design ............................................................... 51
4.2.1
Rationale for Study Design ............................................................................... 51
4.2.2
Rationale for T-DXd in HER2-mutant Metastatic NSCLC................................. 51
4.2.3
Rationale for Study Endpoints .......................................................................... 53
4.3
Justification for Dose........................................................................................ 53
4.3.1
PK Comparability Between Metastatic Breast Cancer and Metastatic NSCLC .. 53
4.3.2
Efficacy Comparison Between Metastatic Breast Cancer and Metastatic 
NSCLC............................................................................................................. 55
4.3.3
Safety Comparison Between Metastatic Breast Cancer and Metastatic NSCLC. 56
4.3.4
Summary .......................................................................................................... 57
4.4
End of Study Definition.................................................................................... 57
5
STUDY POPULATION.................................................................................... 57
5.1
Inclusion Criteria .............................................................................................. 58

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5.2
Exclusion Criteria ............................................................................................. 61
5.3
Lifestyle Considerations ................................................................................... 64
5.3.1
Meals and Dietary Restrictions ......................................................................... 64
5.3.2
Tobacco ............................................................................................................ 64
5.4
Screen Failures ................................................................................................. 64
6
STUDY INTERVENTION ............................................................................... 65
6.1
Study Intervention(s) Administered................................................................... 65
6.1.1
Investigational Products.................................................................................... 65
6.1.1.1
Duration of Treatment....................................................................................... 66
6.1.1.2
Treatment Beyond Progression: CNS-only Progression..................................... 66
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 67
6.2.1
T-DXd Preparation, Administration and Storage ............................................... 67
6.3
Measures to Minimise Bias............................................................................... 69
6.4
Study Intervention Compliance......................................................................... 71
6.5
Concomitant Therapy........................................................................................ 71
6.5.1
Prohibited Concomitant Medications ................................................................ 72
6.5.2
Other Protocol Restrictions or Supportive Treatments....................................... 73
6.6
Dose Modification ............................................................................................ 74
6.7
Intervention After the End of the Study............................................................. 77
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 77
7.1
Discontinuation of Study Intervention............................................................... 77
7.1.1
Follow-up of Participants Post-discontinuation of Study Intervention ............... 78
7.1.2
Follow-up for Survival...................................................................................... 79
7.1.3
Continuation on Study Intervention After CNS-only Progression...................... 79
7.2
Participant Withdrawal from the Study.............................................................. 80
7.3
Lost to Follow-up ............................................................................................. 81
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 82
8.1
Efficacy Assessments........................................................................................ 83
8.1.1
Imaging Tumour Assessments........................................................................... 83
8.1.2
Central Reading of Scans.................................................................................. 84
8.1.3
Mandatory Tumour Tissue Sample.................................................................... 84
8.1.4
Mandatory Blood Sample for Plasma-based ctDNA HER2 Mutation Testing .... 85
8.1.5
Overall Survival................................................................................................ 85
8.2
Safety Assessments........................................................................................... 85
8.2.1
Physical Examinations...................................................................................... 86
8.2.2
Vital Signs ........................................................................................................ 86
8.2.3
Electrocardiograms........................................................................................... 87
8.2.4
Clinical Safety Laboratory Assessments............................................................ 87
8.2.5
Other Safety Assessments ................................................................................. 89
8.2.5.1
Echocardiogram/Multiple Gated Acquisition Scan ............................................ 89
8.2.5.2
Pulmonary Assessments.................................................................................... 89

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8.2.5.3
ILD/Pneumonitis Investigation ......................................................................... 90
8.2.5.4
WHO/ECOG Performance Status ..................................................................... 91
8.2.5.5
Ophthalmologic Assessments............................................................................ 92
8.3
Adverse Events and Serious Adverse Events..................................................... 92
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 92
8.3.2
Follow-up of AEs and SAEs ............................................................................. 93
8.3.3
Causality Collection.......................................................................................... 94
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 94
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 95
8.3.6
Hy’s Law.......................................................................................................... 95
8.3.7
Disease Progression.......................................................................................... 95
8.3.8
Disease Under Study......................................................................................... 96
8.3.9
New Cancers..................................................................................................... 96
8.3.10
Deaths .............................................................................................................. 96
8.3.11
Adverse Events of Special Interest.................................................................... 96
8.3.12
Safety Data to be Collected Following the Final DCO of the Study................... 97
8.3.13
Reporting of Serious Adverse Events................................................................ 98
8.3.14
Pregnancy......................................................................................................... 98
8.3.14.1
Maternal Exposure............................................................................................ 99
8.3.14.2
Paternal Exposure............................................................................................. 99
8.3.15
Medication Error............................................................................................. 100
8.4
Overdose ........................................................................................................ 100
8.5
Human Biological Samples............................................................................. 100
8.5.1
Pharmacokinetics............................................................................................ 101
8.5.1.1
Determination of Drug Concentration ............................................................. 101
8.5.2
Immunogenicity Assessments ......................................................................... 101
8.5.3
Pharmacodynamics......................................................................................... 101
8.6
Human Biological Sample Biomarkers ........................................................... 101
8.6.1
Collection of Mandatory Samples for Biomarker Analysis .............................. 101
8.6.1.1
Mandatory Tumour Tissue Samples ................................................................ 102
8.6.1.2
Mandatory Blood Sample for Plasma-based ctDNA HER2 Mutation Testing .. 102
8.6.1.3
Handling of Human Biological Samples ......................................................... 102
9
STATISTICAL CONSIDERATIONS.............................................................. 103
9.1
Statistical Hypotheses..................................................................................... 103
9.2
Sample Size Determination............................................................................. 103
9.3
Populations for Analyses................................................................................. 104
9.4
Statistical Analyses ......................................................................................... 104
9.4.1
General Considerations................................................................................... 104
9.4.2
Efficacy .......................................................................................................... 106
9.4.2.1
Primary Endpoint(s)........................................................................................ 106
9.4.2.2
Secondary Endpoint(s).................................................................................... 107
9.4.2.3
Tertiary/Exploratory Endpoint(s) .....................................................................111
9.4.3
Safety ..............................................................................................................111
9.4.4
Other Analyses................................................................................................ 113

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9.4.4.1
Pharmacokinetics............................................................................................ 113
9.4.4.2
Biomarkers ..................................................................................................... 113
9.4.4.3
Immunogenicity Data...................................................................................... 113
9.5
Interim Analyses............................................................................................. 113
9.6
Data Monitoring Committee ........................................................................... 114
9.6.1
ILD Adjudication Committee.......................................................................... 114
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ...................................................................................... 115
11
REFERENCES............................................................................................... 172
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 22
Figure 2
Intact T-DXd and DXd Cycle 1 AUC Values for HER2-positive Patients 
with Breast Cancer or NSCLC Based on PopPK Analyses....................... 55
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 24
Table 2
Risk Assessment...................................................................................... 44
Table 3
Objectives and Endpoints......................................................................... 48
Table 4
T-DXd Efficacy and Safety Outcomes in HER2-mutant NSCLC per 
RECIST 1.1 (Study J101 and Study U204) Compared to China Studies... 52
Table 5
Cycle 1 PK Parameters (Mean ± Standard Deviation) of T-DXd at 
 Dose in HER2-positive or HER2-low Breast Cancer and 
HER2-expressing or -mutant NSCLC ...................................................... 54
Table 6
Parameters for Adequate Organ and Bone Marrow Function.................... 59
Table 7
Adequate Treatment Washout Periods ..................................................... 60
Table 8
Study Intervention ................................................................................... 65
Table 9
Dose Reduction Levels of T-DXd............................................................ 74
Table 10
Laboratory Safety Variables..................................................................... 88
Table 11
Spirometry Component............................................................................ 90
Table 12
Populations for Analysis ........................................................................ 104
Table 13 
Summary of Outcome Variables and Analysis Populations .................... 105
Table 14
Hy’s Law Laboratory Kit for Central Laboratories................................. 133
Table 15
Summary of Imaging Modalities for Tumour Assessment...................... 134
Table 16
RECIST 1.1 Evaluation of Target Lesions ............................................. 141
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Table 17
RECIST 1.1 Evaluation of Non-Target Lesions ..................................... 142
Table 18
RECIST 1.1 Overall Visit Response ...................................................... 143
Table 19
Highly Effective Methods of Contraception (<1% Failure Rate) ............ 147
Table 20
Restricted Medications Therapies .......................................................... 148
Table 21
Prohibited Medications/Therapies.......................................................... 149
Table 22
Supportive Medications/Therapies......................................................... 150
Table 23
COVID-19 Dose Modification Criteria .................................................. 153
Table 24
Toxicity Management Guidelines for T-DXd......................................... 158
Table 25
Study-qualifying Activating HER2 Exon 19 and 20 Mutations .............. 167
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 116
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 121
Appendix C
Handling of Human Biological Samples ................................................ 126
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 128
Appendix E
Guidelines for Evaluation of Objective Tumour Response Using 
RECIST 1.1 Criteria (Response Evaluation Criteria in Solid Tumours).. 134
Appendix F
Contraception Requirements.................................................................. 145
Appendix G
Concomitant Medications ...................................................................... 148
Appendix H
Instructions Related to COVID-19......................................................... 151
Appendix I
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 154
Appendix J
Guidance for Management of Participants with Drug-induced 
ILD/Pneumonitis ................................................................................... 156
Appendix K
Toxicity Management Guidelines .......................................................... 158
Appendix L
List of Qualifying Activating HER2 exon 19 and 20 Mutations ............. 166
Appendix M
Abbreviations ........................................................................................ 168

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: An Open-label, Single-arm, Phase 2 Study to Evaluate the Efficacy and Safety 
of Trastuzumab Deruxtecan (T-DXd) for Patients with HER2-mutant Metastatic NSCLC who 
have Disease Progression on or after at least One-line of Treatment (DESTINY-Lung05)
Short Title: Phase 2 study of the Efficacy and Safety of Trastuzumab Deruxtecan for Patients 
with HER2-mutant Metastatic NSCLC who have Disease Progression on or after at least 
One-line of Treatment
Rationale:
NSCLC is one of the leading causes of cancer-related mortality worldwide, accounting for 
approximately 18% of all cancer deaths. HER2 mutations have been identified in 
approximately 2% to 4% of NSCLC globally including China. 
Currently, there are no therapies specifically approved for patients with NSCLC whose 
tumours have a HER2 mutation (also referred to as HER2-mutant NSCLC). In the absence of 
an approved anti-HER2 therapy, treatment of patients with metastatic HER2-mutant NSCLC 
generally follows the treatment paradigm for those patients without an actionable mutation. 
For these patients, platinum-based chemotherapy combined with anti-PD-1 or anti-PD-L1 
targeted immunotherapy are typically given as the front-line treatment. 
 
 
 
Docetaxel 
or immunotherapy (if not used in the first-line) was recommended by the CSCO as the 
second-line therapy for these patients, although the efficacy is also limited. 
T-DXd (Enhertu®, DS-8201a) is a HER2-targeting ADC. T-DXd is being developed as a 
therapeutic candidate for the treatment of HER2-expressing tumours, as well as for solid 
tumours that exhibit somatic HER2 activating mutations including NSCLC. Clinical 
development of T-DXd in HER2-mutant NSCLC is supported by encouraging preliminary 
clinical efficacy data from 2 studies, Study DS8201 A-J101 (Phase 1) and 
Study DS8201-A-U204 (DESTINY-Lung01) (Phase 2). 
Considering the unmet medical need and that there are currently no approved therapies for 
patients with HER2-mutant NSCLC in China, and based on T-DXd nonclinical and clinical 
data, DESTINY-Lung05 is proposed as an opportunity to bring a novel HER2 targeted therapy 
to this patient population; adult patients with HER2-mutant mNSCLC, with disease 
progression on or after at least one-line of treatment. 
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Objectives
Endpoints
To evaluate the safety and tolerability 
of T-DXd.
Occurrence of TEAEs, SAEs and AESIs, physical examination 
findings, ECOG PS, vital sign measurements, standard clinical 
laboratory parameters, ECG parameters, ECHO/MUGA findings, and 
ophthalmologic findings.
ADA = anti-drug antibody; AESI = adverse event of special interest; BOR, best observed response; 
CNS-PFS = central nervous system progression-free survival; CR = complete response; DCR = disease 
control rate; DoR = duration of response; DXd = MAAA-1181a; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; 
HER2 = human epidermal growth factor receptor 2; ICR = independent central review; MUGA = multiple 
gated acquisition; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PK = pharmacokinetic(s); PopPK = population pharmacokinetic(s); 
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.
For tertiary/ exploratory objectives and endpoints, see Section 3 of the CSP. 
Overall Design
Disclosure Statement: This is a Phase 2, open-label, single-arm, multicentre study in China 
assessing the efficacy and safety of T-DXd in participants with metastatic non-squamous 
NSCLC whose tumours have a HER2 exon 19 or 20 mutation, with disease progression on or 
after at least one-line of treatment.
Participant Population:
The target population of interest in this study is participants with metastatic non-squamous 
NSCLC whose tumours have a HER2 exon 19 or 20 mutation, with disease progression on or 
after at least one-line of treatment. 
HER2 mutation for eligibility will be based on study qualifying activating HER2 exon 19 or 
20 mutation either from a pre-existing tissue test result obtained from qualified local 
laboratory/assay or have the tissue HER2 mutation test result detected prospectively in a 
central laboratory. Retrospective central confirmation will be performed for those enrolled 
based on existing local HER2 mutation(s) results during study. Note: In addition, mandatory 
archival (preferred) or newly collected tissue samples are required for central testing. Should 
discordance between local and central test be higher than anticipated, enrolment by local test 
may be closed. If a modification to not allow further enrolment of participants on the basis of 
a pre-existing HER2 mutation result is made, this change will be communicated to 
participating sites in a timely manner. Prospective analysis of HER2 mutation status of tumor 
tissue using central laboratory testing is encouraged.
Number of Participants:
 
 
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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 
CSP. 
Intervention Groups and Duration:
All participants will receive T-DXd at 
 
 Participants will continue to receive T-DXd until PD per RECIST 1.1 as 
assessed by the investigator, unless unacceptable toxicity, withdrawal of consent, or other 
criterion for withdrawal is met (with the exception of CNS-only progression; see note below). 
Note: For participants with objective radiological CNS-only progression (based on 
RECIST 1.1), who in the investigator’s opinion, continue to receive benefit from study 
intervention and meet the criteria for treatment in the setting of CNS-only progression may 
continue to receive study intervention on study for as long as they are gaining clinical benefit 
and are without any discontinuation criteria, until one of the criteria in Section 6.1.1.2 is met.
Tumour evaluation scans will be performed at screening (as baseline) with follow-ups at 
Week 6 (±1)-week intervals from the date of enrolment for 48 weeks, and then every 
9 (±1) weeks thereafter, starting at Week 57 until RECIST 1.1-defined radiological PD per 
investigator assessment (plus one additional follow-up scan [4 weeks later], if clinically 
feasible). In the case of CNS-only progression, participants continuing to receive study 
intervention should follow the on-treatment data collection schedule, including RECIST 1.1 
tumour assessments, until a second progression (CNS or body; plus one additional follow-up 
scan [4 weeks later], if clinically feasible). 
Intervention beyond RECIST 1.1-defined PD is not permitted in this study when the site of 
PD is outside of the CNS. In the setting of PD outside of the CNS, participant level 
risk-to-benefit ratio favours discontinuing treatment as participants are highly unlikely to 
derive clinical benefit post-progression and remain at risk of ILD and other toxicities if 
treatment is continued.
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 of discontinuation) and will be followed up for safety assessments 
40 (+ 7) 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 
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radiological progression, confirmed by investigator assessment, will be followed up with 
tumour assessments according to the SoA (Table 1) until RECIST 1.1-defined 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.
In addition, all participants will be followed up after intervention discontinuation 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 (ie, progression/survival follow-up), as per the SoA (Table 1).
See Section 6.7 for a description of assessments following DCO.
Statistical Methods
The primary endpoint of the study is confirmed ORR by ICR according to RECIST 1.1, 
defined as the number (percentage) of participants with confirmed CR or PR as assessed by 
ICR based on RECIST 1.1. ORR by ICR will be estimated with a 2-sided 95% exact CI based 
on the FAS who signed the ICF and were enrolled in the study.
The DCO for the primary analysis of ORR by ICR will occur approximately 6 months after 
the last participant has initiated study intervention. DoR, DCR, and available safety, 
immunogenicity, and 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 DS8201-A-U204, 
months is sufficient time for participants to reach a response 
(median time to response was 1.4 months) and to allow DoR to be determined for responders
(median confirmed DoR was 12 months). The full final analysis will report the analyses of all 
primary and secondary endpoints, including updated ORR and DoR, DCR, BOR, PFS, OS, 
CNS-PFS, PK, immunogenicity and safety.
Safety data will be summarised descriptively.
Sparse sampling of T-DXd PK will be performed in this study to enable PopPK analysis in the 
treated population with measurable serum concentrations of T-DXd. Summary of intact 
T-DXd, total anti-HER2 antibody and DXd concentrations by visit will also be provided. 
Immunogenicity will be evaluated in the T-DXd treated participants in this study.
1.2
Schema
Figure 1
Study Design
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Table 1
Schedule of Activities
Procedure
Screening
Intervention Period [Days or Weeks, etc]
Post-intervention Follow-up Period
Notes
Details in 
CSP 
section 
Treatment Cycle
C1
C2
C3
C4 and 
subseque
nt cycles 
until PD
EoT 
or 
E/D
Safety FU 
(40 + 7 days 
after last 
dose)
Progression/ 
survival FU 
(q3 months 
± 14 days)
Day
1
8 
15
1 
1
1
Window (± days)
-28 to -1 a
NA
± 1
± 1
± 2
± 2
± 2
+ 7
Informed consent b
X
5.1
Inclusion and exclusion criteria
X
5.1, 5.2
Demography
X
5.1
Full physical examination
X
8.2.1
Targeted physical examination
X c
X c
X c
X c
X
X
8.2.1
Height
X
8.2.1
Weight
X
X c 
X c
X c
X c
X
X
8.2.1
Medical history 
(includes substance usage)
X
X d
Substances: tobacco. 
Include history, type 
and frequency of 
tobacco use, 
e-cigarette use, and
vaping (including 
dates)
5.1, 5.2
Past and current medical 
conditions
X
X d
5.1, 5.2
WHO/ECOG PS
X
X c
X c
X c
X c
X
X
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Table 1
Schedule of Activities
Procedure
Screening
Intervention Period [Days or Weeks, etc]
Post-intervention Follow-up Period
Notes
Details in 
CSP 
section 
Treatment Cycle
C1
C2
C3
C4 and 
subseque
nt cycles 
until PD
EoT 
or 
E/D
Safety FU 
(40 + 7 days 
after last 
dose)
Progression/ 
survival FU 
(q3 months 
± 14 days)
Day
1
8 
15
1 
1
1
Window (± days)
-28 to -1 a
NA
± 1
± 1
± 2
± 2
± 2
+ 7
Serum/urine pregnancy test 
(WOCBP only) e
X
X
X
X
X
X
X
5.1, 5.2, 
8.2.4
Hepatitis B/C serology
X
5.2,
8.2.4
HIV antibody test (as required 
by local regulations or IEC)
X
5.2, 
8.2.4
Clinical safety laboratory 
assessments (clinical chemistry, 
haematology)
X
X c d
X
X
X c
X c
X c
X
X
8.2.4
Coagulation f
X
As clinically indicated
8.2.4
Urinalysis
X
As clinically indicated
8.2.4
Troponin
X
If at any time a participant reports signs or 
symptoms suggesting CHF, myocardial 
infarction, or other causes of myocyte necrosis
X
6.6, 
8.2.4
12-lead ECG
g
X
X c 
C5 (and
every 
4 cycles)
X
X
Before administration 
and if an abnormality 
is detected
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Table 1
Schedule of Activities
Procedure
Screening
Intervention Period [Days or Weeks, etc]
Post-intervention Follow-up Period
Notes
Details in 
CSP 
section 
Treatment Cycle
C1
C2
C3
C4 and 
subseque
nt cycles 
until PD
EoT 
or 
E/D
Safety FU 
(40 + 7 days 
after last 
dose)
Progression/ 
survival FU 
(q3 months 
± 14 days)
Day
1
8 
15
1 
1
1
Window (± days)
-28 to -1 a
NA
± 1
± 1
± 2
± 2
± 2
+ 7
ECHO or MUGA (LVEF)
g
X
C5 (and 
every 
4 cycles )
X
8.2.5.1
Vital signs h
X
X c
X
X
X c
X c
X c
X
X
8.2.2
SpO2 h
X
X c
X
X
X c
X c
X c
X
X
And if 
ILD/pneumonitis is 
suspected
8.2.5.2
Pulmonary function tests (PFT)
i
X
If ILD/pneumonitis is suspected
8.2.5.2
ILD/pneumonitis investigation
If ILD/pneumonitis is suspected
8.2.5.3
HRCT 
j
X
If ILD/pneumonitis is suspected
8.2.5.2
Ophthalmologic assessments 
k
X
As clinically indicated
X
8.2.5.5
 
 
 
X
8.1.3,
8.6
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Table 1
Schedule of Activities
Procedure
Screening
Intervention Period [Days or Weeks, etc]
Post-intervention Follow-up Period
Notes
Details in 
CSP 
section 
Treatment Cycle
C1
C2
C3
C4 and 
subseque
nt cycles 
until PD
EoT 
or 
E/D
Safety FU 
(40 + 7 days 
after last 
dose)
Progression/ 
survival FU 
(q3 months 
± 14 days)
Day
1
8 
15
1 
1
1
Window (± days)
-28 to -1 a
NA
± 1
± 1
± 2
± 2
± 2
+ 7
 
X
8.1.3, 
8.6
Pre-dose blood sample for 
T-DXd PK testing 
X
X
X
X 
(C4, 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 
(C4 only)
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 
(C1D1)
8.5.1
Additional blood sample for 
T-DXd PK testing (if feasible) 
If ILD/pneumonitis is suspected
8.2.5.3
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Table 1
Schedule of Activities
Procedure
Screening
Intervention Period [Days or Weeks, etc]
Post-intervention Follow-up Period
Notes
Details in 
CSP 
section 
Treatment Cycle
C1
C2
C3
C4 and 
subseque
nt cycles 
until PD
EoT 
or 
E/D
Safety FU 
(40 + 7 days 
after last 
dose)
Progression/ 
survival FU 
(q3 months 
± 14 days)
Day
1
8 
15
1 
1
1
Window (± days)
-28 to -1 a
NA
± 1
± 1
± 2
± 2
± 2
+ 7
Pre-dose blood sample for 
immunogenicity testing  
X
X
X (C4, 
then every 
4 cycles)
X
Take samples (within 
8 hours before 
infusion during 
intervention period) at 
time points indicated
8.5.2
AE m
X
At every visit and may be conducted by phone if 
not tied to a visit. 
X
X
8.3
Concomitant therapy including 
medication, surgery and 
radiation therapy 
X
At every visit and may be conducted by phone if 
not tied to a visit
X
X
6.5
Tumour imaging (RECIST 1.1) 
X
Every 6 weeks (±7 days) from the date of enrolment for 48 weeks and then every 
9 weeks (±7 days) thereafter, starting at Week 57, until RECIST 1.1-defined 
radiological PD. Plus an additional follow-up scan at least 4 weeks after 
RECIST 1.1-defined radiological PD if clinically feasible. n
8.1.1
Brain tumour imaging 
(RECIST 1.1) o
X
Participants with brain metastasis every 6 weeks (± 7 days) from the date of 
enrolment for 48 weeks and then every 9 weeks (±7 days) thereafter, starting at 
Week 57, until RECIST 1.1-defined radiological PD, or as needed based on 
neurological symptoms for all participants. p
8.1.1
Survival status
X
X 
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Table 1
Schedule of Activities
Procedure
Screening
Intervention Period [Days or Weeks, etc]
Post-intervention Follow-up Period
Notes
Details in 
CSP 
section 
Treatment Cycle
C1
C2
C3
C4 and 
subseque
nt cycles 
until PD
EoT 
or 
E/D
Safety FU 
(40 + 7 days 
after last 
dose)
Progression/ 
survival FU 
(q3 months 
± 14 days)
Day
1
8 
15
1 
1
1
Window (± days)
-28 to -1 a
NA
± 1
± 1
± 2
± 2
± 2
+ 7
Subsequent anticancer therapy
X
X
7.1.1
Any pre-existing tumour-
specific markers q
X
Study intervention administered 
(IV infusion) r
T-DXd at
 
6
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p
Brain imaging – MRI is preferred unless contraindicated. All participants will have brain scan at screening and EoT. In addition, participants with confirmed brain 
metastases will have brain scans, using the same modality as at baseline as part of each RECIST 1.1 tumour assessment visit, every 6 weeks (± 7 days) from the date of 
enrolment for 48 weeks and then every 9 weeks (±7 days) thereafter, starting at Week 57, until RECIST 1.1-defined radiological PD per investigator assessment (plus 
one additional followup scan [4 weeks later], if clinically feasible). All participants may be scanned (as needed) based on neurological symptoms or suspected brain 
metastases. Note: participants with brain metastases are not required to undergo an additional brain scan at EoT if the latest brain assessment was within 4 weeks of EoT or 
if they discontinue study intervention prior to RECIST 1.1-defined radiological progression per investigator.
q
Pre-existing HER2 mutation results assessed by local lab will be collected. Mutation status of any other tumour-specific markers (including EGFR, ALK, ROS 1, BRAF, 
NTRK MET, KRAS, RET or other driver mutation), and PD-L1 expression status collected by enquiry only (previously tested), no sample needed.
r
Every effort should be made to minimise the time between enrolment (confirmation of eligibility) and starting study intervention (ie, within 3 days). Participants should 
continue to receive T-DXd until PD per RECIST 1.1 as assessed by the investigator, unless unacceptable toxicity, withdrawal of consent, or other criterion for withdrawal 
is met. Participants with objective radiological CNS-only progression (based on RECIST 1.1), who in the investigator’s opinion, continue to receive benefit from study 
intervention and meet the criteria for treatment in the setting of CNS-only progression may continue to receive study intervention on study for as long as they are gaining 
clinical benefit and are without any discontinuation criteria, until one of the criteria in Section 6.1.1.2 is met.
Note: All assessments on treatment 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; ALK = anaplastic lymphoma kinase; BRAF = v-raf murine sarcoma viral oncogene homolog B1; C = cycle; CHF = congestive heart failure; CNS = central 
nervous system; CSP = Clinical Study Protocol; CT = computed tomography; D = day; DLCO = diffusion capacity of the lungs for carbon monoxide; ECG = electrocardiogram; 
ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; E/D = Early Study Intervention/Discontinuation; EGFR = epidermal growth factor receptor; 
EoT = End-of-Treatment; FEV = forced expiratory volume; FEV1 = FEV in 1 second; FEV6 = FEV in 6 seconds; FFPE = formalin-fixed and paraffin-embedded; FU = follow-
up; FVC = forced vital capacity; HER2 = human epidermal growth factor receptor 2; HIV = human immunodeficiency virus; HRCT = high-resolution computed tomography; 
IEC = Independent Ethics Committee; ILD = interstitial lung disease; IV = intravenous; KRAS = kirsten rat sarcoma 2 viral oncogene homolog; L = litres; LVEF = left 
ventricular ejection fraction; MET = MET proto-oncogene, receptor tyrosine kinase; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition; NA = not 
applicable; NTRK = neurotrophic receptor tyrosine kinase; PEF = peak expiratory flow; PD = progressive disease; PFT = pulmonary function test; PK = pharmacokinetic(s); 
PS = performance status; q3 = every 3; RECIST 1.1 = Response Evaluation Criteria in Solid Tumours, Version 1.1; RET = rearranged during transfection; ROS = ROS proto-
oncogene receptor tyrosine kinase; RV = residual volume; SAE = serious adverse event; SpO2 = pulse oximetry; T-DXd = trastuzumab deruxtecan; TLC = total lung capacity; 
WHO = World Health Organisation; WOCBP = women of childbearing potential. 

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2
INTRODUCTION
T-DXd is a HER2-targeting ADC in development as a candidate therapy for breast cancer and 
other tumour types including lung cancer. 
2.1
Study Rationale
NSCLC is one of the leading causes of cancer-related mortality worldwide, accounting for 
approximately 18% of all cancer deaths (Jemal et al 2011). HER2 mutations have been 
identified in approximately 2% to 4% of NSCLC globally including China (Arcila et al 2012, 
Mazieres et al 2013, Tomizawa et al 2011, Wei et al 2020). 
Currently, there are no therapies specifically approved for patients with NSCLC whose 
tumours have a HER2 mutation (also referred to as HER2-mutant NSCLC). In the absence of 
an approved anti-HER2 therapy, treatment of patients with metastatic HER2-mutant NSCLC 
generally follows the treatment paradigm for those patients without an actionable mutation. 
For these patients, platinum-based chemotherapy combined with anti-PD-1 or anti-PD-L1 
targeted immunotherapy are typically given as the front-line treatment. 
 
 
 
 
 
Docetaxel or immunotherapy (if not used in the first-line) was 
recommended by the CSCO as the second-line therapy for these patients, although the 
efficacy is also limited (CSCO 2020, NSCLC Guideline).
 
 
 
 
 
 
Considering the unmet medical need and that there are currently no approved therapies for 
patients with HER2-mutant NSCLC in China, and based on T-DXd nonclinical and clinical 
data, DESTINY-Lung05 is proposed as an opportunity to bring a novel HER2 targeted therapy 
to this patient population; adult patients with HER2-mutant mNSCLC, with disease 
progression on or after at least one-line of treatment. 
T-DXd is expected to be beneficial in a similar population to Study U204 in Chinese patients, 
given that the disease prevalence, progress and treatment practice for NSCLC are similar 
between China and Western countries, and that T-DXd is considered ethnically insensitive. 
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2.2
Background
A detailed description of the chemistry, pharmacology, mechanism of action, efficacy, and 
safety of T-DXd is provided in the T-DXd IB.
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. 
 
 
 
 
 
Due to incorporation of a novel linker, T-DXd achieves a higher 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 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 studies with T-DXd, either alone or in combination, 
across multiple HER2-expressing tumour types including breast cancer, gastric cancer, 
NSCLC, and colorectal cancer (please refer to the T-DXd IB for a list of completed and 
ongoing trials and most recent patient exposure data).
2.2.1
Background on HER2-mutant NSCLC
Lung cancer is the most common cancer, with an estimated 2.09 million new cases in 2018 
globally, and was also the most common cause of death from cancer in 2018, with 1.8 million 
deaths, 18.4% of the total cancer deaths (International Agency for Research on Cancer 2019). 
At the time of diagnosis, approximately 70% of patients with NSCLC already have advanced 
or metastatic disease not amenable to surgical resection (Bray et al 2018). The 5-year survival 
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rate for all NSCLC, independent of the stage, is 24%. For mNSCLC the 5-year survival rate is 
6% (American Cancer Society 2020, Howlader et al 2020).
NSCLC represent approximately 84% of all lung cancers (American Cancer Society 2021). 
The 2 predominant NSCLC histological phenotypes are adenocarcinoma (~50%) and 
squamous cell carcinoma (~40%) (Davidson et al 2013, Langer et al 2010).
Tobacco smoking remains the main cause of lung cancer and the geographics and patterns of 
the disease largely reflect tobacco consumption during the previous decades (Ordonez-
Mena et al 2016). An increase in the proportion of NSCLC in never-smokers has been 
observed, especially in Asian countries (Toh et al 2006). These new epidemiological data have 
resulted in ‘non-smoking-associated lung cancer’ being considered a distinct disease entity, 
where specific molecular and genetic tumour characteristics have been identified (Couraud et 
al 2015).
Recently, in-depth analyses of lung cancer genomes and signalling pathways have further 
defined NSCLCs as a group of distinct diseases with genetic and cellular heterogeneity 
(Chen et al 2014, Langer et al 2010). Recurrent mutations and amplifications in many 
potentially targetable oncogenes have since been identified in lung adenocarcinomas, 
including HER2 (also known as ERBB2), MET, FGFR1 and FGFR2, as well as fusion 
oncogenes involving ALK, the ROS1 receptor tyrosine kinase, NRG1, NTRK1 and RET14-22 
among others. Subtype analysis of NSCLC has come full circle now that EGFR, ALK, and 
ROS1 mutations are not only identifiable but their targeted treatment results in responses 
better than that with standard chemotherapy (Sholl 2015). Approximately 15% to 30% of 
non-Asian patients and 30% to 60% of Asian patients with adenocarcinoma have a mutation 
of the EGFR gene. The ALK gene mutations present in 2% to 7% of US patients with 
NSCLC; ROS1 rearrangements are identified in 1% to 2% of NSCLC patients (Bergethon et 
al 2012). The improved response to TKIs specific to these mutations has led the College of 
American Pathologists Guideline to recommend testing for EGFR and ALK mutations in all 
advanced-stage adenocarcinomas, mixed cancers, and those with NSCLC in whom an 
adenocarcinoma component cannot be excluded (Lindeman et al 2013). Patients without 
targetable mutations are currently receiving an immuno-based treatment based on their PD-L1 
status (Pabani and Butts 2018).
Despite advances in the diagnosis, imaging, staging and treatment of NSCLC, the estimated 
overall 5-year survival for patients continues to be low, being improved to approximately 16% 
in recent years (Pabani and Butts 2018) and the median PFS still less than 12 months even 
with the latest trial results from promising combinations (Gandhi et al 2018, Mok et al 2019,
Reck et al 2016).
HER2 alterations (mutation, gene amplification and protein overexpression) have been 
identified as a possible target in NSCLC, however there is currently an unmet medical need 

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for new treatment options to further improve outcomes.
In China in 2010, 605900 patients were diagnosed and 486600 patients died of lung cancer 
and the mortality of lung cancer has dramatically increased over the last 3 decades (Chen et al 
2015). The SoC treatment for patients with mNSCLC is currently based on molecular 
characterisation and matched targeted therapy for specific driver-mutated subsets (Heigener et 
al 2019). For mNSCLC patients without EGFR or ALK genomic tumour aberrations, platinum 
doublet chemotherapy with anti-PD-1/anti-PD-L1 targeting immunotherapy is the SoC based 
on results from KEYNOTE189 (Gandhi et al 2018).
Although HER2 alterations have been widely studied as a predictive biomarker in breast 
cancer, with multiple therapeutic options having been developed against them, there have yet 
to be any approved therapies for HER2 alterations in mNSCLC. 
A number of large-scale sequencing efforts and tumour-specific sequencing studies have 
identified somatic mutations in the extracellular, transmembrane, and kinase domains of 
HER2 in a wide range of cancers, including NSCLC (Bose et al 2013, Chang et al 2018, 
Greulich et al 2012, Kavuri et al 2015, Ou et al 2017, Ross et al 2016, Yamamoto et al 2014, 
Zabransky et al 2015). HER2 activating mutations are causally implicated in oncogenesis, can 
promote HER2 protein gain of function (Cocco et al 2019, Zabransky et al 2015), and have 
been described in at least 25 different tumour types with mutation hotspots varying by 
malignancy (Robichaux et al 2019). These mutations confer an invasive growth advantage on 
neoplastic cells with positive selection in the tumour microenvironment (Bose et al 2013). 
Nonclinical data also indicate that HER2 activating mutations lead to increased dimerisation 
and/or activation at the C-terminal kinase domain (Greulich et al 2012, Wang et al 2006). 
HER2 mutations are a not associated with HER2 amplification suggesting a distinct 
therapeutic target (Li et al 2016).
HER2 mutations have been identified in approximately 2% to 4% of NSCLC (Arcila et al 
2012, Mazieres et al 2013, Tomizawa et al 2011, Wei et al 2020). The most common HER2 
mutations are exon 20 insertions found in the tyrosine kinase domain; their frequency, as a 
group, has been reported to range from 35% to 70% of all HER2 mutations in NSCLC (Ou et 
al 2019, Singh et al 2020, Wei et al 2020). More rarely, HER2 mutations are observed in the 
extracellular domain (eg, S310F, S310Y in exon 8), outside of exon 20 in the tyrosine kinase 
domain (eg, L755P in exon 19), and in the transmembrane domain, representing 
approximately 25%, 16%, and 10% of HER2 mutations, respectively (Robichaux et al 2019). 
In general, HER2-mutant NSCLC is more commonly associated with female patients, 
non-smokers, and adenocarcinoma histology (Arcila et al 2012). HER2 mutations and other 
driver oncogene abnormalities are reported to be mutually exclusive (Mazieres et al 2013, 
Pillai et al 2017), although rare cases of non-tyrosine kinase domain HER2 mutations have 
been observed with concurrent EGFR mutations (Ou et al 2019, Wei et al 2020). Tumour 

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protein 53 has been described as a frequent co-mutation and other mutations including 
KEAP1, STK11, and KRAS have also been observed (Wei et al 2020). HER2 co-amplification 
has been described in approximately 5% to 15% of HER2-mutant NSCLC (Ou et al 2019, 
Singh et al 2020).
2.2.2
Relevance of HER2-mutant NSCLC
HER2 is a member of the HER superfamily that initiates signal transduction via the 
PI3K/protein kinase b (Akt) and Ras/mitogen-activated protein kinase pathways 
(Archer et al 1995). In human advanced solid tumours, expression of HER2 protein has been 
reported in various tumour tissues and in a variety of cultured tumour cell lines including lung 
cancer (Li et al 2012) among others like breast cancer (Ross et al 2009) and gastric cancer 
(Gravalos and Jimeno 2008).
HER2 alterations in mNSCLC are usually a marker of poor prognosis and fall into 3 distinct 
mechanistic categories: HER2 mutations (2% to 4%) (Hirsch et al 2017), HER2 gene 
amplification (1% to 20%) and HER2 protein overexpression (6% to 35%) (Hirsch et al 2017, 
Li et al 2016, Mar et al 2015, Mazieres et al 2013, Ou et al 2019, Singh et al 2020).
HER2 mutations are predominantly mutually exclusive of other actionable oncogenic drivers 
(such as EGFR, KRAS and ALK alterations) and in lung cancer are associated with a poor 
prognosis (Arcila et al 2012, Li et al 2016, Mazieres et al 2013, Pillai et al 2017).
2.2.3
Therapies in mNSCLC and HER2-mutant mNSCLC
Until recently, common first-line treatment regimens for advanced NSCLC in major global 
markets were typically platinum-based doublets and include carboplatin and paclitaxel (eg, 
nab paclitaxel [Abraxane®]), carboplatin and gemcitabine (squamous only), carboplatin and 
pemetrexed (non-squamous only), cisplatin and gemcitabine (squamous only), and cisplatin 
and pemetrexed (non-squamous only). Maintenance therapy, with pemetrexed has been shown 
to improve OS and PFS, particularly in non-squamous histology (Ciuleanu et al 2009, Paz-
Ares et al 2019).
More recently, the treatment landscape has changed based on targetable molecular 
characterisation. Approximately, 10% of Caucasian patients and up to 50% of Asian patients 
with NSCLC will harbour a targetable activating EGFR mutation, the most common of which 
are L858R and deletions in exon 19 (Ettinger et al 2019). For these patients, the third 
generation EGFR TKI osimertinib (Tagrisso) has been approved as a first-line treatment 
option after the Phase 3 FLAURA study (NCT02296125) demonstrated a statistically 
significant improvement in PFS (18.9 months) compared to either erlotinib or gefitinib 
(10.2 months) in patients with EGFR-mutated mNSCLC (Soria et al 2018). Recently, the 
FLAURA study (NCT02296125) reported updated results with a median OS rate of 
38.6 months in the osimertinib group compared to 31.8 months in the comparator group 

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(Ramalingam et al 2020). Moreover, for patients lacking EGFR or ALK/ROS1 mutations, 
immune checkpoint inhibitors were found to be more efficacious and better tolerated than 
first-line platinum-based chemotherapy. 
Among patients with a tumour proportion score for PD-L1 of 50% or greater, pembrolizumab 
as a monotherapy is considered a first-line treatment of choice (Gandhi et al 2018). For 
patients with a lower expression of PD-L1, the treatment of choice is platinum doublet 
chemotherapy with anti-PD-1/PD-L1 targeting immunotherapy (Pabani and Butts 2018) 
Two recent studies (CHECKMATE 227 [NCT02477826] and CHECKMATE-9LA 
[NCT03215706]) have demonstrated benefit for nivolumab plus ipilimumab, with or without 
chemotherapy, versus chemotherapy alone, in advanced mNSCLC (Hellman et al 2019, Reck 
et al 2016). Based on these data, nivolumab plus ipilimumab has been approved by the FDA 
for adult patients with mNSCLC without EGFR or ALK genomic tumour alterations with 
PD-L1 expression ≥ 1 %; nivolumab plus ipilimumab is also approved with 2 cycles of 
platinum-based chemotherapy in tumours lacking EGFR and ALK alterations, irrespective of 
PD-L1 expression (FDA 2020). 
Immunotherapy with anti-PD-1 or anti-PD-L1 checkpoint inhibitors was first investigated in 
the Phase 1 study of nivolumab reported in 2012 (Topalian et al 2014). NSCLC patients 
included in this study showed responses, some of which were durable. Subsequent trials of 
nivolumab and other agents, eg, pembrolizumab and atezolizumab (Borghaei et al 2015, 
Brahmer et al 2015, Herbst et al 2016), have confirmed responses and improved survival 
outcomes compared with docetaxel chemotherapy in the second-line treatment setting. The 
benefit is seen across adenocarcinoma and squamous carcinoma histology but there are poorer 
outcomes in EGFR and ALK-mutant tumours, possibly related to a lower mutational tumour 
burden and a poorer immune infiltrate in these tumours (Peters et al 2019).
While there are no direct HER2-targeted therapies approved for NSCLC, further investigation 
of HER2-targeting strategies are warranted in this patient population. Results from clinical 
studies suggest a potential role of HER2-targeting ADC in NSCLC. Two retrospective 
international studies of afatinib showed modest activity in patients with HER2-mutant NSCLC 
(Peters et al 2018, Lai et al 2019). A study of T-DM1 in NSCLC based on HER2 IHC 
expression showed an ORR of 0% for IHC 2+ tumours but did demonstrate efficacy with 
ORR 20% in IHC 3+ tumours (Peters et al 2019). A separate T-DM1 study reported an ORR 
of 44% in patients with HER2-mutant NSCLC (Li et al 2018). A recent Phase 1 dose 
escalation study of T-DXd monotherapy in patients with advanced solid malignant tumours 
(NCT02564900) confirmed responses in 6 solid tumour types, including HER2-expressing 
and HER2-mutant mNSCLC. In the HER2-expressing or HER2-mutant mNSCLC subgroup, 
55.6% (10/18) of patients had a confirmed ORR, with a median DoR of 10.7 (95% CI: 6.9, 
11.5) months and the median PFS was 11.3 (95% CI: 7.2, 14.3) months. Among the subset of 
patients with mNSCLC with HER2-mutant disease, the confirmed ORR was 72.7% (8/11), 

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with a median DoR of 9.9 (95% CI: 6.9, 11.5) months (Tsurutani et al 2020). More recently, in 
an ongoing open-label Phase 2 study (NCT03505710), T-DXd monotherapy (
) 
is administered as a second-line treatment, in patients with HER2-overexpressing (Cohort 1) 
or HER2-mutated (Cohort 2) NSCLC. Preliminary data from an interim analysis showed 
promising results for Cohort 2 (n = 42) with an ORR of 61.9% and an estimated PFS of 
14 months. 59.5% (n = 25) of patients showed PR and 28.6% (n = 12) showed signs of SD.
A substantial unmet medical need exists for patients with NSCLC who have received 
platinum-doublets and immune checkpoint inhibitors. For these patients, the mainstay of 
treatment has been cytotoxic chemotherapy, with modest benefit and potential for significant 
toxicity. Although 30% to 40% of patients initially respond to platinum-based chemotherapy, 
they eventually progress on or after treatment. The introduction of immunotherapeutic agents 
targeting PD-1/PD-L1 has changed the treatment paradigm for these patients. These 
immunotherapies have been shown to be superior to chemotherapy in the second-line setting 
(Bose et al 2013, Bray et al 2018, Borghaei et al 2015, Herbst et al 2016), and have 
demonstrated improved outcomes for patients with tumours expressing PD-L1 in the first-line 
setting (Reck et al 2016). The combination of pembrolizumab plus chemotherapy has also 
been established as a new first-line SoC in NSCLC regardless of PD-L1 expression (Gandhi et 
al 2018).
Clinical outcomes with second-line therapies like docetaxel are generally poor with ORR of 
approximately 10%, median PFS of less than 4 months and median OS of 7 to 9 months (Bose 
et al 2013, Bray et al 2018, Borghaei et al 2015). 
In the randomised Phase 3 trial investigating ramucirumab plus docetaxel versus docetaxel 
(Garon et al 2014), patients with NSCLC who had progressed after first-line platinum-based 
chemotherapy regimen were treated with ramucirumab or placebo in combination with 
docetaxel. Patients were screened between December 2010 and January 2013 and 
1253 patients were randomly assigned to treatment. In 628 patients treated with ramucirumab 
plus docetaxel, the median OS was 10.5 months (95% CI: 9.5, 11.2), median PFS was 
4.5 months (95% CI: 4.2, 5.4), and investigator assessed ORR was 22.9% (95% CI: 19.7, 
26.4). Subgroup analysis for the population with HER2-mutant NSCLC was not reported. 
In the randomised open-label Phase 3 CheckMate 078 study in a predominantly Chinese 
patient population, patients with squamous or non-squamous NSCLC that had progressed 
during/after platinum-based doublet chemotherapy were treated with nivolumab or docetaxel 
(Wu et al 2019). Patients were enrolled between December 2015 and November 2016. Median 
OS was 12.0 months for patients treated with nivolumab and 9.6 months for patients treated 
with docetaxel. The ORR was 16.6% (95% CI: 12.8, 21.0) with nivolumab and 4.2% (95% CI: 
1.7, 8.5) with docetaxel. 
In the randomised open-label Phase 3 RATIONALE 303 study of the anti-PD-1 antibody 
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tislelizumab was compared to docetaxel as second- or third-line therapy for patients with 
locally advanced or mNSCLC. Interim results, which were recently published in American 
Association for Cancer Research 2021 (Zhou et al 2021), indicate that the median OS was 
17.2 months (95% CI: 15.28, 20.04) in the tislelizumab arm compared to 11.9 months 
(95% CI: 10.18, 13.93) in the docetaxel arm (p < 0.0001), median PFS in the tislelizumab arm 
was 4.1 months (95% CI: 3.75, 5.03) compared to 2.6 months (95% CI: 2.17, 3.78) in the 
docetaxel arm (descriptive p < 0.0001), and ORR in the tislelizumab arm was 21.9% 
compared to 7.0% in the docetaxel arm, with a difference of 14.9% (95% CI: 10.26, 19.56; 
descriptive p < 0.0001) (Business Wire 2021). 
However, immunotherapy has not been well studied in HER2-mutant NSCLC and the benefits 
seen with immunotherapy and with targeted therapies have not been replicated in patients with 
HER2-mutant NSCLC. To date there are no approved therapies specifically targeting HER2 
activating mutations. Therefore, HER2-mutant mNSCLC represents an important unmet 
medical need. 
To better understand clinical outcomes following systemic therapy, the nationwide (US-based) 
de-identified FH-FMI CG was used to analyse data for patients with HER2 mutations and 
HER2 wild-type in 2013 or later. In the FH-FMI CG database, among all unique 
advanced/metastatic non-squamous NSCLC patients who were treated with any systemic 
therapy in the second-line setting, the median real world PFS was 3.31 months (n = 71, 
95% CI: 2.43, 4.13 months) versus 4.56 months (n = 2638, 95% CI: 4.20, 4.82 months) in 
patients with activating HER2 mutation versus HER2 wild-type patients respectively (data on 
file). These data suggest a possible trend for poorer clinical outcomes in NSCLC patients with 
activating HER2 mutations treated with currently available therapies compared to patients 
with HER2 wild-type NSCLC.
The IMMUNOTARGET registry included 29 cases of HER2 exon 20 mutated NSCLC treated 
with anti-PD-1/anti-PD-L1 monotherapy across first- and later-line settings. Median PFS from 
start of anti-PD-1/anti-PD-L1 therapy for patients with HER2 mutations was 2.5 months 
(95% CI: 1.8, 3.5), compared to 3.2 months (95% CI: 2.7, 4.5) for patients with KRAS 
mutations, and 2.1 months (95% CI: 1.8, 2.7) for patients with EGFR mutations. PD-L1 
expression has generally been reported to be low in patients with HER2-mutant NSCLC, with 
over 80% of patients having PD-L1 < 10% (Lai et al 2018, Mazieres et al 2019), although 
tumour mutational burden has been reported to be similar to unselected NSCLC, ie, not 
selected per any criteria (Lai et al 2018). Some studies of patients with HER2-mutant 
mNSCLC have suggested lack of immunotherapy benefit in patients treated across various 
lines of therapy (Fang et al 2019, Mazieres et al 2019), but more definitive conclusions are 
limited owing to the rarity of this disease subgroup (Guisier et al 2020, Lai et al 2018).
Retrospectively collected data from a web-based patient registry and hospital chart review in 

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China included 75 patients with advanced or recurrent NSCLC with de novo HER2 mutations. 
Between October 2012 and December 2018, 65 patients with in-frame insertion mutations, 
8 with point mutations and 2 with gene amplification were found. The most common subtypes 
of insertion mutations were A775_G776insYVMA, G776delinsVC, and V777_G778insGSP. 
HER2 mutated patients were mostly young-aged, females, never or light smokers, with 
adenocarcinoma. Chemotherapy achieved better outcomes than HER2-TKIs (median PFS: 5.5 
versus 3.7 months in the first-line setting and 4.2 versus 2.0 months in the second-line setting, 
p = 0.001 and 0.031, respectively). In particular for the most common subtype, YVMA 
insertions, PFS was significantly longer in chemotherapy than HER2-TKIs both in the 
first-line (6.0 versus 2.6 months, p = 0.008) and the second-line (4.2 versus 2.6 months 
p < 0.001) (Xu et al 2020).
Patients who were diagnosed with advanced lung cancer and had undergone molecular testing 
from April 2016 to December 2018 at Zhongshan Hospital in China were reviewed. 
Forty-four patients that had HER2-mutant advanced lung cancer, were analysed for clinical 
and molecular features and clinical outcomes. Their median age was 56 years, with the 
majority being women (n = 24), never-smokers (n = 32), and having the adenocarcinoma 
genotype (n = 42). A 12-base pair in-frame insertion in exon 20 with p.771insAYVM was the 
most common subtype in patients with known detail variants of HER2 mutation (9/27). The 
median OS from the date of advanced disease diagnosis was 9.9 months with 24 deaths, and a 
median follow-up of 12.7 months for survivors. For patients with a known HER2 exon 20 
insertion mutation, OS tended to be superior (though not statistically) in the first-line 
HER2 TKI group to that in the group receiving chemotherapy (10.8 versus 9.8 months, 
p = 0.40). However, patients that received first-line chemotherapy had a median PFS of 
5.9 months, numerically longer than that of the HER2-TKI group (4.6 months, p = 0.63). 
Patients who received HER2 targeted therapy as first-line therapy had an improved OS (10.8 
versus 10.1 months, p = 0.30) and PFS (4.6 versus 2.8 months, p = 0.36) relative to those who 
received HER2 targeted therapy as subsequent-line therapy, although they did not meet the 
threshold for statistical significance (Zhou et al 2020b).
TKIs, including those traditionally used for EGFR-mutated NSCLC (eg, dacomitinib, 
afatinib), have demonstrated at best modest activity against HER2 mutations in small clinical 
studies, including patients with exon 20 mutations. In a Phase 2 study of 26 mostly pre-treated 
patients with NSCLC harbouring HER2 exon 20 mutations, dacomitinib therapy resulted in an 
ORR of 12%, median PFS of 3 months, and median OS of 9 months (Kris et al 2015). 
Afatinib has shown more limited activity in a Phase 2 study of 13 pre-treated patients with 
mNSCLC and HER2 exon 20 mutations where only 1 PR was observed (Dziadziuszko et al 
2019). Pyrotinib, a pan-ErbB TKI, in a Phase 2 study of 60 pre-treated NSCLC patients 
demonstrated an ORR of 30%, median DoR of 6.9 months (95% CI: 4.9, 11.1), and median 
PFS of 6.9 months (95% CI: 5.5, 8.3). Notably, SD or response was seen in patients with 
non-exon 20 insertion mutations such as exon 20 single nucleotide variants (eg, G776X) or 

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exon 19 mutations (eg, L755P, V777L) (Zhou et al 2020a).
HER2-targeted therapy such as TKIs or trastuzumab has shown limited efficacy in 
HER2-mutant NSCLC amongst small cohorts of patients treated in either the first-line or later 
setting. Chemotherapy has shown higher median PFS compared to TKIs with anti-HER2 
activity in both first-line (5.5 months versus 3.7 months) and second-line (4.2 months versus 
2.0 months) HER2-mutant NSCLC (Xu et al 2020). Use of trastuzumab-based therapy 
typically in combination with chemotherapy has also been described in these patients, 
although limited conclusions can be made regarding its comparative efficacy to other systemic 
options owing to limited data (Li et al 2020, Mazieres et al 2013, Patil et al 2020). 
Amongst NSCLC patients treated with pemetrexed-based chemotherapy, patients with 
NSCLC harbouring HER2 mutations demonstrated a median PFS of 5.1 months, which was 
similar to the median PFS for KRAS mutations (5.0 months, p = 0.971), numerically shorter 
than the median PFS for EGFR mutations (6.5 months, p = 0.247) and statistically shorter than 
the median PFS for ALK and ROS1 mutations (9.2 months, p = 0.004) (Wang et al 2018). 
When evaluated retrospectively using propensity score matching, NSCLC patients with HER2 
mutations had a worse prognosis than wild-type NSCLC patients (median OS 28.4 months 
versus 62.8 months, p = 0.005) (Wei et al 2020).
Considering the current treatment options available for mNSCLC patients with HER2 
mutation, a clear need for more effective therapies exists.
HER2 ADCs are recognised as a promising therapeutic option (NCCN 2020). Activity of 
HER2-directed ADCs in HER2-mutant tumours has been demonstrated in cell line 
experiments, and a proposed mechanism of action for targeted apoptotic cell death is increased 
receptor and ADC internalisation for HER2-mutant tumours compared to wild-type tumours. 
Furthermore, studies have shown that radionuclide-tagged trastuzumab accumulates in 
HER2-mutant and -amplified lung cancer patients on PET imaging, suggesting that 
HER2-mutant tumours selectively accumulate HER2 targeting agents (Li et al 2020. 
In a Phase 2 clinical study, T-DM1 showed activity in patients with NSCLC and HER2 
mutations. T-DM1 demonstrated an investigator-assessed ORR of 50% (14/28, 95% CI: 
31, 69) amongst patients with HER2-mutant NSCLC and 50% (5/10, 95% CI: 19, 81) 
amongst patients with concurrent HER2 mutation and amplification. Amongst the HER2 
mutation or amplification population, ORR was 51% (25/49, 95% CI: 36, 66), median DoR 
was 4.4 months (95% CI not reported), and median PFS was 5.0 months (95% CI: 3.5, 5.9) 
(Li et al 2020). 
The activity of T-DXd has been reported in patient-derived xenograft models of S310F with 
ERBB2 amplification and exon 20 YVMA insertion mutated lung cancers that developed 
resistance to T-DM1 over time. In these nonclinical models, T-DXd induced responses 

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resulting in complete tumour regression in all mice. It was concluded that T-DXd showed 
deeper and more durable responses in the xenograft models when compared to T-DM1 (Li et 
al 2020). In addition, T-DXd has also demonstrated promising preliminary clinical efficacy in 
the setting of heavily pre-treated NSCLC patients with HER2 exon 19 and 20 mutations and 
T-DXd response durability appears improved over that of T DM1 from nonclinical and clinical 
data. 
Study J101 included 18 patients with NSCLC that were treated with T-DXd of which 
11 patients had a diagnosis of HER2-mutant NSCLC. T-DXd showed promising efficacy in 
these 11 patients and results were consistent with patients with HER2-positive breast cancer, 
representing the majority of patients enrolled in Study J101. In these 11 patients 72.7% 
(95% CI: 39.0, 94.0) had confirmed ORR, median DoR was 9.9 months (95% CI: 6.9, 11.5), 
and median PFS was 11.3 months (95% CI: 8.1, 14.3). Median OS had not been reached as of 
the date of DCO. T-DXd demonstrated an acceptable and generally manageable safety profile. 
A total of 289 patients received at least 1 dose of T-DXd of which the majority (99.7%) 
experienced at least 1 TEAE, with most of the common TEAEs being gastrointestinal or 
haematological in nature. TEAEs of ≥ Grade 3 were reported in 59.9% of patients and 49.5% 
had TEAEs of ≥ Grade 3 that the investigator considered to be related to the study drug. 
Across all tumour types, a numerically higher proportion of patients in the 
 dose 
group than in the 
 group experienced AEs of ≥ Grade 3.
Study U204 included 78 HER2-mutant NSCLC patients of which treatment (T-DXd) in 
38 patients (48.7%) was ongoing at the time of DCO (31 May 2020). At the DCO, of 
66 patients with HER2-mutant NSCLC, 1 (1.5%) patient had a confirmed BOR of CR, 
32 (48.5%) patients had a confirmed BOR of PR, 24 (36.4%) patients had a confirmed BOR 
of SD, 3 (4.5%) patients had progressive disease (PD), and 6 (9.1%) patients were NE. 
Confirmed ORR was 50.0% (95% CI: 37.4, 62.6), median DoR was 12.0 months (95% CI: 
5.6, 18.3) and estimated median PFS was 13.8 months (95% CI: 6.0, 19.5). A total of 
125 patients have received T-DXd in this study to DCO of which the majority (98.4%) 
experienced at least 1 TEAE. A total of 62.4% of patients experienced ≥Grade 3 TEAEs with 
the most commonly (≥10% of patients) reported ≥ Grade 3 events, by Preferred Term being 
neutrophil count decreased (20.0%) and anaemia (10.4%). 
When taken together, considering the low response rate and short PFS of available treatment 
options, there is a clear unmet medical need for NSCLC patients harbouring HER2 mutation 
who are recurrent from prior anticancer therapy. The nonclinical and clinical findings suggest 
that T-DXd may have clinically meaningful benefit over SoC therapy in HER2-mutant 
NSCLC patients who are recurrent or relapsed from prior treatments. However, T-DXd has not 
been investigated in Chinese patients with HER2-mutant NSCLC and warrants further 
investigation in this population. 
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2.3
Benefit/Risk Assessment
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 cumulative review of safety data from nonclinical, clinical, epidemiologic 
information, scientific literature and taking into account biological plausibility, 
ILD/pneumonitis and neutropenia, including febrile neutropenia, are considered important 
identified risks associated with administration of T-DXd. Based on the available nonclinical 
data, review of the cumulative literature, reported toxicities for the same class of agents, the 
important potential risks for T-DXd are LVEF decrease (re labelled as ‘Left ventricular 
dysfunction’ as the undesirable clinical outcome of LVEF reductions, in accordance with the 
Revision 2 of the EMA guidelines on Good Pharmacovigilance Practice (EMA 2017). This 
re-labelling of the risk does not affect the nature or monitoring methods of the LVEF decrease 
as a potential risk associated with T-DXd), and embryofoetal toxicity. 
In the T-DXd clinical development programme, specific inclusion/exclusion criteria and 
monitoring/management guidelines are currently in place to mitigate the important identified 
risks of ILD/pneumonitis and neutropenia, including febrile neutropenia, and important 
potential risks of LVEF decrease and embryofoetal toxicity. 
ILD/pneumonitis and LVEF decrease are considered as AESIs and are closely monitored in 
the T-DXd clinical development programme. 
The potential risks of T-DXd are shown in Table 2. These identified and potential risks are 
generally manageable through dose modification and routine clinical practice.

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Table 2
Risk Assessment
Identified and Potential Risks of 
Clinical Significance
Summary of Data/Rationale for 
Risk
Mitigation Strategy
Study Intervention: T-DXd 
ILD/pneumonitis and neutropenia, 
including febrile neutropenia are 
considered important identified 
risks associated with 
administration of T-DXd
LVEF decrease and embryofoetal 
toxicity are considered important 
potential risks for T-DXd.
Keratitis is considered a potential 
risk for T-DXd.
Other identified risks for T-DXd 
are infusion-related reactions,
haematological AEs (anaemia, 
leukopenia, lymphopenia, 
thrombocytopenia), 
pulmonary/respiratory AEs 
(cough, dyspnoea, upper 
respiratory tract infection, 
epistaxis), gastrointestinal AEs 
(abdominal pain, constipation, 
diarrhoea, dyspepsia, nausea, 
stomatitis, vomiting), hepatic AEs 
(hepatic function abnormality, 
ALT, AST and ALP increased), 
skin AEs (alopecia, rash, pruritis), 
blood bilirubin increased, 
pneumonia, dry eye, dehydration, 
hypokalaemia, decreased appetite, 
dizziness, fatigue, peripheral 
oedema, pyrexia and headache
T-DXd has not been studied in 
participants with severe/moderate 
hepatic impairment or severe renal 
impairment.
Based on cumulative review of 
safety data from nonclinical, 
clinical, epidemiologic 
information, scientific literature 
and taking into account biological 
plausibility
Based on the available nonclinical 
data, review of the cumulative 
literature, and reported toxicities 
for the same class of agents, the 
important potential risks for 
T-DXd are LVEF decrease 
(re-labelled as ‘Left ventricular 
dysfunction’ as the undesirable 
clinical outcome of LVEF 
reductions, in accordance with the 
Revision 2 of the EMA guidelines 
on Good Pharmacovigilance 
Practice (EMA 2017). This 
re-labelling of the risk does not 
affect the nature or monitoring 
methods of the LVEF decrease as 
a potential risk associated with 
T-DXd) and embryofoetal toxicity
Specific inclusion/exclusion 
criteria (Section 5) and 
monitoring/management 
guidelines (Appendix K) are 
currently in place to mitigate the 
important identified risks of 
ILD/pneumonitis and neutropenia, 
including febrile neutropenia, and 
important potential risks of LVEF 
decrease and embryofoetal 
toxicity.
ILD/pneumonitis and LVEF 
decrease are considered as AESIs 
and are closely monitored in the 
T-DXd clinical development 
programme.
These identified and potential risks 
are generally manageable through 
dose modification (Section 6.6) 
and routine clinical practice.
AE = adverse event; AESI = adverse event of special interest; ALP = alkaline phosphatase; ALT = alanine 
transaminase; AST = aspartate transaminase; EMA = European Medicines Agency, ILD = interstitial lung 
disease; LVEF = left ventricular ejection fraction; T-DXd = trastuzumab deruxtecan.

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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 T-DM1 (Kadcyla®), and 
HER1- and 2-associated TKI, 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 CHF 
(NYHA Class II to IV) or asymptomatic cardiac dysfunction, including LVEF decrease. 
Cardiac dysfunction, mainly asymptomatic LVEF decrease, has also been observed with 
pertuzumab in combination with trastuzumab. Similarly, cardiac dysfunction has been 
observed in participants receiving T-DM1, at a lower incidence than in participants receiving 
trastuzumab. Most 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/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/infusion-related reactions: The administration of therapeutic proteins is 
associated with a risk of hypersensitivity and/or infusion reactions. 
Hypersensitivity/infusion-related reactions have been reported with trastuzumab, pertuzumab 
and T-DM1. These can range from mild reactions to severe anaphylactic shock with fatal 
outcome, as has been the case for trastuzumab.
Hepatic toxicity: Cases of hepatic toxicity have occurred with T-DM1, lapatinib, and 
trastuzumab. In 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 DILI.
Haematological toxicity: Haematological toxicity has been observed with all HER2-targeted 
therapies. Neutropenia, febrile neutropenia, leukopenia, 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 

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thrombocytopenia have also occurred with trastuzumab and pertuzumab when used in 
combination with chemotherapy.
Refer to Appendix K for T-DXd 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 
and gastrointestinal 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.
Acute 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 gastrointestinal toxicities being the most 
significant groups of events.
2.3.2 Benefit Assessment
T-DXd is under development for the treatment of HER2-mutant tumours. Based on 
preliminary clinical observations in a Phase 1 study (Study J101 [Phase 1; NCT02564900]) 
and a Phase 2 U204 study (Study DESTINY-Lung01; [NCT03505710]) T-DXd demonstrated 
antitumour activity in HER2-mutant cancers and a generally acceptable safety profile in these 
populations. 
A tabular summary of clinical studies using T-DXd is presented in the IB. Refer to 
Section 2.2.3 and Table 4 for a brief summary of Study J101 and Study U204.
2.3.3 Overall Benefit: Risk Conclusion
As of 08 Jun 2020, an estimated 2345 patients have been treated with T-DXd (alone or as a 
combination therapy), or with a comparator in 16 completed or ongoing clinical studies. The 
clinical development programme has investigated the use of T-DXd in breast cancer, gastric 
cancer, colorectal cancer, NSCLC, and multiple tumours.

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Taking into account the measures taken to minimise risk to participants in this study, the 
potential risks identified in association with T-DXd are justified by the anticipated benefits 
that may be afforded to participants with HER2-mutant mNSCLC who have disease 
progression on or after at least one-line of treatment.
The important identified risks associated with administration of T-DXd are ILD/pneumonitis 
and neutropenia, including febrile neutropenia; LVEF decrease and embryofoetal toxicity are 
considered important potential risks. To specifically mitigate the incidence of pulmonary 
toxicities, strict inclusion/exclusion criteria have been included in this CSP, prohibiting most 
patients with pre-existing pulmonary co-morbidities from entering the study. In addition, 
baseline pulmonary function tests will be performed for all patients. For haematological 
toxicities, the use of growth factors is allowed at the discretion of the investigator. Participants 
will be monitored closely throughout the study and clinical and laboratory assessments will be 
performed before every cycle. TMGs are added to assist with the management of the most 
commonly seen AEs (Appendix K). 
The emergence of COVID-19 presents a potential safety risk for participants, therefore, 
several risk mitigation factors have been implemented in this study. Details regarding 
instructions related to COVID-19 and a more detailed description of benefit/risk 
considerations relevant to COVID-19 are provided in Appendix H. 
T-DXd has the potential to provide meaningful clinical benefit. Considering the measures to 
minimise risks to participants, the benefit/risk assessment supports the proposed study.
There are no approved anti-HER2 targeted therapies for patients with HER2 mutations and 
unresectable or mNSCLC, so there is a significant unmet medical need for providing more 
treatment options and outcome in this patient population.
To date, the overall safety and tolerability profile of T-DXd monotherapy across the 
programme has been acceptable and the data available on the efficacy of T-DXd suggest that 
the overall benefit-risk assessment supports further clinical development.

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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, open-label, single-arm multicentre study in China assessing the efficacy and 
safety of T-DXd in participants with metastatic non-squamous NSCLC whose tumours have a 
HER2 exon 19 or 20 mutation, with disease progression on or after at least one-line of 
treatment.
 
 
 
 
 
 
 
 
 
 
 
 
 
4.1.1
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 AstraZeneca 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 
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: 
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!
Obtaining reconsent for the mitigation procedures (note, in the case of verbal 
[consent/reconsent], the ICF should be signed at the participant’s next contact with the 
study site).
!
Rescreening: Additional (one) 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. 
!
Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
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 second-line therapy of NSCLC without actionable mutation as recommended by the 
CSCO 2020 NSCLC Guideline, ie, docetaxel, other chemotherapy or immunotherapy, only 
provides an ORR of no more than 20% and a relatively short PFS as shown in Table 4 (Li et al 
2012, Wu et al 2019). According to Study J101 and interim Study U204 data, T-DXd showed a 
compelling ORR of 72.7% and 50% respectively in patients with metastatic HER2-mutant 
NSCLC as a later-line treatment (Table 4). Considering the limited efficacy of current 
therapies, the high response rate observed for T-DXd, and the small number of patients with 
HER2-mutant NSCLC, DESTINY-Lung05 will be a single-arm design. This will enable all 
participants to be treated with T-DXd, and hence potentially obtain a more efficacious 
treatment compared to conventional therapy.
4.2.2
Rationale for T-DXd in HER2-mutant Metastatic NSCLC
HER2 mutations have been identified in approximately 2% to 4% of NSCLC globally 
including China (Arcila et al 2012, Mazieres et al 2013, Tomizawa et al 2011, Wei et al 2020). 
Currently, there are no therapies specifically approved for patients with HER2-mutant NSCLC 
as described in Section 2.2.3. In the absence of an approved anti-HER2 therapy, treatment of 
patients with metastatic HER2-mutant NSCLC generally follows the treatment paradigm for 
those patients without an actionable mutation. Patients with HER2 mutations have a poor 
prognosis when compared to patients with other mutations (Section 2.2.2).
 
 
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Table 4
T-DXd Efficacy and Safety Outcomes in HER2-mutant NSCLC per RECIST 1.1 (Study J101 and Study U204) 
Compared to China Studies
Checkmate 078 Study
(Wu et al 2019)
Pemetrexed vs Docetaxel
(Li et al 2012)
Study J101
(DCO 01 Feb 2019)
Study U204
(Interim Analysis 
DCO 31 May 2020)
Population
Patients from China, Russia, and 
Singapore with NSCLC
Patients from China, Stage IIIB 
or IV NSCLC
Patients from global, HER2-mutation NSCLC 
cohort
Arm
Nivolumab
Docetaxel
Pemetrexed
Docetaxel
T-DXd
T-DXd
Number
338
166
132
128
11
66
Age, median (range), years
60 (27 to 78)
60 (38 to 78)
58.2 (38 to 75)
55.6 (33 to 75)
-
60.0 (
)
Male, n (%)
263 (78)
134 (81)
67 (63.2)
74 (72.5)
-
20 (30.3)
Received line of therapy
1
1
-
2 (median)
Efficacy
   ORR (95% CI), %
16.6 (12.8, 21.0)
4.2 (1.7, 8.5)
9.4
4.9
72.7 (39.0, 94.0)
50.0 (
) 
   DoR, months
NR 
(range: 2.3, 
19.2+)
5.3
(range: 2.2+ to 
8.6+)
not stated
not stated
9.9
(95% CI: 6.9, 11.5) 
12.0
(95% CI: 
)
   mPFS (95% CI), months
2.8 (2.4, 3.4)
2.8 (1.6, 2.9)
not stated
not stated
11.3 (8.1, 14.3)
13.8 (
)
   mOS (95% CI), months
12.0 (10.4, 14.0)
9.6 (7.6, 11.2)
not stated
not stated
-
15.3 (
)
Safety
   ≥Grade 3, %
10
48
not stated
not stated
-
53.8
   AE leading to discontinuation, %
4
8
not stated
not stated
-
26.9
AE = adverse event; CI = confidence interval; DCO = data cut-off; DoR = duration of response; HER2 = human epidermal growth factor receptor 2; 
mOS = median overall survival; mPFS = median progression-free survival; NR = not reached; NSCLC = non-small cell lung cancer, ORR = objective response 
rate; T-DXd = trastuzumab deruxtecan; vs = versus.
PPD
PPD
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4.2.3
Rationale for Study Endpoints
The primary endpoint is confirmed ORR, defined as the proportion of participants with 
confirmed CR or PR, as assessed by ICR based on 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 considering the unmet medical needs and the encouraging 
efficacy data observed in J101 and U204. 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 by investigator assessment; DoR, DCR, BOR, 
PFS by investigator assessment and ICR; CNS-PFS by ICR, and OS) will be used to further 
evaluate efficacy and to corroborate the benefits of antitumour effects demonstrated by 
confirmed ORR as assessed by ICR.
As part of the secondary endpoint assessment, blood samples will be taken to allow for 
research into the PK and immunogenicity of T-DXd.
4.3
Justification for Dose
T-DXd will be administered at a dose of 
 
 
4.3.1
PK Comparability Between Metastatic Breast Cancer and Metastatic 
NSCLC
From a PK perspective, the systemic exposure parameters (Cmax, AUC0-21d, and Ctrough in 
Cycle 1) of intact T-DXd and DXd were similar across patients with metastatic breast cancer 
and HER2-expressing or -mutant NSCLC at T-DXd 
 (Table 5).
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Table 5
Cycle 1 PK Parameters (Mean ± Standard Deviation) of T-DXd at 
 Dose in HER2-positive or HER2-low Breast Cancer and 
HER2-expressing or -mutant NSCLC
Analyte
PK Parameter (units)
T-DXd 
HER2-positive breast 
cancer
HER2-low breast 
cancer
HER2-expressing 
or -mutant NSCLC
intact T-DXd
Cmax (μg/mL)
165.2 ± 51.0 [122]
171.7 ± 91.5 [79]
162.1 ± 36.1 [19]
AUC0-21d (μg·d/mL)
756.5 ± 205.1 [115]
680.9 ± 147.5 [79]
675 ± 212.2 [19]
Ctrough (μg/mL)
9.25 ± 20.0 [116]
7.3 ± 10.4 [78]
6.5 ± 3.8 [ 18]
DXd
Cmax (μg/mL)
10.5 ± 9.34 [122]
13.4 ± 4.35 [79]
11.5 ± 3.72 [19]
AUC0-21d (μg·d/mL)
43.6 ± 31.40 [103]
40.6 ± 11.94 [76]
40.4 ± 12.75 [19]
Ctrough (μg/mL)
0.35 ± 0.244 [115]
0.33 ± 0.201 [78]
0.37 ± 0.210 [18]
Values in the table are mean ± standard deviation [N].
HER2-positive breast cancer and HER2-low breast cancer data were combined across Studies DS8201-A J101, 
DS8201-A-J102, DS8201-A-A103, and DS8201-A-U201. NSCLC group includes 18 patients from 
Study DS8201-A-J101 and 1 patient from Study DS8201-A-A103. Data from NSCLC patients in 
Study DS8201-A-U204 were not included as PK sampling was sparse, compared to Study DS8201-A-J101, to 
provide robust non-compartmental analysis-based PK parameter estimates. 
AUC0-21d = area under the concentration-time curve from time 0 to Day 21; Cmax = maximum observed 
concentration; Ctrough = trough serum concentration on Day 2; DXd = deruxtecan; HER2 = human epidermal 
growth factor receptor 2; NSCLC = non-small cell lung cancer; PK = pharmacokinetic(s); T-DXd = trastuzumab 
deruxtecan.
These data are reinforced by preliminary PopPK analysis, which showed similar systemic 
exposures for intact T-DXd and DXd (Cmax and AUC0-21d in Cycle 1 or at steady state) in 
patients with breast cancer and NSCLC administered T-DXd 
 (Figure 2).
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NSCLC 
T-DXd 
 has shown promising preliminary efficacy in HER2-mutant NSCLC 
patients in Study J101. The confirmed ORR was 72.7% among HER2-mutant NSCLC patients 
(N =11). 
Moreover, preliminary data from interim analyses of Study U204 have shown promising
clinical efficacy of T-DXd 
 in HER2-mutant NSCLC patients. At the first interim 
analysis (DCO 25 Nov 2019), efficacy results were reported for 42 patients administered 
T-DXd 
 Q3W. Median follow-up duration was 8.0 months (range: 1.4, 14.2). The 
ICR-assessed confirmed ORR was 61.9% (95% CI: 45.6, 76.4) (Smit et al 2020). At the 
second interim analysis (DCO 31 May 2020), efficacy results were reported for 66 patients 
administered T-DXd 
 Q3W. Median follow-up duration was 8.2 months (range 0.7 
to 19.5). The ICR-assessed confirmed ORR was 50.0% (95% CI: 37.4, 62.6). 
Therefore, the ORR observed in HER2-mutant NSCLC patients in Study U204 are reasonably 
similar to the ORR reported in metastatic breast cancer patients in Study J101. 
These preliminary data suggest that the ORR observed with T-DXd in HER2-mutant NSCLC 
is substantially higher than the ORR that has been reported for current SoC treatment for 
second-line or later NSCLC, namely nivolumab, docetaxel, or docetaxel and ramucirumab.
4.3.3
Safety Comparison Between Metastatic Breast Cancer and Metastatic 
NSCLC
The exposure-response analyses for safety in breast cancer patients estimated a numerically 
higher incidence (approximately 1% to 7%) for the safety endpoints analysed, AEs associated 
with discontinuation, dose reduction or drug interruption, AEs ≥ Grade 3, SAEs, anaemia, 
neutropenia or thrombocytopenia and ILD (any grade and ≥ Grade 3), and decreased LVEF 
(≥Grade 2), at a dose of T-DXd 
 compared to a dose of T-DXd 
.  
A total of 48 patients with breast cancer received T-DXd 
 in Study U201. As of 
31 May 2020, 78 patients with NSCLC had been administered T-DXd
in 
Study U204. The incidence of AEs associated with discontinuation, dose interruption, and 
dose reduction was 13%, 33%, and 40%, respectively, in Study U201, compared to 27%, 41%, 
and 28%, respectively, in Study U204. Grade ≥ 3 AEs were reported in 69% of patients in 
Study U201 and 54% of patients in Study U204. The most frequent ≥ Grade 3 AE was 
neutrophil count decreased in both Study U201 (21%) and Study U204 (19%). Adjudicated 
drug-related ILD was also reported at a similar incidence in Study U201 (8%) and Study U204 
(9%). 
Therefore, the safety profile of T-DXd 
 Q3W was similar in breast cancer patients 
and NSCLC patients.
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4.3.4
Summary
In summary, T-DXd will be administered at a dose of 
 this study. 
 
 
 
 
 
 
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 (Table 1) including 
follow-up for OS determination.
The study may be stopped if, in the judgement of AstraZeneca, study participants are placed at 
undue risk because of clinically significant findings.
The end of the study is defined as the time of the final DCO for the final analysis. Final 
analysis is planned to be performed approximately 15 months after the last participant has 
initiated study intervention. Based on data from Study U204, 15 months is sufficient time for 
participants to reach a response (median time to response is 1.4 months) and to allow DoR to 
be determined for responders (median confirmed DoR is 12 months). Participants may be 
withdrawn from the study at this time; however, participants may remain on study intervention 
beyond closure of the database if, in the opinion of the investigator, they continue to receive 
benefit from study intervention and have no evidence of disease progression (Section 6.7).
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 interest in this study is participants with metastatic non-squamous 
NSCLC whose tumours have a study-qualifying HER2 exon 19 or 20 mutation, with disease 
progression on or after at least one-line of treatment.
Prospective approval of 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; refer to 
Section 5.4.
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5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Informed Consent
1
Capable of giving signed informed consent as described in 10, which includes compliance 
with the requirements and restrictions listed in the ICF and in this CSP.
Age
2
Male and female participants must be ≥18 years at the time of signing the ICF. 
Type of Participant and Disease Characteristics
3
Pathologically documented metastatic non-squamous NSCLC. Participants with mixed 
histology are eligible if adenocarcinoma is the predominant histology.
4
Has relapsed from or is refractory to at least one-line of anticancer treatment in the 
metastatic setting.
5
Documented study-qualifying activating 
 either from a pre-
existing tissue test result obtained from qualified local laboratory/assay or have the tissue 
HER2 mutation test result detected prospectively in a central laboratory. 
6
Is willing and able to either:
∀
 
 
∀
 
 
 
 
7
WHO or ECOG performance status of 0 or 1.
8
Presence of at least one measurable lesion assessed by the investigator based on 
RECIST 1.1. 
9
Has adequate organ and bone marrow function within 14 days before enrolment as defined 
in Table 6. All parameters must meet the inclusion criteria on the same day, and must be 
the most recent results available.
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Table 6
Parameters for Adequate Organ and Bone Marrow Function
Adequate bone marrow function
Platelet count
≥ 100 × 109/L. (Platelet transfusion is not allowed within 1 week prior to 
screening assessment)
Haemoglobin
≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth 
factor support to maintain haemoglobin ≥9.0 g/dL are not eligible. (Red 
blood cell transfusion is not allowed within 1 week prior to screening 
assessment)
Absolute neutrophil count
≥ 1.5 × 109/L. (granulocyte-colony stimulating factor administration is not 
allowed within 1 week prior to screening assessment)
Adequate hepatic function
ALT and AST
≤ 3 × ULN (< 5 × ULN in participants with liver metastases)
TBL
≤ 1.5 × ULN if no liver metastases or < 3 × ULN in the presence of 
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver 
metastases at baseline
Serum albumin
≥ 2.5 g/dL
Adequate renal function
CrCL
≥ 30 mL/min as determined by Cockcroft Gault (using actual body weight).
Males:
CrCL (mL/min) = 
[140 — age (years)] × weight (kg)
72 × serum creatinine (mg/dL)
Females:
CrCL (mL/min) =
[140 — age (years)] × weight (kg)
72 × serum creatinine (mg/dL) × 0.85
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; TBL = total bilirubin; ULN = upper limit of normal.
10 LVEF ≥50% within 28 days before enrolment.
11 Minimum life expectancy of 12 weeks at screening.
12 Has adequate treatment washout period before enrolment, as defined in Table 7 below:

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Table 7
Adequate Treatment Washout Periods
Treatment
Minimum Washout Period
Major surgery (as defined by the investigator) within 28 days 
prior to first dose or still recovering from prior surgery. Note: 
Local procedures (eg, placement of a systemic port, CNB, and 
prostate biopsy) are allowed if completed at least 24 hours prior 
to the administration of the first dose of study intervention
≥ 4 weeks
Radiation therapy including palliative stereotactic radiation 
therapy to chest 
≥ 4 weeks
Palliative stereotactic radiation therapy to other anatomic areas 
including whole brain radiation (except as specified for CNS 
radiation, see exclusion criterion 2)
≥ 2 weeks
Anticancer chemotherapy (Immunotherapy [non-antibody-based 
therapy]), retinoid therapy, hormonal therapy
≥ 3 weeks
Antibody-based anticancer therapy
≥ 4 weeks
Targeted agents and small molecules 
≥ 2 weeks or 5 half-lives, whichever is 
longer
Nitrosoureas or mitomycin C
≥ 6 weeks
TKIs approved for treatment of NSCLC
≥ 1 week a
Chloroquine/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 
a
Baseline CT scan must be completed after discontinuation of TKI.
CART = cell-free and concentrated ascites reinfusion therapy; CNB = core needle biopsy; CNS = central nervous 
system; NSCLC = non-small cell lung cancer; TKI = tyrosine kinase inhibitor.
Reproduction
13 Evidence of post-menopausal status or negative serum pregnancy test for females of 
childbearing potential who are sexually active with a non-sterilised male partner. For 
WOCBP, a negative result for serum pregnancy test (test must have a sensitivity of at least 
25 mIU/mL) must be available at the screening visit and urine β-HCG pregnancy test prior 
to each administration of T-DXd. 
WOCBP are defined as those who are not surgically sterile (ie, underwent bilateral 
salpingectomy, bilateral oophorectomy, or complete hysterectomy) or post-menopausal. 
Women will be considered post-menopausal if they have been amenorrhoeic for 
12 months without an alternative medical cause. 
14 Female participants of childbearing potential who are sexually active with a non-sterilised 
male partner must use at least one highly effective method of contraception. Not all 
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effective birth control methods). 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 T-DXd). Female participants must refrain from breastfeeding while 
on study and for 7 months after the last dose of T-DXd. Complete heterosexual abstinence 
for the duration of the study and drug 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 study); however, periodic or occasional abstinence, the rhythm 
method, and the withdrawal method are not acceptable.
15 Non-sterilised male participants who are sexually active with a female partner of 
childbearing potential must use a condom with spermicide from screening to 4 months 
after the final dose of T-DXd. Complete heterosexual abstinence for the duration of the 
study and drug washout period is an acceptable contraceptive method if it is in line with 
the participant’s usual lifestyle (consideration must be made to the duration of the clinical 
study); however, periodic or occasional abstinence, the rhythm method, and the 
withdrawal method are not acceptable. It is strongly recommended for the female partners 
of a male participant to also use at least one highly effective method of contraception 
throughout this period. In addition, male participants should refrain from fathering a child, 
or freezing or donating sperm from the time of screening, during the study and for 4 
months after the last dose of T-DXd. Preservation of sperm should be considered prior to 
entering the study.
16 Female participants must not donate, or retrieve for their own use, ova from the time of 
screening and throughout the study intervention period, and for at least 7 months after the 
final study drug administration. Preservation of ova may be considered prior to entering 
the study. 
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Mixed small cell lung cancer, squamous histology NSCLC, and sarcomatoid histology 
variant NSCLC.
2
Any spinal cord compression, leptomeningeal disease, or clinically active CNS metastases. 
Note: Clinically active CNS metastases are defined as untreated AND symptomatic, or 
requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. 
Participants with CNS metastases must have previously completed local therapy.
∀
Participants with previously treated CNS metastases are allowed if asymptomatic or 
neurologically stable and have recovered from the acute toxic effects of prior therapy.
∀
Participants with CNS metastases treated by radiation must be:

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o
≥7 days since stereotactic radiosurgery or gamma knife prior to enrolment.
o
≥14 days since whole brain radiation therapy prior to enrolment.
3
Has a pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal 
shunt, or cell-free and concentrated ascites reinfusion therapy (CART). 
4
Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the investigator.
5
Multiple primary malignancies within 3 years with the exception of:
∀
adequately resected non-melanoma skin cancer.
∀
curatively treated in-situ disease.
∀
other solid tumours curatively treated. 
6
Participants with a medical history of myocardial infarction (MI) within 6 months before 
enrolment, symptomatic CHF (NYHA Class II to IV). Note: Participants with troponin 
levels above ULN at screening (as defined by the manufacturer), and without any 
myocardial related symptoms, should have a cardiologic consultation before enrolment to 
rule out MI.
7
Corrected QT interval (QTcF) prolongation to > 470 ms (females) or > 450 ms (males), 
based on average of the screening triplicate 12-lead ECG.
8
History of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
screening.
9
Lung criteria:
a)
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 COPD, restrictive lung disease, pleural effusion 
etc).
b)
Any autoimmune, connective tissue or inflammatory disorders (ie, rheumatoid 
arthritis, Sjogren’s, sarcoidosis, etc) where there is documented, or a suspicion of 
pulmonary involvement at the time of screening. Full details of the disorder should 
be recorded in the eCRF for participants who are included in the study.
c)
Prior complete pneumonectomy. Note: Prior lobar or segmental resection is 
permitted.
10 Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals or active 
infection including tuberculosis (clinical evaluation that includes clinical history, physical 
examination, and radiographic findings, and tuberculosis testing in line with local 
practice).
11 Active primary immunodeficiency, known HIV infection, or active hepatitis B or C 
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1 Day 1. Note: Participants positive for HCV antibody are eligible only if PCR is negative 
for HCV RNA. Participants should be tested for HIV prior to enrolment if required by 
local regulations or IEC. Subjects with past or resolved hepatitis B virus  (HBV) infection 
who are anti-HBc positive (+) are eligible only if they are HBsAg negative (-).
12 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 T-
DXd. Note: Participants, if enrolled, should not receive live vaccine during the study and 
up to 30 days after the last dose of T-DXd.
13 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.
Prior/Concomitant Therapy
14 Has unresolved toxicities from previous anticancer therapy, defined as toxicities 
(excluding alopecia) not yet resolved to Grade < 1 or baseline. Note: participants may be 
enrolled with chronic, stable Grade 2 toxicity (defined as no worsening to >Grade 2 for at 
least 3 months prior to enrollment and managed with standard of care treatment) that the 
investigator deems related to previous anticancer therapy, such as:
!
Chemotherapy-induced neuropathy
!
Fatigue
!
Residual toxicities from prior IO treatment: Grade 1 or Grade 2 endocrinopathies 
which may include:
a)
Hypothyroidism/hyperthyroidism
b)
Type 1 diabetes
c)
Hyperglycaemia
d)
Adrenal insufficiency
e)
Adrenalitis
f)
Skin hypopigmentation (vitiligo)
15 Has been previously treated with HER2-targeted therapies, except for pan-HER class 
TKIs, or has received prior treatment with an ADC which consists of an exatecan 
derivative that is a topoisomerase I inhibitor.
16 Any concurrent anticancer treatment (see Table 7 for adequate washout periods). 
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, insulin for 
diabetes and HRT) is allowed.
Prior/Concurrent Clinical Study Experience
17 Known allergy or hypersensitivity to T-DXd or any of the study drug excipients.
18 History of severe hypersensitivity reactions to other mAbs.

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Other Exclusions
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site).
20 Judgement 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.
21 Pregnant (confirmed with positive pregnancy test) or breastfeeding female participants, or 
participants who are planning to become pregnant. 
22 Has social, familial, or geographical factors that would interfere with study participation 
or follow-up.
23 Is a family member of the study site personnel or AstraZeneca personnel.
5.3
Lifestyle Considerations
The following restrictions apply while the participant is receiving study intervention and for 
the specified times before and after:
1
Participants must follow the contraception requirements outlined in Appendix F.
2
Participants should not donate blood or blood components while participating in this 
study and through 40 (+ 7) days after the last dose of T-DXd. 
3
Male participants should consider to preservation of sperm prior to entering the study.
4
Female participants must not donate, or retrieve for their own use, ova from the time of 
screening and throughout the study treatment period, and for at least 7 months after the 
final study drug administration. They should refrain from breastfeeding throughout this 
time. Female patients may wish to consider preservation of ova prior to entering the 
study.
Restrictions relating to concomitant therapies are described in Appendix G 1.
5.3.1
Meals and Dietary Restrictions
In general, there are no dietary restrictions for the study assessments or treatment with T-DXd.
5.3.2
Tobacco
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.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently assigned to study intervention. 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 

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queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened a single time. Rescreened participants should be assigned the same participant 
number (ie, E-code) as for the initial screening. However, rescreening should be documented 
so that its effect on study results, if any, can be assessed. 
Generally, all assessments should be repeated for rescreening unless they are within 28 days of 
enrolment (the date the participant is confirmed as eligible in the IRT). As of necessity of 
repeating central HER2 testing for defining eligibility, please contact AstraZeneca to discuss 
on a case-by-case basis.
These participants should have the reason for study withdrawal recorded in 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 (ie, participants 
who are not entered in the study). Participant enrolment is described in Section 6.3.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the CSP.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
AstraZeneca will supply T-DXd. 
The treatment schedule is described in Section 1.3
Dose modifications are described in Section 6.6.
Table 8
Study Intervention
ARM Name
T-DXd arm
Intervention Name
T-DXd
Type 
Drug
Dose Presentation
Vial
Unit Dose Strength(s)
Powder for concentrate for solution for infusion 
/vial
Dosage Level(s)/frequency
Route of Administration
IV infusion
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Use
Experimental
IMP and NIMP
IMP
Sourcing
Provided centrally by AstraZeneca
Packaging and Labelling
Study intervention will be provided in 
 vials in carton. 
Each vial and carton will be labelled in accordance with GMP 
Annex 13 and per country requirements a
Current/Former Name(s) or 
Alias(es)
DS-8201a
a
Label text for trastuzumab deruxtecan (T-DXd, DS-8201a) will show “DS-8201a”, depending on the agreed 
product name used in the respective approved study master label document. All naming conventions for 
these compounds are correct during this transitional period.
GMP = Good Manufacturing Practice; IMP = investigational medicinal product; IV = intravenous; 
NIMP = non-investigational medicinal product; Q3W = every 3 weeks; T-DXd = trastuzumab deruxtecan.
6.1.1.1
Duration of Treatment
Participants will receive T-DXd 
 
 Participants will continue to receive T-DXd until PD per RECIST 1.1 as assessed by the 
investigator, unless unacceptable toxicity, withdrawal of consent, or other criterion for 
withdrawal is met. 
Participants with objective radiological CNS-only progression (based on RECIST 1.1), who in 
the investigator’s opinion, continue to receive benefit from study intervention and meet the 
criteria for treatment in the setting of CNS-only progression may continue to receive study 
intervention on study for as long as they are gaining clinical benefit, as judged by the 
investigator, and are without any discontinuation criteria, until one of the criteria in 
Section 6.1.1.2 is met. Aside from within this context, study intervention treatment is not 
planned beyond progression with T-DXd. Participant level risk-to-benefit ratio favours 
discontinuing treatment as participants are highly unlikely to derive clinical benefit 
post-progression and remain at risk of ILD and other toxicities if treatment is continued.
6.1.1.2
Treatment Beyond Progression: CNS-only Progression
For participants with objective radiological CNS-only progression (based on RECIST 1.1), 
who in the investigator’s opinion, continue to receive benefit from study intervention and 
meet the criteria for treatment in the setting of CNS-only progression may continue to receive 
study intervention on study for as long as they are gaining clinical benefit (see Section 7.1.3
for details) and are without any discontinuation criteria, until one of the following criteria is 
met:
1. Meets any of the discontinuation criteria.
2. Clinical symptoms or signs indicating clinically significant PD such that the benefit-risk 
ratio of continuing therapy is no longer justified based on investigator judgement.
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3. Decline in WHO/ECOG performance status compared to baseline.
4. Rapid PD or threat to vital organs/critical anatomical sites (eg, spinal cord compression) 
requiring urgent alternative medical intervention, and/or continuation of study treatment 
would prevent institution of such intervention.
CNS-directed radiotherapy (stereotactic radiosurgery, gamma knife, or whole brain radiation 
therapy) for CNS-only progression is permitted on study only after consultation with the 
AstraZeneca study physician. Participants who pursue local definitive radiotherapy for 
CNS-only progression must not receive study intervention ± 7 days within receiving 
stereotactic radiosurgery or gamma knife, or ± 14 days within receiving whole brain 
radiotherapy. Those who receive CNS-directed radiotherapy for CNS-only progression, 
providing there is no other systemic progression, may be allowed to continue study 
intervention until a second progression (CNS or body) is observed. Study intervention will be 
discontinued at the time of second progression. 
Study intervention treatment is NOT permitted beyond progression when the site of PD is 
outside of the CNS. In the setting of PD outside of the CNS, participant level risk to-benefit 
ratio favours discontinuing treatment as participants are highly unlikely to derive clinical 
benefit post-progression and remain at risk of ILD and other toxicities if treatment is 
continued.
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.
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
The preparation, handling, storage, and administration instructions for T-DXd will follow the 
IP handling instructions.

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T-DXd will be supplied by AstraZeneca as a 
vial lyophilised powder for concentrate 
for solution for infusion. Following reconstitution with sterile water for injection, the solution 
contains 
 T-DXd in 
mM histidine/histidine hydrochloric acid, 
mg/mL sucrose, 
 polysorbate 80; it has a pH of 
. The post-reconstitution label-claim volume is 
5 mL.
The reconstituted product is a 
 
 
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 hrs.
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. Antiemetics 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. 
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 minutes ± 10 minutes for the first 
infusion. If the first infusion is well tolerated and the participant does not experience an 
infusion-related reaction, then the minimum infusion time for subsequent cycles is 30 minutes 
± 10 minutes. However, if there are interruptions during infusion, the total allowed time must 
not exceed 3 hours at room temperature. 
The participant’s weight at screening (baseline) will be used to calculate the initial dose. If, 
during the course of treatment, the participant’s weight changes by ≥ ± 10% of the screening 
(baseline) weight, the dose will be recalculated based on the participant’s updated weight.
Other drugs should not be co-administered with T-DXd through the same infusion line. 
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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 1).
Management of study intervention-related toxicities are described in Appendix K. As with any 
biologic product, allergic reactions to dose administration are possible. Therefore, appropriate 
drugs and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to 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. Storage conditions stated in the respective IBs may be 
superseded by the label storage instructions.
T-DXd vials are to be stored at 2 °C to 8 °C (36 °F to 46 °F) and must not be frozen. T-DXd 
must be kept in 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. 
Participants will begin treatment on the day of enrolment (confirmation of eligibility); every 
effort should be made to minimise the time between enrolment and first dose of study 
intervention (no later than 3 days). If it is anticipated that dosing cannot occur within 3 days, a 
discussion with the AstraZeneca study physician is required. Before the study is initiated, 
directions for the IRT will be provided to each site. The IRT will provide the kit identification 
number to be allocated to the participant at each dispensing visit.
If a participant withdraws from the study, then his/her enrolment code cannot be reused. 
Withdrawn participants will not be replaced.
Investigators should keep a record (ie, the participant screening log) of participants who 
entered screening.

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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. 
However, all screening laboratory and imaging results must have been obtained within 
28 days with exception that, if any case is out of this time window due to the central 
HER2 exon 19 and 20 mutation testing for defining eligibility or ophthalmologic 
assessments, the site should confirm with AstraZeneca on a case-by-case basis before 
moving to Cycle 1 Day 1. 
!
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.
!
Local results of EGFR, ALK, ROS 1, BRAF, NTRK, MET, KRAS, RET, or other driver 
mutation testing and PD-L1 expression status will be collected in the eCRF if available.
!
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 treatment on Day 1. Participants must not be enrolled and treated 
unless all eligibility criteria have been met.
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 enrolled in error, or 

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incorrectly started on treatment, the investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the investigator regarding whether to continue or discontinue the 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.
Methods for Assigning Treatment Groups
Not applicable; this is a single-group study.
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.
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.
Deviation(s) 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, or vaccine (including over-the-counter 
or prescription medicines, vitamins, and/or herbal supplements or other specific categories of 
interest) that the participant is receiving from the time of screening or receives during the 
study including the 40-day (+7-day) 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.

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The study physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
If any concomitant therapy is administered due to 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.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix G 1.
Drug-drug Interactions
There is no information to date on drug-drug interactions with T-DXd, either nonclinically or 
in participants. There may be a hypothetical interaction between T-DXd and 
hydroxychloroquine and/or chloroquine, therefore concomitant treatment with 
hydroxychloroquine or chloroquine is not allowed during the study intervention.
Guidance regarding potential interactions with concomitant medications is provided in 
Appendix G 1. Refer to Section 6.5.2 for details of required supportive treatments to be given 
with the study treatment interventions.
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. AstraZeneca 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 treatment). Concurrent use of hormones for noncancer-related conditions 
(eg, insulin for diabetes and HRT) is acceptable.

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∀
T-DXd cannot be administered when the participant is taking immunosuppressive 
medications, including corticosteroids with the following exceptions:
!
Short-term courses (< 2 weeks) of low to moderate dose (< 10 mg prednisolone 
per day or equivalent) .
!
Long-term, alternate-day treatment with short-acting preparations.
!
Maintenance physiologic doses (replacement therapy).
!
Administered topically (skin or eyes), by aerosol, or by intra-articular, bursal, 
or tendon injection. 
!
Treatment with corticosteroids to prevent or treat hypersensitivity reactions to 
radiographic contrast agents is allowed. A temporary period of steroid 
treatment will be allowed for different indications after discussion with the 
study physician (eg, COPD, radiation, nausea, etc). For steroid treatment of 
suspected ILD refer to TMGs.
!
Participants with bronchopulmonary disorders may use bronchodilators (such 
as albuterol) if only administered intermittently. 
!
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 SARS-CoV-2 infection (ie 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. Antiemetics 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.
!
Haematopoietic growth factors may be used for prophylaxis or treatment based on the 
clinical judgement of the investigator.

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!
Concomitant use of dietary supplements, medications not prescribed by the investigator, 
and alternative/complementary treatments is discouraged, but not prohibited.
!
Prophylactic or supportive treatment of study-drug induced AEs will be otherwise as per 
investigator’s discretion and institutional guidelines.
6.6
Dose Modification
In case a dose reduction is necessary, the study intervention will be administered as follows: 
Table 9
Dose Reduction Levels of T-DXd
T-DXd = trastuzumab deruxtecan.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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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 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 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 “Other non-laboratory adverse events” outlined in Appendix K. 
CCI

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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 8.2.5.3. 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.
All cases of potential ILD/pneumonitis will be reviewed internally by medical monitor and 
study safety physician. Safety Knowledge Group (SKG) members will also be consulted if 
needed. 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 
!
LVEF will be measured by either ECHO or MUGA scan. All ECHOs/MUGAs will be 
evaluated by the investigator or delegated physician for monitoring cardiac function. 
!
Troponin-T (preferably high-sensitivity troponin-T) will be measured locally at screening, 
EoT, and if at any time a participant reports signs or symptoms suggesting CHF, 
myocardial infarction, or other causes of cardiac myocyte necrosis. If ECG is abnormal, 
follow institutional guidelines. 
!
ECGs will be performed at timelines as specified in the SoA (Table 1) and if an 
abnormality is detected or if there is a troponin increase. Triplicate ECGs will be 
performed at screening and before infusion on C1D1. Subsequent ECGs will be
performed in triplicate only if abnormalities are noted. Twelve-lead ECGs will be 
performed, and standard ECG parameters will be measured, including RR, PR, QT 
intervals, and QRS duration. All ECGs must be evaluated by investigator or delegated 
physician for the presence of abnormalities prior to the injection of study intervention at 
every cycle. Whether or not measurement is performed, date performed, results, and 
findings for each parameter are to be recorded in the eCRF.  
!
Refer to Section 8.2.3 (ECG) and Section 8.2.5.1 (ECHO/MUGA) or details of 
investigations of cardiac function.
!
Refer to Appendix K for information on the management of cardiac toxicities related to 
the study intervention.

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Dose Modification Criteria for Suspected or Confirmed COVID-19
Refer to Appendix I for the dose modification and management plan for participants with 
confirmed or suspected COVID-19 who are being treated with T-DXd.
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.
After the final DCO for this study, AstraZeneca will continue to supply T-DXd to participants 
who received T-DXd until PD occurs as judged by the investigator or until meeting any other 
discontinuation criteria as defined in Section 7.1. 
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 
extension study would ensure treatment continuation with visit assessments per its protocol, as 
applicable. Any participant who would be proposed to move to such a study would be given a 
new informed consent, as applicable.
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 that 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 receipt of study intervention 
will need to be discontinued from the IRT.
Participants may be discontinued from study intervention in the following situations: 
!
RECIST 1.1-defined radiological progression per investigator outside of CNS (refer to 
Section 8.1.1 and Appendix E). See Section 6.1.1.2 for details of treatment beyond CNS-
only progression.
!
The investigator determination that the participant is no longer benefiting from study 
intervention.

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!
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 contraceptive requirements.
!
Initiation of subsequent anticancer therapy, including another investigational agent.
!
Study terminated by AstraZeneca.
!
Participant lost to follow-up.
!
Subjective disease progression (global deterioration of health status) without objective
evidence of PD according to RECIST 1.1.
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
Participants who are permanently discontinued from further receipt of study intervention, 
regardless of the reason, will be identified as having permanently discontinued treatment. 
End-of-Treatment is described as the date that the investigator makes the decision to 
discontinue the participant from all study intervention and not the last date that the participant 
received study intervention. The visit should occur within 7 days of the decision. Note: If EoT 
is > 40 days (+ 7 days) after last treatment, then EoT assessments can also function as the 
40-day (+ 7 days) follow-up visit (See Section 1 for details). In this instance, all assessments 
for the EoT visit as well as the 40-Day (+ 7 days) follow-up visit must be performed as 
indicated in . If T-DXd is discontinued due to RECIST 1.1-defined progression by 
investigator, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria, the 
EoT visit should be performed as soon as the participant is permanently discontinued from the 
last study intervention and will enter follow-up as Table 1.
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 days (+ 7 days) days after their last dose of study intervention. Additional 
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(Table 1). For ILD/pneumonitis, safety follow-up will continue until the resolution of 
ILD/pneumonitis.
Participants who have discontinued study intervention prior to objective RECIST 1.1-defined 
radiological progression, regardless of whether or not they have commenced subsequent 
anticancer therapy, will be followed up with tumour assessments as indicated in the SoA 
(Table 1) until RECIST 1.1-defined PD (plus one additional follow-up scan (4 weeks later), if 
clinically feasible) 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 1) 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, or local death registries as described in Section 7.2. Additional 
assessments to be performed at the time of survival follow-up are detailed in the SoA 
(Table 1).
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO). If participants are confirmed to be alive or 
if the death date is after the DCO date, then these participants will be censored at the date of 
DCO. 
7.1.3
Continuation on Study Intervention After CNS-only Progression
If a participant is found to have isolated progression in the CNS (including either 
parenchymal brain or dural metastases but not skull-based or leptomeningeal metastases) and 
does not have progression of disease outside the CNS, the participant may be eligible to 
continue on study interventions after completion of local treatment (radiotherapy) of the 
brain/dural metastases. Treatment with T-DXd must be temporarily stopped during local 
treatment of all participants with brain metastases (active or stable) and may continue until 
either systemic progression of disease or a second isolated CNS progression. The participant 
may continue on study provided the following criteria are met and the participant continues to 
demonstrate clinical benefit:
!
The participant is not experiencing any worsening of cancer-related symptoms. 
Participants who are clinically deteriorating and unlikely to receive further benefit from 
continued treatment should discontinue study intervention.
!
The participant is tolerating study intervention.
!
Review and concurrence by the AstraZeneca Study Physician or delegate.

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!
Participant has no evidence of unequivocal systemic progression of disease.
!
Participant has not had a previous isolated CNS progression while on study.
Study intervention may be withheld up to 126 days (from the date of last infusion) to allow 
local CNS therapy. Longer delays must be discussed and approved by the AstraZeneca Study 
Physician or delegate. All study interventions are to be withheld for a minimum of 1 week 
prior to planned CNS-directed therapy. Plans for holding and re-initiating study interventions 
before and after local therapy will require discussion with, and documented approval from, the 
AstraZeneca Study Physician or delegate. The durations of delays to study intervention that 
are required following radiation therapy are outlined in Section 6.1.1.2.
Following CNS-directed therapy for CNS-PD, the Investigators will continue to follow the 
participants and report CNS progression (worsening of current/new lesions) or systemic 
progression. Participants who undergo CNS-directed therapy while on study should maintain 
their regular assessment schedule, including monitoring of all AEs. All scans should continue
as scheduled for brain, chest, abdomen, and pelvis (see Table 1).
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 follow-up on any ongoing AEs and 
concomitant medications (eg, telephone contact at 40 days [+ 7 days] after study 
intervention is discontinued, 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 1). See SoA for 
data to be collected at the time of study withdrawal and follow-up 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, AstraZeneca 
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 he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
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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 CSP.
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, 
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. AstraZeneca 
personnel will not be involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of 10.
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participants in the Full Analysis and the Safety Analysis Sets should be re-checked; this 
includes those 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 (the applicable eCRF modules will be updated).
!
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 are summarised in the SoA (Table 1). 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.
!
Immediate safety concerns should be discussed with the AstraZeneca 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 
(Table 1), 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 (Table 1).
!
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.

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!
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 “progression/survival follow-up” site visits indicated in the SoA 
(Table 1). 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 evaluation scans will be performed at screening (as baseline) with follow-ups at 
Week 6 (±1)-week intervals from the date of enrolment for 48 weeks, and then every 
9 (±1) weeks thereafter, starting at Week 57 until RECIST 1.1-defined radiological PD per 
investigator assessment (plus one additional follow-up scan [4 weeks later], if clinically 
feasible). In the case of CNS-only progression, participants continuing to receive study 
intervention should follow the on-treatment data collection schedule, including RECIST 1.1 
tumour assessments, until a second progression (CNS or body; plus one additional follow-up 
scan [4 weeks later], if clinically feasible).
Tumour assessments use images from CT (preferred) or MRI, with IV contrast, of the chest, 
abdomen (including the entire liver and both adrenal glands), and pelvis, collected during 
screening/baseline and at regular (follow-up) intervals (at timelines as specified in the SoA, 
Table 1) during study intervention. Any other areas of disease involvement should be 
additionally imaged at screening based on known metastasis sites or by the signs and 
symptoms of individual participants. Scans (CT or MRI) of the chest, abdomen, and pelvis are 
mandatory. Brain CT or MRI is mandatory for all participants at screening and EoT
(participants with brain metastases are not required to undergo an additional brain scan at EoT 
if the latest brain assessment was within 4 weeks of EoT or if they discontinue study 
intervention prior to RECIST 1.1-defined radiological progression per investigator). 
Participants who are enrolled with baseline stable brain metastases will have mandatory brain 
scans at regular (follow-up) intervals during study intervention as per SoA (Table 1). 
Additional scans can be performed as clinically indicated (including for cases where the 
investigator suspects a participant develops new brain metastases). The imaging modality used 
for baseline tumour assessment, CT/MRI for chest and abdomen and MRI for brain, 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 

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to the SoA, Table 1) relative to the date of enrolment. Screening/baseline imaging should be 
performed no more than 28 days prior to enrolment starting (the date the participant is 
confirmed as eligible in the IRT) 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 
radiological progression (refer to Appendix E) unless unacceptable toxicity, withdrawal of 
consent, or other criterion for withdrawal is met (with the exception of CNS-only 
progression). 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. Scanning will 
continue if participants discontinue study intervention due to toxicity without progression until 
PD is detected.
The RECIST 1.1 assessments of baseline images identify TLs (defined as measurable) and 
NTLs. On-study images are evaluated for TLs and NTLs chosen at baseline, and for 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 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 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
Mandatory Tumour Tissue Sample
HER2 mutation for eligibility will be based on study qualifying activating HER2 exon 19 or 
20 mutation either from a pre-existing tissue test result obtained from qualified local 
laboratory/assay or have the tissue HER2 mutation test result detected prospectively in a 
central laboratory. Retrospective central confirmation will be performed for those enrolled 
based on existing local HER2 mutation(s) results during study. Note: In addition, mandatory 
archival (preferred) or newly collected tissue samples are required for central testing. Should 
discordance between local and central test be higher than anticipated, enrolment by local test 
may be closed. If a modification to not allow further enrolment of participants on the basis of 
a pre-existing HER2 mutation result is made, this change will be communicated to 
participating sites in a timely manner. Prospective analysis of HER2 mutation status of tumor 
tissue using central laboratory testing is encouraged. 

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A mandatory tissue sample will be required from all participants at screening. For participants
entering the study based upon a pre-existing local tumor tissue result, the pre-existing local 
HER2 mutation laboratory report and detailed information on the test method should be 
collected, maintained as a source document and captured in the eCRF. Participants entering 
the study based upon a pre-existing local tumor tissue result are still mandated to provide a 
FFPE tumor tissue for retrospective central confirmation testing. Central confirmation will not 
be mandated before enrolment for participants with a positive tissue HER2 mutation test result 
obtained from local laboratory. Discordance between pre-existing local HER2 results and 
confirmed central laboratory HER2 testing results has no impact on enrolment and study 
treatment of participants with study qualifying activating HER2 exon 19 or 20 mutation 
detected by local laboratory.
Archived FFPE surgical samples are preferred, however if participants do not have an 
adequate archival FFPE tumour tissue sample (surgical, CNB or FNA), for assessment of 
study-qualifying activating HER2 exon 19 and exon 20 mutation status (Section 8.6.1), then a 
CNB or FNA tumour tissue samples will be taken/biopsied to generate FFPE samples. These 
will be analyzed for study-qualifying activating HER2 exon 19 and exon 20 mutation status 
by a central laboratory designated by AstraZeneca. Samples collected will be used for 
eligibility check (for participants enrolled based on central lab assessment) or respective 
central confirmation (for participants enrolled based on existing local HER2 mutation results), 
and potential companion diagnostic filing if required by NMPA. See Section 8.6.1.1 for details 
of tumour sample collection.
8.1.4
Mandatory Blood Sample for Plasma-based ctDNA HER2 Mutation 
Testing
All participants must provide blood samples during screening period. The collected blood 
samples are to be tested to determine HER2 exon 19 and exon 20 mutation status 
retrospectively by a central laboratory designated by AstraZeneca for potential companion 
diagnostic development and filing in China.  See Section 8.6.1.2 for details of blood sample 
collection.
8.1.5
Overall Survival
Assessments for survival will be conducted every 3 months ± 14 days following objective PD 
or treatment discontinuation from the date of the safety follow-up. 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 Section 7.2.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).

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Whenever ECGs, vital signs, and blood draws are scheduled for the same nominal time, the 
suggested order is: ECG assessments 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 time points indicated in the SoA (Table 1). 
8.2.1
Physical Examinations
!
A complete physical examination will be performed and 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, gastrointestinal, endocrine, 
haematologic/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 and weight, will be performed at 
timelines as specified in the SoA (Table 1); investigators should pay special attention to 
clinical signs related to previous serious illnesses, new or worsening abnormalities may 
qualify as AEs, see Section 8.3.5 for details.
8.2.2
Vital Signs
Vital signs will be performed at timelines as specified in the SoA (Table 1). Vital signs should 
be evaluated by the investigator or the delegate physician prior to and at the end of infusion of 
study intervention on Day 1 of each cycle.
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
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.
Situations in which vital signs results should be reported as AEs are described in 
Section 8.3.5. 
For any AEs of infusion reactions, the vital signs values should be entered into the eCRF.

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8.2.3
Electrocardiograms
Triplicate ECGs will be performed at screening and before infusion on C1D1. Subsequent 
ECGs will be performed in triplicate only if abnormalities are noted. Single 12-lead ECGs will 
be performed at timelines as specified in the SoA (Table 1) after the participant has been 
resting for at least 5 minutes and recorded while the participant is in a supine/semi-recumbent 
position using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF intervals. Refer to 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 ECGs are required, 3 individual ECG tracings should be 
obtained in succession, no more than 2 minutes apart. The full set of triplicates should be 
completed within 5 minutes. If ECG is abnormal follow institutional guidelines.
Situations in which ECG results should be reported as AEs are described in Section 8.3.5. 
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 (Table 1).
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 clinical chemistry, haematology and urinalysis will be performed at a local laboratory at 
or near to 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 (serum at screening or urine 
other time points), and hepatitis B and C serology and HIV antibody test. Pregnancy tests may 
be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal 
clinically significant laboratory results should be repeated as soon as possible (preferably 
within 24 to 48 hours). 
Pregnancy tests will be conducted within 72 hours before enrolment for all WOCBP; a 
positive urine pregnancy test result must immediately be confirmed using a serum test. Repeat 
pregnancy tests (urine or serum test per institutional guideline) should be performed 72 hours 
before infusion of each cycle and at EoT. A negative result for serum pregnancy test (test must 
have a sensitivity of at least 25 mIU/mL) must be available at the screening visit and urine 
β-HCG pregnancy test prior to each administration of study intervention.

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The following laboratory variables included in Table 10 will be measured.
Table 10
Laboratory Safety Variables
Haematology/Haemostasis (Whole Blood)
Clinical Chemistry (Serum or Plasma) a
Haemoglobin
Creatinine
TBL
Leukocyte differential count (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
ALP
Platelet count
AST
Absolute neutrophil count
ALT
Absolute lymphocyte count
Albumin
Total white blood cell count
Potassium
Total red blood cell count
Calcium, total/Calcium
Haematocrit
Sodium
Gamma-glutamyl transferase
Urinalysis
Glucose (random)
Haemoglobin/erythrocytes/blood 
Lactate dehydrogenase
Protein/albumin 
Protein, total
Glucose 
Urea nitrogen/blood urea nitrogen/Urea
pH
Troponin (high-sensitive troponin-T preferred) b
Specific gravity
Magnesium
Chloride
Coagulation
Coagulation variables c (INR or PT and either PTT or 
aPTT)
a
Other tests may be performed if the investigator suspects an AE. 
b
See Section 6.6 for details of requirements for troponin testing.
c
Coagulation tests performed only at screening include INR and aPTT.
ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; 
AST = aspartate aminotransferase; INR = international normalised ratio; PT = prothrombin time; 
PTT = partial thromboplastin time; TBL = total bilirubin.
The investigator should assess the available results with regard to clinically relevant 
abnormalities in documentation. Any clinically significant abnormal laboratory values should 
be repeated as clinically indicated and recorded on the eCRF. Situations in which laboratory 
safety results should be reported as AEs are described in Section 8.3.5.
All 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.

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NB. In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN 
please refer to Appendix D “Actions required in cases of increases in liver biochemistry and 
evaluation of HL”, for further instructions. 
8.2.5
Other Safety Assessments
8.2.5.1
Echocardiogram/Multiple Gated Acquisition Scan 
An ECHO or MUGA scan to assess LVEF will be performed at the visits as shown in SoA 
(Table 1). 
The modality of the cardiac function assessments must be consistent for a given participant 
(ie, if ECHO is used for the screening assessment 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 or MUGA scan is not required unless 
clinically indicated. If a participant has any clinically significant decrease in LVEF (greater 
than 10 percentage points to below 50%), 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
SpO2 should be evaluated by investigator or the delegate physician prior to and after the 
administration of study intervention at each visit.
Pulmonary function tests should include basic spirometry at a minimum with optional 
additional components as mentioned in Table 11.

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Table 11
Spirometry Component
Required spirometry components
Optional spirometry components
FVC (L)
PEF
FVC % predicted
DLCO
FEV1 (L)
FEV6
FEV1 % predicted
TLC
FEV1/FVC %
RV
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; L = litres; PEF = peak expiratory flow; 
RV = residual volume; TLC = total lung capacity.
DLCO will be performed/encouraged if feasible, but for participants with prior severe and/or 
prior clinically significant pulmonary disorders, DLCO is strongly encouraged. In the event of 
suspected ILD/pneumonitis, refer to Section 8.2.5.3 additional pulmonary assessments.
HRCT of the chest will be preferred and recommended if feasible (otherwise CT is acceptable, 
CT Scan should be used only when HRCT is not available) 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.
8.2.5.3
ILD/Pneumonitis Investigation
If new or worsening pulmonary symptoms (eg, dyspnoea, cough or fever) or radiological 
abnormality suggestive of ILD/pneumonitis is observed, study intervention should be 
interrupted and a full investigation is required as described in the T-DXd TMGs 
(Appendix K). Refer to Appendix J for guidelines on management of study 
intervention-induced ILD/pneumonitis. 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.
!
Blood culture and complete blood count (CBC)  
!
Arterial blood gases, if clinically indicated.
!
Pulmonary function tests (Section 8.2.5.2) and SpO2.
!
Bronchoscopy and bronchoalveolar lavage, as clinically indicated and feasible.
!
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!
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.
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 done 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 the 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 (KL-6, SP-D) and β-D-glucan.
o
Tumour markers: particular tumour markers that are related to disease 
progression.
* Additional clinical chemistry: C-reactive protein, lactate dehydrogenase.
8.2.5.4
WHO/ECOG Performance Status
WHO/ECOG performance status will be assessed at the times specified in the SoA (Table 1) 
based on the following:
0
Fully active; able to carry out all usual activities without restrictions.
1
Restricted in strenuous activity, but ambulatory and able to carry out light work or work 
of a sedentary nature (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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8.2.5.5
Ophthalmologic Assessments
Ophthalmologic assessments will be performed as specified in the SoA (Table 1) and will 
include visual acuity testing, slit lamp examination and fundoscopy.
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.
AEs 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.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs and SAEs (other than ILD/pneumonitis) 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). For ILD/pneumonitis, safety 
follow-up will be continued until resolution of ILD/pneumonitis. 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 intervention, 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 AstraZeneca.
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 initiating the study intervention 
until 47 days after last dose of the study intervention.
The following types of events should be reported by the investigator in the AE/SAE eCRF 
pages 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 cases should be reported within 24 hours; including both serious and 
non-serious potential ILD cases (potential ILD/pneumonitis is described by the Event 
Adjudication Site Manual).

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!
Hepatic events (both serious and non-serious) which meet the 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.
!
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. 
!
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 EDC.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment or other assessment/visit 
as appropriate in the study are followed up by the investigator for as long as medically 
indicated, 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 when 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(s) (yes or no).
!
Action taken with regard to study intervention(s).
!
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:

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!
Date AE met criteria for SAE.
!
Date investigator became aware of SAE.
!
Seriousness criteria.
!
Date of hospitalisation.
!
Date of discharge.
!
Probable cause of death.
!
Date of death.
!
Autopsy performed.
!
Causality assessment in relation to study procedure(s).
!
Causality assessment to other medication.
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.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: “Have you had any health problems since the previous visit you were 
last asked?”, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.

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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 CSR. 
Deterioration as compared with baseline in protocol-mandated laboratory values, vital signs, 
physical examinations, ECGs, and ECHO/MUGA scans 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 limited to consideration as to whether treatment or non-planned 
visits were required or other action was taken with the study intervention, eg, dose adjustment 
or study intervention interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (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 AE(s).
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. Death due to disease progression should be 
recorded on the Death eCRF.

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8.3.8 Disease Under Study
Disease under study commonly occur in studies of chronic diseases with a variable pattern, eg, 
asthma; COPD; rhinitis; neuropsychiatric conditions such as depression, seizure disorders or 
multiple sclerosis; and cardiac disorders such as angina or heart failure. Symptoms of disease 
under study are those which might be expected to occur as a direct result of NSCLC. 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 
one of the serious criteria. New primary cancers are those that are not the primary reason for 
the administration of study intervention and are 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 PD 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.
!
Deaths 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, then it should also 
be reported as an SAE.
8.3.11
Adverse Events of Special Interest
AESIs are events of scientific and medical interest specific to the further understanding of 

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T-DXd safety profile and require 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.
AESIs 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.
Based on the available nonclinical 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: 
ILD/pneumonitis
ILD/pneumonitis is considered an important identified risk-based on a comprehensive 
cumulative review of potential ILD/pneumonitis cases reviewed by the independent ILD 
Adjudication Committee, the available safety data from the clinical development 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. 
Refer to Section 8.2.5.3 for details of investigations of ILD/pneumonitis.
LVEF Decrease
LVEF decrease in association with T-DXd is considered to be an important potential 
risk-based on the available nonclinical data, literature and available safety information for 
drugs of similar class. Refer to the current T-DXd IB for a summary of preliminary clinical 
trial data.
Refer to Section 8.2.3 (ECGs) and Section 8.2.5.1 (ECHO/MUGA) 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 the Final DCO of the Study
For participants continuing to receive T-DXd after the final DCO, AEs and SAEs will be 
collected, but only SAEs will be reported. In addition, it is recommended that investigators 
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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 notes but, with the exception of SAEs, will 
not otherwise be reported for the purposes of this study.
All SAEs that occur in participants still receiving T-DXd (or within the 40 +7 days following 
the last dose of T-DXd) after the final DCO must be reported as detailed in Section 8.3.13. 
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, then 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.
The reference document for definition of expectedness/listedness for T-DXd is the 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.

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8.3.14.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, 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 
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 in the course of the study, then the investigator or other site personnel 
informs 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 
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 and the PREGOUT is 
used to report the outcome of 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.

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8.3.15
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs 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 
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.
The definition of a medication error can be found 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 inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for overdoses associated with an SAE (see Section 8.3.13) 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 will be stored and disposed of according to local laws and regulations. PK 
and ADA samples will be destroyed after finalisation of Bioanalytical Report or completion of 
CSR.
For further details on Handling of Human Biological Samples, see Appendix C. 

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8.5.1
Pharmacokinetics
!
Serum samples will be collected for measurement of serum concentrations of intact 
T-DXd, total anti-HER2 antibody, and DXd as specified in the SoA (Table 1). 
!
Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and AstraZeneca, eg, 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 intact T-DXd, total anti-HER2 antibody, 
and DXd. Samples collected for analyses of intact T-DXd, total anti-HER2 antibody, and 
DXd serum 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 ADA and neutralising ADA in serum will be collected per 
the SoA (Table 1). 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 and or other 
exploratory safety biomarker. Please also refer to Appendix H.
8.5.3
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
Participant consent to the study includes participation in the mandatory biomarker assessment 
components of the study. 

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Tumour tissue and blood samples for biomarker assessment are required and will be collected 
from all participants in this study as specified in the SoA (Table 1).
8.6.1.1
Mandatory Tumour Tissue Samples
Tumour tissue samples will be tested by a central laboratory for study-qualifying activating 
HER2 exon 19 and 20 mutations to define eligibility to be enrolled for the study or 
retrospective central confirmation, and evaluate their association with the observed clinical 
responses to T-DXd.
Archived surgical resection samples are most preferred, however CNB is second preference 
and FNA is acceptable if surgical resection or CNB samples are not available. 
Unstained, archived FFPE tumour tissue slides with at least 20% tumour tissue remaining to 
allow for analysis (see the Laboratory Manual) must be made available. 
If an archived tumour block is not available, then newly cut, unstained slides with tissue 
sections of 
 thick may be provided for analysis as described in the Laboratory Manual. 
Participants will only undergo tumour biopsy (CNB or FNA) if it is considered a medically 
acceptable risk by the investigator and archived surgical tissue samples are not available.
The mandatory tumour biopsy must not be taken from a previously irradiated lesion. In case 
of CNB or FNA, 2 cores should be placed in formalin and processed to a single paraffin-
embedded block, as described in the Laboratory Manual. Tumour lesions used for newly 
acquired biopsies should not be the same lesions used as RECIST 1.1 TLs, unless there are no 
other lesions suitable for biopsy and in this instance only CNB or FNA is allowed.
Tumour tissue sample must be archived surgical resection, CNB or FNA FFPE samples or 
FFPE samples generated from CNB or FNA taken/biopsied following progression on the latest 
line of therapy.
Collection of tumour cells from fluid such as ascites or pleural effusion is not permitted.
8.6.1.2
Mandatory Blood Sample for Plasma-based ctDNA HER2 Mutation Testing
All participants must provide blood samples during screening period for retrospective central 
ctDNA testing to determine HER2 exon 19 and exon 20 mutation status.
8.6.1.3
Handling of Human Biological Samples
Tumour tissue and blood samples collected for HER2 exon 19 and exon 20 mutation testing 
from participants will be destroyed or repatriated maximally 5 years after study intervention is 
approved for marketing in China. To meet regulatory requirement, sections of the tumour and 
collected plasma may be retained that allow this for potential companion diagnostic filing in 
China, as requested by the NMPA.
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For further details on Handling of Human Biological Samples, including storage, re-use and 
destruction, refer to Appendix C and 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, 
with final amendments completed prior to database lock.
9.1
Statistical Hypotheses
This is a Phase 2, open-label, single-arm study in which all participants will receive the same 
study intervention at the same dose and schedule. The primary objective of the study is to 
evaluate the efficacy of T-DXd 
 by evaluating the confirmed ORR by ICR in 
participants with metastatic non-squamous NSCLC whose tumours have a HER2 exon 19 or 
20 mutation, with disease progression on or after at least one-line of treatment.
The primary endpoint of the study is confirmed ORR by ICR, defined as the proportion of 
participants with CR or PR, as assessed by ICR based on RECIST 1.1. The analysis will 
include enrolled participants with study qualifying activating HER2 exon 19 or 20 mutation 
assessed 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, confirmed ORR by ICR per RECIST 1.1 is considered an early signal for clinical 
benefit.
9.2
Sample Size Determination
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.3
Populations for Analyses
Analysis populations are defined in Table 12.
Table 12
Populations for Analysis
Population/Analysis Set
Description
ITT Analysis Set
All participants who signed an ICF and were enrolled in the study.
FAS
All enrolled participants with HER2 exon 19 or 20 mutation assessed by central 
laboratory.
Safety analysis set
All enrolled participants who have received at least 1 dose of study intervention. 
RES
All enrolled participants with HER2 exon 19 or 20 mutation assessed by central 
laboratory who received at least 1 dose of study intervention and had measurable 
disease at baseline by ICR.
PK analysis set
All enrolled participants who have 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 T-DXd 
ADA result and at least one non-missing post-baseline T-DXd ADA result.
ADA = anti-drug antibody; FAS = full analysis set; ICF = informed consent form; ICR = independent central 
review; ITT = intent to treat; PK = pharmacokinetic(s); RES = response evaluable set; T-DXd = trastuzumab 
deruxtecan.
9.4
Statistical Analyses
The SAP will be finalised prior to enrolment of the first participant in the study and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and secondary endpoints. Table 13 provides a summary of 
endpoints and corresponding analysis populations.
9.4.1
General Considerations
The DCO for the primary analysis of ORR by ICR will occur approximately 6 months after 
the last participant has initiated study intervention. DoR, DCR, and available safety, 
immunogenicity, and 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 U204, 
months is sufficient time for participants to reach a response (median time to response was 
1.4 months) and to allow DoR to be determined for responders (median confirmed DoR was 
12 months). The full final analysis will report the analyses of all primary and secondary 
endpoints, including updated ORR and DoR, DCR, BOR, PFS, OS, CNS-PFS, PK, 
immunogenicity and safety.
Table 13 provides a summary of endpoints and corresponding analysis populations.
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Summaries of data relating to participants diagnosed with COVID-19, and 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 
the SAP.
Table 13
Summary of Outcome Variables and Analysis Populations
Outcome variable
Population(s)
Primary Efficacy Variable
Confirmed ORR by ICR per RECIST 1.1
Primary analysis: FAS
Supplementary analyses: ITT Analysis 
Set, RES
Secondary Efficacy Variables
• Confirmed ORR by investigator assessment per RECIST 1.1
• DoR, DCR, BOR, and PFS, by ICR and by investigator 
assessment per RECIST 1.1 
• OS
• CNS-PFS
FAS a
Supplementary analyses: ITT Analysis 
Set a(only for ORR, DoR, PFS and OS)
Baseline and Other Variables
• Demography, baseline, and disease characteristics
• Important deviations
• Medical/surgical history
• Previous and subsequent anticancer therapy
• Concomitant medications/procedures
Primary analysis: FAS
Supplementary analyses: ITT Analysis 
Set (only for demography, disease 
characteristics and important deviations)
Pharmacokinetics
• PK data
PK analysis set
Immunogenicity
• ADAs
T-DXd ADA evaluable set
Safety
• Exposure to study intervention
• Safety data
Safety Analysis Set
a
DoR analysis will be based on the subset of participants in the corresponding analysis population who 
achieved confirmed response.
ADA = anti-drug antibody; BOR = best observed response; CNS = central nervous system; 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(s); 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
Primary Endpoint(s)
9.4.2.1.1
Calculation or Derivation of Tumour Response Variables
Investigator RECIST 1.1-based Assessments 
All RECIST 1.1 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 enrolment. The 
tumour response endpoints (PFS, ORR, BOR, and DoR) will then be derived from the scan 
dates and overall visit responses.
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). Endpoints (ORR, DoR, DCR, BOR, and PFS) 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.
9.4.2.1.2
Primary Endpoint: Confirmed ORR by ICR
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 number (percentage) of 
participants with a confirmed response of CR or PR as assessed by ICR based on RECIST 1.1. 
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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Analyses of Primary Endpoint
The primary analysis of the primary endpoint will be based on the 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 tumour response. 
Supplementary Analysis
Supplementary analysis of the primary endpoint will be performed in the RES and in the ITT 
Analysis Set 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.
9.4.2.2
Secondary Endpoint(s)
9.4.2.2.1
Confirmed ORR by Investigator Assessment
The secondary efficacy endpoint of confirmed 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.
Analysis Methods
Investigator assessed ORR will be estimated using the same methods as those specified for 
ORR by ICR for the FAS and ITT Analysis Set (see Section 9.4.2.1.2).
9.4.2.2.2
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).
Duration of Response by Investigator Assessment
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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 in the subset of participants in the FAS and ITT Analysis Set who 
achieved confirmed response.
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).
9.4.2.2.3
Disease Control Rate
Disease Control Rate by ICR
The DCR by ICR at the time of each DCO 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.
Disease Control Rate by Investigator Assessment
The DCR by investigator assessment at the time of each DCO 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.
Analysis Methods
DCR will be summarised descriptively with the number and percentage of participants with a 
confirmed CR/PR or SD for at least 5 weeks for the FAS.
9.4.2.2.4
Best Observed Response
Confirmed BOR by ICR
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 by ICR or the 
last evaluable assessment in the absence of RECIST 1.1-defined progression by ICR.
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 
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Confirmed BOR 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.
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 tumour 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 date of enrolment, 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 enrolment, BOR will be assigned to 
the NE category.
Analysis Methods
Confirmed BOR will be summarised descriptively by n (%) for each category (confirmed CR, 
confirmed PR, SD, PD, and NE) for the FAS.
9.4.2.2.5
Progression-Free Survival
Progression-free Survival by ICR
PFS by ICR will be defined as the time from the date of enrolment until the date of objective 
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 enrolment + 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 
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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] plus 1 week 
allowing for a late assessment within the visit window).
Progression-free Survival by Investigator Assessment
PFS by investigator assessment is defined as the time from the date of enrolment until the date 
of 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 enrolment + 1).
Data will be handled as described above for the PFS and ITT Analysis Set by ICR.
Analysis Methods
PFS will be summarised for the 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). 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 date of enrolment will be estimated.
9.4.2.2.6
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 analysed for the FAS and ITT Analysis Set.
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 (if calculable) using the Brookmeyer-Crowley method with log-log 
transformation (Brookmeyer and Crowley 1982). The proportion of participants alive at 
3-monthly intervals from the date of enrolment will be estimated.
9.4.2.2.7
CNS-PFS
CNS-PFS is defined as the time from the date of enrolment until the date of documented 
disease progression in the CNS as assessed by ICR using RECIST 1.1 or death by any cause 
in the absence of CNS progression. If CNS progression occurs, the date of CNS progression 
will be recorded as the date of the earliest RECIST 1.1 assessment where CNS progression 
was identified. Participants who have neither CNS progression nor death before the time of 
analysis will be censored at the latest date of their last evaluable RECIST 1.1 assessment. The 
analysis will include all enrolled participants defined in the FAS, regardless of whether the 

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participant withdraws from study intervention or receives another anticancer therapy.
A Kaplan-Meier plot of CNS-PFS will be presented. Summaries of the number and percentage 
of participants experiencing a CNS-PFS event and the type of event (RECIST 1.1 CNS-PD or 
death) will be provided along with appropriate descriptive statistics (based on Kaplan-Meier 
estimates).
9.4.2.3
Tertiary/Exploratory Endpoint(s)
 
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 for statistical analysis is the last non-missing value prior to 
administration of the first dose of study intervention. Details are described in the SAP.
Adverse Events
AEs will be coded using the most recent version of MedDRA that will be released for 
execution at AstraZeneca and NCI CTCAE v5.
Any TEAE occurring until 47 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. 
Separate TEAE tables will be provided taking into consideration the relationship to study 
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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.
AEs occurring prior to start of study intervention, TEAEs and post-treatment AEs will be 
presented separately.
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 = 

√
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 performed 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)
A shift table for urinalysis will be presented with baseline assessment against the maximum on 
study intervention category. 

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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 WHO/ECOG 
performance status, elevated troponin levels, ECHO/MUGA, and ophthalmologic findings, 
will be listed.
More detail will be described in the SAP.
9.4.4
Other Analyses
9.4.4.1
Pharmacokinetics
Serum PK concentration data for intact T-DXd, total anti-HER2 antibody and DXd will be 
listed for each sampling time for each participant, and a summary will be provided for all 
participants in the PK Analysis Set. Descriptive statistics may be calculated.
Details of PK, PopPK, and/or exposure-response analyses will be described in the SAP prior 
to enrolment of the first participant in the study. The PopPK and exposure-response analyses 
will be presented separately from the main CSR. 
9.4.4.2
Biomarkers
Biomarker status will be assessed for all participants, more detailed information will be 
described in the SAP. 
9.4.4.3
Immunogenicity Data 
Anti-drug antibody data will be summarised 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.
9.5
Interim Analyses 
An interim analysis is not planned in this study.

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9.6
Data Monitoring Committee
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 independent 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. This data collection will be triggered for 
adverse events reported based on a set of pre-defined list of PTs eligible for adjudication as 
described by the Event Adjudication Site Manual. Further details can be found in the ILD 
Adjudication Charter.

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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 CSP 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 CSP, CSP 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 CSP 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 
CRO but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for Serious Adverse Events
!
Prompt notification by the investigator to AstraZeneca 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.
!
AstraZeneca has a legal responsibility to notify both the local Regulatory Authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the Regulatory Authority, 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 AstraZeneca 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 AstraZeneca will 
review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 

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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.
If a participant’s partner becomes pregnant during or within 4 months after the last dose of 
study intervention, the partner is asked to sign the “Adult Study Informed Consent Form for 
Pregnant Partners of Study Participants” and provide information about the pregnancy 
accordingly.
A 4
Data Protection
!
Participants will be assigned a unique identifier by AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca 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 
AstraZeneca 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 

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AstraZeneca, by appropriate IRB/IEC members, and by inspectors from Regulatory 
Authorities.
Unless previously specified, the biomarker data will have unknown clinical significance and 
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 
CSP.
A 5
Committees Structure
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.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov, and https://www.clinicaltrialsregister.eu/ as will the summary of 
the study results when they are available. The clinical study and/or summary of study results 
may also be available on other websites (www.chinadrugtrials.org.cn) according to the 
regulations of the country (China) 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 AstraZeneca 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 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

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!
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.
!
AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
CROs).
!
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 CSP 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 CSP) 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 
AstraZeneca. No records may be transferred to another location or party without written 
notification to AstraZeneca.
A 8
Source Documents
!
Source documents provide evidence for the existence of the 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.
!
All information in original records and certified copies of original records of clinical 
findings, observations, or other activities in a clinical study necessary for the 
reconstruction and evaluation of the study are defined as source documents. Source data 
are contained in source documents (original records or certified copies).
!
A digital copy of all imaging scans should be stored as source documents.
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.
AstraZeneca designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of AstraZeneca. Study sites will be closed upon study 

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completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by AstraZeneca or investigator may include but 
are not limited to:
!
Failure of the investigator to comply with the CSP, the requirements of the IRB/IEC or 
local health authorities, AstraZeneca’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, AstraZeneca shall promptly inform the 
investigators, the IECs/IRBs, the Regulatory Authorities, and any CRO(s) 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 AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments.
!
AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca will generally 
support publication of 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 (eg, 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-patient 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.
AEs 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 judgement 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 removed via cone biopsy.
The above instruction applies only when the malignant tumour event in question is a new 

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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 judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, 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 
judgement must be used.
!
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment.
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine.
!
Intensive treatment in an emergency room or at home for allergic bronchospasm.
!
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation.
!
Development of drug dependency or drug abuse.

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Intensity Rating Scale
The grading scales found in the revised NCI CTCAE latest version 5.0 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.
In difficult cases, other factors could be considered such as:

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!
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 judgement. 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, eg, 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.
!
Drug not stored as instructed, eg, kept in the fridge when it should be at room 
temperature. 

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!
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 centre 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 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. If the participant withdraws consent without opting 
out for the subsequent use of the donated samples, then the samples will be used as per CSP.
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, eg, 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, eg, 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).
!
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI

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CCI

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CCI

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CCI

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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 15.
Table 15
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 = positron emission tomography; MRI = magnetic resonance imaging.
CT and MRI 
CT with IV contrast is the preferred imaging modality (although MRI with IV contrast is 
acceptable if CT is contraindicated) to generate reproducible anatomical images for 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 Table 1), 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 (Table 1). 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 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.
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.

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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 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 
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.

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18F-Fluoro-deoxyglucose-PET/CT
18F-fluoro-deoxyglucose-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 
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 
                                               
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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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
!
Previously irradiated lesions.4
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.
                                               
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.
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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!
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 
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.

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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).
Special Cases for TL Assessment at Follow-up:
!
If a lesion has completely disappeared, the diameter should be recorded as 0 mm. If a 
lesion appears in the same location on a subsequent scan, it will be recorded as an NL.
!
If a TL splits into 2 or more parts, the sum of the diameters of those parts should be 
recorded.
!
If 2 or more TLs merge, then the sum of the diameters of the combined lesion should be 
recorded for one of the lesions and 0 mm recorded for the other lesion(s). If the merged 

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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 16
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 
baseline. Measurements are not required for these lesions, but their status should be followed 
at subsequent visits. At each visit, an overall assessment of the NTL response should be 
recorded by the investigator.
To achieve “unequivocal progression” on the basis of NTLs, there must be an overall level of 
substantial worsening in non-target disease such that, even in presence of SD or PR in TLs, 

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the overall tumour burden has increased sufficiently to merit unequivocal progression by 
NTLs. A modest “increase” in the size of one 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 17
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 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.
NE
Only relevant when one 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.
NA
Only relevant if no NTLs present at baseline.
CR = complete response; NA = not applicable; NE = not evaluable; NTL = non-target lesion; 
PD = progression of disease; 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 one 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, eg, 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.
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 18.

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Table 18
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.
Evaluation of Scans Subsequent to RECIST 1.1-defined Progression
A follow-up scan is requested at least 4 weeks after a RECIST 1.1-defined radiological 
progression and no longer than the next regularly scheduled imaging visit. The follow-up 
scans provide additional information to the investigator for participant management and 
further treatment decisions, and since the published RECIST 1.1 criteria (Eisenhauer et al 
2009) do not provide guidance on how to assess scans acquired after RECIST 1.1-defined PD, 
supplemental instructions for investigators on how to evaluate these follow-up scans are 
provided below. An immediate prior RECIST 1.1-defined radiologic PD would be considered 
confirmed if any of the following criteria are met in the subsequent follow-up scan:
!
≥20% increase and at least a 5 mm increase in the sum of diameters of TLs compared 
with the nadir sum of diameters at 2 consecutive visits, and a further increase of ≥5 mm 

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in the sum of diameters at the follow-up scan time point compared with the immediate 
prior time point.
!
Significant progression (worsening) of NTLs at the follow-up scan time point compared 
with the immediate prior time point.
!
Significant progression (worsening) of previously NLs (pre-existing NLs) at the 
follow-up scan time point compared with the immediate prior time point.
!
Additional brand-new unequivocal lesions at the follow-up scan time point.
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.
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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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F 2
Male Participants with a Female Partner of Childbearing 
Potential
 
 
 
 
 
 
 
 
 
 
F 3
Highly Effective Methods of Contraception
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly, are described in Table 19. 
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 19
Highly Effective Methods of Contraception (<1% Failure Rate)
Non-Hormonal Methods
Hormonal Methods
•
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of the 
participant)
•
Vasectomised sexual partner (with participant 
assurance that partner received post-vasectomy 
confirmation of azoospermia)
•
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 H
Instructions Related to COVID-19
The instruction below should only be implemented if allowable by local/regional guidelines 
and following agreement from AstraZeneca.
Benefit-Risk Considerations for COVID-19
The emergence of 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 Section 5.2).
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion Criteria
!
Prior and Concomitant Medications
 
 
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COVID-19 Assessment(s)
 
 
 
 
Dose Modification Criteria
 
 
 
Dose Modification Criteria for Suspected or Confirmed COVID-19
 
 
 
 
 
                                               
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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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 AstraZeneca.
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 re-screen a participant in addition to that 
detailed in Section 5.4. The procedures detailed in Section 6.3 must be undertaken to confirm 
eligibility. Rescreened participants should retain the same participant number as for the initial 
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Telemedicine Visit to Replace On-site Visit (Where Applicable)
In this appendix and the associated Study Instruction Manual for Mitigation Due to Civil 
Crisis, Natural Disaster or Public Health Crisis, the term telemedicine visit refers to remote 
contact with the participants using telecommunications technology including phone calls, 
virtual or video visits, and mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs and concomitant medication to be reported and 
documented.
Data collected during telemedicine will be captured by the participant themselves.

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Appendix K
Toxicity Management Guidelines
Table 24
Toxicity Management Guidelines for T-DXd
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 24
Toxicity Management Guidelines for T-DXd
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 24
Toxicity Management Guidelines for T-DXd
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 24
Toxicity Management Guidelines for T-DXd
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 24
Toxicity Management Guidelines for T-DXd
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 24
Toxicity Management Guidelines for T-DXd
 
 
 
 
 
 
 
 
 
 
 
.
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Appendix L
 
 
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Table 25
Study-qualifying Activating HER2 Exon 19 and 20 Mutations
HER2 Mutation
Gene Location
SNV or InDel
p.D769H 
TKD - Exon 19
SNV
p.D769N
TKD - Exon 19
SNV
p.D769Y
TKD - Exon 19
SNV
p.I767F
TKD - Exon 19
SNV
p.L755_E757delinsS
TKD - Exon 19
InDel
p.L755_T759delLRENT
TKD - Exon 19
InDel
p.L755A
TKD - Exon 19
SNV
p.L755M 
TKD - Exon 19
SNV
p.L755P
TKD - Exon 19
SNV
p.L755S
TKD - Exon 19
SNV
p.L755W
TKD - Exon 19
SNV
p.I767M
TKD - Exon 19
SNV
p.A775_G776insV
TKD - Exon 20
InDel
p.A775_G776insYVMA (p.Y772_A775dup)
TKD - Exon 20
InDel
p.A775_G776insTVMA 
(p.Y772_V773insVMAT)
TKD - Exon 20
InDel
p.G776_V777insL
TKD - Exon 20
InDel
p.G776_V777insVC
TKD - Exon 20
InDel
p.G776_V777insVGC (p.G778_S779insCVG)
TKD - Exon 20
InDel
p.G776>LC
TKD - Exon 20
InDel
p.G776delinsVC (p.G776>VC)
TKD - Exon 20
InDel
p.G776C
TKD - Exon 20
SNV
p.G776S
TKD - Exon 20
SNV
p.G776V 
TKD - Exon 20
SNV
p.G778dup (p.V777_G778insG)
TKD - Exon 20
InDel
p.G778_P780dup (p.P780_Y781GSP, 
V777_G778insGSP)
TKD - Exon 20
InDel
p.G778_S779insCPG (p.V777_G778insGCP)
TKD - Exon 20
InDel
p.G778_S779insLPS
TKD - Exon 20
InDel
p.S779_P780insVGS
TKD - Exon 20
InDel
p.V777_G778insCG
TKD - Exon 20
InDel
p.V777L
TKD - Exon 20
SNV
p.V777M 
TKD - Exon 20
SNV
p.T798I
TKD - Exon 20
SNV
HER2 = human epidermal growth factor receptor 2.

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Appendix M Abbreviations
Abbreviation or Special 
Term
Explanation
5-HT3
5-hydroxytryptamine 3
ADA
anti-drug antibody
ADC
antibody-drug conjugate
AE
adverse event
AESI
adverse event of special interest
Akt
PI3K/protein kinase b
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-21d
area under the concentration-time curve from time 0 to Day 21
β-HCG 
beta-human chorionic gonadotropin
BOR
best observed response
BRAF
v-raf murine sarcoma viral oncogene homolog B1
CHF
congestive heart failure
CI
confidence interval
Cmax
maximum observed concentration
CNB
core needle biopsy
CNS
central nervous system
CNS-PFS
central nervous system progression-free survival
COPD
chronic obstructive pulmonary disorder
COVID-19
coronavirus disease
CR
complete response
CRO
Contract Research Organisation
CSCO
Chinese Society of Clinical Oncology
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
Ctrough
trough serum concentration 
DAR
drug-antibody ratio

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Abbreviation or Special 
Term
Explanation
DCO
data cut-off
DCR
disease control rate
DILI
drug-induced liver injury
DLCO
diffusion capacity of the lungs for carbon monoxide
DoR
duration of response
DXd
MAAA-1181a (deruxtecan)
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EoT
end-of-treatment
FAS
full analysis set
FDA
Food and Drug Administration
FFPE
formalin-fixed and paraffin-embedded
FH-FMI CG
Flatiron Health-Foundation Medicine NSCLC clinico-genomic [database] 
FNA
fine needle aspirate
GCP
Good Clinical Practice
GGFG
glycine–glycine–phenylalanine–glycine
HCV
hepatitis C virus
HER2
human epidermal growth factor receptor 2
HIV
human immunodeficiency virus
HL
Hy’s Law
HRCT
high-resolution computed tomography
HRT
hormone replacement therapy
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
immunohistochemistry

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Abbreviation or Special 
Term
Explanation
ILD
interstitial lung disease
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous
KEAP1
kelch-like ECH-associated protein 1 
KRAS
kirsten rat sarcoma 2 viral oncogene homolog
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MAPK
mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
mNSCLC
metastatic non-small cell lung cancer
MET
MET proto-oncogene, receptor tyrosine kinase
MRI
magnetic resonance imaging
MUGA
multigated acquisition
NCI
National Cancer Institute
NE
not evaluable
NK1
Neurokinin 1
NL
new lesion
NMPA
National Medical Products Administration
NRG1
neuregulin 1
NSCLC
non-small cell lung cancer
NTL
non-target lesion
NTRK1
neurotrophic receptor tyrosine kinase
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
PD
progression of disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death-ligand 1
PET
positron emission tomography
PFS
progression-free survival
PHL
Potential Hy’s Law
PK
pharmacokinetic(s)
PopPK
population pharmacokinetic(s)

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Abbreviation or Special 
Term
Explanation
PR
partial response
Q3W
every 3 weeks
QTcF 
QT interval corrected by Fridericia’s formula
RECIST 1.1
Response Evaluation Criteria in Solid Tumours, Version 1.1
RET
rearranged during transfection
RNA
ribonucleic acid
ROS
ROS proto-oncogene receptor tyrosine kinase
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SD
stable disease
SoA
Schedule of Activities
SoC
standard of care
SpO2
pulse oximetry
STK11
serine/threonine kinase 11 
TBL
total bilirubin
T-DM1
trastuzumab emtansine
T-DXd
trastuzumab deruxtecan
TEAE
treatment emergent adverse event
TKI
tyrosine kinase inhibitor
TL
target lesion
TMG
toxicity management guideline
ULN
upper limit of normal
US
United States 
WHO
World Health Organisation
WOCBP 
woman/women of childbearing potential
w/v
weight per volume

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7811c00001-csp-v2
Document Title:
D7811C00001 Clinical Study Protocol version 2
Document ID:
Version Label:
2.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
27-Apr-2022 16:26 UTC
Content Approval
27-Apr-2022 09:20 UTC
Management Approval
27-Apr-2022 10:27 UTC
Qualified Person Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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