A Phase 2, Multicenter, Randomized, Study of Trastuzumab Deruxtecan in Participants With HER2-overexpressing Locally Advanced, Unresectable or Metastatic Colorectal Cancer (DESTINY-CRC02)
Phase: PHASE2
Conditions: Advanced Colorectal Cancer
Sponsor: Daiichi Sankyo

 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
A PHASE 2, MULTICENTER, RANDOMIZED STUDY OF 
TRASTUZUMAB DERUXTECAN IN SUBJECTS WITH 
HER2-OVEREXPRESSING LOCALLY ADVANCED, 
UNRESECTABLE OR METASTATIC COLORECTAL 
CANCER (DESTINY-CRC02) 
 
 
PROTOCOL NUMBER: DS8201-A-U207  
IND NUMBER 136179  
EudraCT NUMBER 2020-004782-39  
 
VERSION 1.0, 29 Oct 2020 
 
DAIICHI SANKYO, INC 
211 MOUNT AIRY ROAD 
BASKING RIDGE, NEW JERSEY 07920 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc.  The information is 
provided to you in confidence which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo, Inc.

PPD
PPD

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 3 
DOCUMENT HISTORY 
 
 
Version Number 
Version Date 
1.0 
29 Oct 2020 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 4 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
1. 
PROTOCOL SUMMARY ..............................................................................................12 
1.1. 
Protocol Synopsis ............................................................................................................12 
1.2. 
Study Schema ..................................................................................................................22 
1.3. 
Schedule of Events ..........................................................................................................23 
2. 
INTRODUCTION ...........................................................................................................39 
2.1. 
Background ......................................................................................................................39 
2.1.1. 
Investigational Product Trastuzumab Deruxtecan (T-DXd; DS-8201a) .........................40 
2.2. 
Study Rationale ...............................................................................................................40 
2.3. 
Benefit and Risk Assessment ..........................................................................................41 
2.3.1. 
Benefit/Risk in Regard to SARS-CoV-2 .........................................................................42 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS ....................................43 
3.1. 
Rationale for Selection of Primary and Secondary Endpoints ........................................47 
4. 
STUDY DESIGN ............................................................................................................48 
4.1. 
Overall Design .................................................................................................................48 
4.1.1. 
Design Overview .............................................................................................................48 
4.1.2. 
End of Study ....................................................................................................................50 
4.1.3. 
Dose Regimen .................................................................................................................50 
4.1.4. 
Duration ...........................................................................................................................51 
4.2. 
Rationale for Study Design .............................................................................................51 
4.3. 
Justification for Dose .......................................................................................................51 
5. 
STUDY POPULATION ..................................................................................................53 
5.1. 
Inclusion Criteria .............................................................................................................53 
5.2. 
Exclusion Criteria ............................................................................................................55 
5.3. 
Screening Failures, Rescreening, and Subject Replacement ...........................................57 
6. 
STUDY TREATMENT ...................................................................................................58 
6.1. 
Study Drug Description ...................................................................................................58 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug ..............................58 
6.2.1. 
Preparation, Handling, and Disposal ...............................................................................58 
6.2.2. 
Administration .................................................................................................................58 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 5 
6.2.3. 
Storage .............................................................................................................................59 
6.2.4. 
Drug Accountability ........................................................................................................59 
6.3. 
Measure to Minimize Bias: Randomization and Blinding ..............................................60 
6.3.1. 
Method of Treatment Allocation .....................................................................................60 
6.3.1.1. Stage 1 .............................................................................................................................60 
6.3.1.2. Stage 2 .............................................................................................................................60 
6.3.2. 
Blinding ...........................................................................................................................60 
6.3.3. 
Emergency Unblinding Procedure ..................................................................................61 
6.4. 
Treatment Compliance ....................................................................................................61 
6.5. 
Guidelines for Dose Modification ...................................................................................61 
6.5.1. 
Dose Reduction Guidelines .............................................................................................62 
6.5.2. 
Dose Interruption and Modification / Toxicity Management Guidelines for 
T-DXd ..............................................................................................................................62 
6.6. 
Prior and Concomitant Medications ................................................................................69 
6.6.1. 
Prohibited Therapies/Products .........................................................................................69 
6.6.2. 
Permitted Therapies/Products ..........................................................................................70 
6.6.3. 
Restricted Products ..........................................................................................................70 
7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION FROM 
THE STUDY ...................................................................................................................71 
7.1. 
Discontinuation of Study Drug ........................................................................................71 
7.1.1. 
Procedures for Discontinuation from Study Drug ...........................................................72 
7.1.2. 
Modified Follow-up Options ...........................................................................................72 
7.2. 
Subject Withdrawal/Discontinuation from the Study ......................................................72 
7.2.1. 
Withdrawal Procedures ...................................................................................................73 
7.3. 
Lost to Follow-up ............................................................................................................74 
8. 
STUDY PROCEDURES .................................................................................................75 
8.1. 
Eligibility Assessment .....................................................................................................75 
8.1.1. 
Informed Consent ............................................................................................................75 
8.1.2. 
Qualifying Tumor Tissue Specimen ................................................................................75 
8.1.3. 
Colorectal Cancer History ...............................................................................................76 
8.1.4. 
HER2-overexpression Status ...........................................................................................76 
8.1.5. 
General Medical History and Baseline Conditions .........................................................76 
8.1.6. 
Demographics ..................................................................................................................76 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 6 
8.1.7. 
Human Immunodeficiency Virus Antibody Test ............................................................76 
8.1.8. 
Hepatitis Screening ..........................................................................................................76 
8.2. 
Randomization/Registration ............................................................................................76 
8.3. 
Efficacy Assessments ......................................................................................................77 
8.3.1. 
Primary Efficacy Endpoint ..............................................................................................77 
8.3.2. 
Secondary Efficacy Endpoints ........................................................................................77 
8.3.3. 
Exploratory Efficacy Endpoints (Including QoL and Biomarker) ..................................77 
8.3.4. 
Radiographic Tumor Assessments ..................................................................................78 
8.3.5. 
Response Assessment ......................................................................................................79 
8.3.6. 
Subsequent Anticancer Treatments .................................................................................79 
8.3.7. 
Survival Follow-up ..........................................................................................................79 
8.4. 
Safety Assessments .........................................................................................................80 
8.4.1. 
Adverse Event .................................................................................................................80 
8.4.1.1. Method to Detect Adverse Events ...................................................................................80 
8.4.1.2. Time Period for Collecting Adverse Events, Including AESIs and Serious 
Adverse Events ................................................................................................................80 
8.4.1.3. Reporting Procedure for Investigators .............................................................................81 
8.4.1.4. Disease-Specific AEs and SAEs .....................................................................................81 
8.4.1.5. Treatment-Emergent Adverse Events ..............................................................................81 
8.4.1.6. Serious Adverse Events Reporting ..................................................................................81 
8.4.1.7. Overdose ..........................................................................................................................82 
8.4.1.8. Combined Elevations of Aminotransferases and Bilirubin .............................................83 
8.4.1.9. Adverse Events of Special Interest ..................................................................................83 
8.4.2. 
Pregnancy ........................................................................................................................85 
8.4.2.1. Pregnancy Test ................................................................................................................85 
8.4.3. 
Clinical Laboratory Evaluations ......................................................................................85 
8.4.4. 
Other Safety .....................................................................................................................86 
8.4.4.1. Physical Examinations .....................................................................................................86 
8.4.4.2. Vital Signs .......................................................................................................................86 
8.4.4.3. ECOG Performance Status ..............................................................................................86 
8.4.4.4. Electrocardiograms ..........................................................................................................86 
8.4.4.5. Multigated Acquisition Scan or Echocardiogram ...........................................................87 
8.4.4.6. Pulmonary Assessments ..................................................................................................87 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 7 
8.4.4.7. Ophthalmological Examinations .....................................................................................87 
8.5. 
Health Economics and Outcomes Research ....................................................................87 
8.5.1. 
Patient-Reported Outcomes .............................................................................................87 
8.5.1.1. EORTC QLQ-C30 and EORTC QLQ-CR29 ..................................................................88 
8.5.1.2. EuroQol-5 Dimensions-5 Levels of Severity ..................................................................88 
8.5.1.3. Patient Global Impression-Treatment Tolerability ..........................................................89 
8.5.1.4. Patient Global Impression-Severity .................................................................................89 
8.5.1.5. Patient Global Impression-Change ..................................................................................89 
8.5.1.6. Administration of Patient-Reported Outcome Measures ................................................89 
8.5.2. 
Hospitalization-Related Endpoints (Healthcare Resource Use) ......................................90 
8.6. 
Pharmacokinetic (PK) Assessment(s) .............................................................................91 
8.7. 
Pharmacodynamic Assessment(s) ...................................................................................92 
8.7.1. 
Pharmacodynamic Assessments in Blood Samples and Tumor Specimens ...................92 
8.7.1.1. Optional Tumor Biopsy Sample ......................................................................................93 
8.7.2. 
Optional Pharmacogenomic (Inherited Genetic) Analysis ..............................................93 
8.7.2.1. Optional Banking of Specimens for Inherited Genetic Analysis ....................................94 
8.7.3. 
Immunogenicity ...............................................................................................................94 
9. 
STATISTICAL CONSIDERATIONS ............................................................................96 
9.1. 
General Statistical Considerations ...................................................................................96 
9.2. 
Statistical Hypothesis ......................................................................................................96 
9.3. 
Sample Size Determination .............................................................................................96 
9.4. 
Population for Analysis Sets ...........................................................................................98 
9.5. 
Statistical Analysis ..........................................................................................................99 
9.5.1. 
Efficacy Analyses ............................................................................................................99 
9.5.1.1. Primary Efficacy Analyses ..............................................................................................99 
9.5.1.2. Secondary Efficacy Analyses ..........................................................................................99 
9.5.1.3. Exploratory Analyses ....................................................................................................100 
9.5.1.4. Multiplicity Adjustment ................................................................................................101 
9.5.2. 
Safety Analyses .............................................................................................................101 
9.5.3. 
HEOR Analysis .............................................................................................................102 
9.5.4. 
Other Analyses ..............................................................................................................103 
9.6. 
Interim Analysis ............................................................................................................103 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 8 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ....................................................................................................105 
10.1. 
Appendix 1 Regulatory and Ethical Considerations .....................................................105 
10.1.1. Regulatory Compliance .................................................................................................105 
10.1.2. Informed Consent ..........................................................................................................106 
10.1.3. Subject Confidentiality ..................................................................................................107 
10.1.4. Data Integrity and Quality Assurance ...........................................................................107 
10.1.5. Committees ....................................................................................................................109 
10.1.6. Study Documentation and Storage ................................................................................109 
10.1.7. Finances .........................................................................................................................110 
10.1.8. Publication, Public Disclosure Policy, and Data Sharing ..............................................111 
10.1.9. Protocol Deviations .......................................................................................................111 
10.1.10. Study and Site Closure ..................................................................................................111 
10.1.11. Product Complaints .......................................................................................................112 
10.2. 
Appendix 2: Central and/or Local Laboratory ..............................................................112 
10.3. 
Appendix 3: Reference Standards .................................................................................113 
10.3.1. Cockcroft-Gault Equation .............................................................................................113 
10.3.2. New York Heart Association (NYHA) .........................................................................113 
10.3.3. Eastern Cooperative Oncology Group Performance Status ..........................................113 
10.3.4. Highly Effective Contraception .....................................................................................114 
10.4. 
Appendix 4: Response Criteria ......................................................................................115 
10.5. 
Appendix 6: General Information - Adverse Events .....................................................122 
10.5.1. Definition of Adverse Event ..........................................................................................122 
10.5.2. Serious Adverse Event ..................................................................................................123 
10.5.3. Grade Assessment .........................................................................................................124 
10.5.4. Causality Assessment ....................................................................................................125 
10.5.5. Action Taken Regarding Study Drug ............................................................................125 
10.5.6. Other Action Taken for Event .......................................................................................125 
10.5.7. Adverse Event Outcome ................................................................................................126 
10.6. 
Appendix 7: Instructions Related to Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2) ......................................................................................126 
10.7. 
Appendix 8: Patient-Reported Outcomes ......................................................................129 
10.7.1. EORTC QLQ-CR29 ......................................................................................................129 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 9 
10.7.2. EORTC QLQ-C30 .........................................................................................................131 
10.7.3. EQ-5D-5L ......................................................................................................................133 
10.7.4. PGI-TT ..........................................................................................................................136 
10.7.5. PGIS ..............................................................................................................................136 
10.7.6. PGIC ..............................................................................................................................136 
11. 
REFERENCES ..............................................................................................................137 
12. 
LIST OF ABBREVIATIONS .......................................................................................140 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 10 
LIST OF TABLES 
Table 1.1: Dose Reduction Levels of Study Treatment ...............................................................20 
Table 1.2: Schedule of Events – Tissue Pre-Screening and Screening ........................................23 
Table 1.3: Schedule of Events – Treatment and Follow-up .........................................................27 
Table 3.1: Description of Objectives, Outcome Measures, and Endpoints .................................43 
Table 6.1: Study Drug Dosing Information .................................................................................58 
Table 6.2: Dose Reduction Levels of T-DXd ..............................................................................62 
Table 6.3: Dose Modification Guidelines for T-DXd ..................................................................63 
Table 8.4: Blood Sampling for Pharmacokinetic Analysis ..........................................................91 
Table 8.5: Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment ..................................................................................92 
Table 8.6: Cell-Free Deoxyribonucleic Acid Sampling Time Points ..........................................93 
Table 9.1: The Probability that the Resulting Clopper-Pearson 95% CI will Exclude the 
Benchmark of 20.0% ORR .........................................................................................97 
Table 9.2: Confidence Interval with 40 and 80 Subjects Under Scenarios of Observed 
Objective Response Rate ............................................................................................98 
Table 10.1: Clinical Laboratory Tests .........................................................................................112 
Table 10.2: New York Heart Association Classifications ...........................................................113 
Table 10.3: Eastern Cooperative Oncology Group Performance Status ......................................114 
Table 10.4: Time Point Response: Subjects With Target (+/–Non-Target) Disease ...................120 
Table 10.5: Best Overall Response When Confirmation of CR and PR Required ......................121 
Table 10.6: SARS-CoV-2 Dose Modification Criteria ................................................................127 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 11 
LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................22 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 12 
1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
Protocol Title 
A Phase 2, Multicenter, Randomized, Study of Trastuzumab Deruxtecan in Subjects with HER2-overexpressing 
Locally Advanced, Unresectable or Metastatic Colorectal Cancer (DESTINY-CRC02) 
Protocol Short Title 
Trastuzumab deruxtecan for subjects with HER2-overexpressing advanced or metastatic CRC 
Protocol Number 
DS8201-A-U207 
Sponsor/Collaborators 
Daiichi Sankyo, Inc./AstraZeneca and Syneos Health 
Registry Identification(s) 
EudraCT Number: 2020-004782-39 
IND Number 
136179 
Study Phase 
Phase 2 
Planned Geographical Coverage, Study Sites, and Location 
Global study at approximately 70 study sites, including but not limited to the Americas, Asia-Pacific, and 
Europe. 
Study Population 
Subjects with human epidermal growth factor 2 (HER2)-overexpressing locally advanced, unresectable, or 
metastatic colorectal cancer (mCRC).  
Study Objectives/Outcome Measures and Endpoints 
The table below lists primary and secondary study objectives and endpoints which have outcome measures. 
Objectives 
Outcome Measures 
Endpoints 
Category 
Primary 
 
 
 
To assess the efficacy of 
trastuzumab deruxtecan 
(T-DXd), as measured by 
the confirmed ORR by 
BICR in 
HER2-overexpressing 
(defined as IHC 3+ or IHC 
2+/ISH+) mCRC subjects 
treated at the 5.4 mg/kg 
and 6.4 mg/kg doses 
Title: Confirmed ORR 
Description: CR and PR 
as assessed by blinded data 
review and based on 
RECIST version 1.1 
Time frame: 12 weeks 
after the first 80 subjects 
are randomized for the IA 
and 6 months after the last 
subject is registered for the 
primary analysis 
The primary efficacy endpoint 
is confirmed ORR, defined as 
the proportion of subjects with 
CR or PR, assessed by BICR 
based on RECIST version 1.1 
Efficacy 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 13 
Secondary 
 
 
 
To evaluate the clinical 
efficacy of T-DXd by 
confirmed ORR by 
Investigator assessment 
Title: Clinical Efficacy 
Description: Evaluation of 
the clinical efficacy of T-
DXd at 5.4 mg/kg and 6.4 
mg/kg doses by confirmed 
ORR by Investigator 
assessment  
Time frame: 12 weeks 
after the first 80 subjects 
are randomized for the IA 
and 6 months after the last 
subject is registered for the 
primary analysis 
Confirmed ORR as indicated 
above assessed by Investigator 
assessment based on RECIST 
version 1.1 
 
Efficacy 
To evaluate the clinical 
efficacy of T-DXd by DoR 
Title: Clinical Efficacy 
Description: Evaluation of 
the clinical efficacy of 
T-DXd at 5.4 mg/kg and 
6.4 mg/kg doses by DoR 
Time frame: 12 weeks 
after the first 80 subjects 
are randomized for the IA 
and 6 months after the last 
subject is registered for the 
primary analysis 
DoR, defined as time from the 
initial response (CR or PR) by 
BICR and Investigator 
assessment until documented 
tumor progression or death 
from any cause 
Efficacy 
To further evaluate the 
clinical efficacy of T-DXd 
by DCR, CBR, PFS, and 
OS 
Title:  Clinical Efficacy 
Description: Further 
evaluation of the clinical 
efficacy of T-DXd at 5.4 
mg/kg and 6.4 mg/kg doses 
by DCR, CBR, PFS, and 
OS 
Time frame: 12 weeks 
after the first 80 subjects 
are randomized for the IA 
(DCR, PFS) and 6 months 
after the last subject is 
registered for the primary 
analysis (DCR, CBR, PFS, 
OS) 
 
Based on BICR and 
Investigator assessment 
according to RECIST version 
1.1 (unless otherwise 
specified):   
 
DCR, defined as the 
proportion of subjects 
who achieved CR, PR, or 
SD for a minimum of 6 
weeks during study 
treatment; DCR based on 
BICR and DCR based on 
Investigator assessments 
will both be determined  
 
CBR, defined as 
proportion of subjects 
who achieved CR, PR, or 
SD for at least 6 months;  
CBR based on BICR and 
CBR based on 
Investigator assessments 
will both be determined 
 
PFS, defined as the time 
from date of 
randomization/ 
registration until first 
objective radiographic 
Efficacy 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 14 
tumor progression or 
death from any cause, 
based on BICR and 
Investigator assessment 
 
OS, defined as the time 
from date of 
randomization/ 
registration until death 
from any cause 
To further evaluate the 
safety and tolerability of 
T-DXd 
Title: TEAEs and other 
safety parameters during 
the study 
Description: Descriptive 
statistics of safety 
endpoints 
Time frame: 12 weeks 
after the first 80 subjects 
are randomized for the IA 
and 6 months after the last 
subject is registered for the 
primary analysis 
Safety endpoints will include, 
incidence and severity of 
(according to the NCI-CTCAE 
version 5.0): 
 
TEAEs (including SAEs 
and AESIs) 
 
TEAEs associated with 
death 
 
Incidence of dose 
interruptions, dose 
modifications, and 
discontinuations due to 
AEs 
 
ECOG PS 
 
Vital sign measurements 
 
Clinical laboratory 
parameters (hematologic 
and non-hematologic) 
 
ECG parameters 
 
ECHO/MUGA 
 
Ophthalmologic 
assessments 
Safety 
To evaluate HEOR 
endpoints including 
patient-reported HRQoL, 
symptoms, and physical 
functioning  
Title: PROs during the 
study 
Description: EORTC 
QLQ-C30 and EORTC 
QLQ-CR29, EQ-5D-5L, 
PGI-TT, PGIS, and PGIC  
Time frame: 6 months 
after the last subject is 
registered or later 
 
PROs include: 
 
Change from baseline in 
EORTC QLQ-C30 and 
EORTC QLQ-CR29 scale 
scores 
 
EQ-5D-5L health state 
utility index 
 
Patient-reported treatment 
tolerability with PGI-TT 
 
Proportion of subjects 
with overall PGIS and 
PGIC  
HEOR 
To evaluate healthcare 
resource utilization for 
both treatment arms 
Title: Healthcare resource 
use during the study 
Description: Healthcare 
resource use 
Healthcare resource use will 
be captured/collected, 
including inpatient 
admissions, intensive care unit 
admissions, and length of stay 
in hospital 
Healthcare 
resource use 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 15 
Time frame: 6 months 
after the last subject is 
registered or later 
To evaluate PK of T-DXd 
Title: PK profile 
Description: Serum 
concentrations 
Time frame: 6 months 
after the last subject is 
registered or later 
The PK endpoints include 
serum concentrations of 
T-DXd, total anti-HER2 
antibody, and MAAA 1181a 
PK  
To evaluate  
immunogenicity of T-DXd 
Title: Immunogenicity 
profile 
Description: Incidence of 
ADA and NAb 
Time frame: 6 months 
after the last subject is 
registered or later 
The immunogenicity endpoint 
includes incidence of ADA 
and NAb 
Immuno-
genicity 
Exploratory 
 
 
 
To further evaluate the 
clinical efficacy of T-DXd 
by TTR, best percent 
change in the SoD for all 
target lesions, and TTD in 
ECOG PS 
Title:  Clinical efficacy 
Description: Further 
evaluation of the clinical 
efficacy of T-DXd at 5.4 
and 6.4 mg/kg doses by 
TTR, SoD, and TTD in 
ECOG PS 
Time frame: 12 weeks 
after the first 80 subjects 
are randomized for the IA 
and 6 months after the last 
subject is registered for the 
primary analysis 
 
 
TTR, defined as the time 
from the date of 
randomization/registration 
to the date of first 
documented objective 
response (CR or PR), 
based on BICR and 
Investigator assessment 
 
Best percentage change 
from baseline in the SoD 
for all target lesions, 
based on BICR and 
Investigator assessment  
 
TTD in ECOG PS, 
defined as the time from 
the date of 
randomization/registration 
to the date when 
ECOG PS score of ≥2 is 
observed for the first time 
Efficacy 
To assess the relationship 
between changes in tumor 
markers (CEA and CA19-
9) and radiographic 
response to T-DXd 
treatment 
Not applicable 
Changes in CEA and CA19-9  
PD 
To evaluate ERBB2 copy 
number detected in cfDNA 
and cfRNA at baseline as 
an exploratory predictive 
biomarker of response 
Not applicable 
ERBB2 copy number at 
baseline and its association 
with clinical outcomes 
 
Biomarker 
To evaluate other potential 
biomarkers of resistance or 
Not applicable 
 
Liquid biomarkers (eg, 
cfRNA) at baseline and 
Biomarker 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 16 
clinical benefit to study 
treatment 
its association with 
clinical outcomes 
 
Potential DNA, RNA, 
and protein-based 
biomarkers evaluated by 
different methodologies 
(eg, cfDNA, NGS based 
analysis of DNA and 
RNA, protein-based 
analysis, IHC digital 
pathology analysis etc. 
of tumor samples) 
To explore an 
exposure/response 
relationship 
Not applicable  
 
T-DXd PK 
concentration versus 
selected safety and 
efficacy endpoints 
PK, Safety, 
and Efficacy 
ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; BICR = blinded 
independent central review; CA19-9 = carbohydrate antigen 19-9; CBR = clinical benefit rate; 
CEA = carcinoembryonic antigen; cfDNA = cell-free deoxyribonucleic acid; cfRNA = cell-free ribonucleic 
acid; CR = complete response; DCR = disease control rate; DNA = deoxyribonucleic acid; DoR = duration 
of response; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology 
Group; EORTC = European Organization for Research and Treatment of Cancer; EQ-5D-5L = EuroQol-5 
dimensions-5 levels of severity; ERBB2 = erb-b2 receptor tyrosine kinase 2; HEOR = Health Economics and 
Outcomes Research; HER2=Human epidermal growth factor receptor 2; HRQoL = health-related quality of 
life; IA = interim analysis; IHC = immunohistochemistry; ISH = in situ hybridization; MAAA-1181a (DXd) 
= released drug; mCRC = metastatic colorectal cancer; MUGA = multigated acquisition; NAb = neutralizing 
antibodies; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events; 
NGS = next-generation sequencing; ORR = objective response rate; OS = overall survival; PD = progressive 
disease; PFS = progression-free survival; PGIC = Patient Global Impression-Change; PGIS = Patient Global 
Impression-Severity; PGI-TT = Patient Global Impression-Treatment Tolerability; PK = pharmacokinetics; 
PR = partial response; PRO = patient-reported outcome; PS = performance status; QLQ = Quality of Life 
Questionnaire; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; 
SAE = serious adverse event; SD = stable disease; SOC = standard of care; SoD = sum of diameters; 
TEAE = treatment-emergent adverse event; TTD = time to deterioration; TTR = time to response. 
Study Design 
The Tissue Pre-Screening Period will start on the day of obtaining a signed and dated written Tissue Pre-
Screening informed consent form (ICF) from the subject prior to collecting tissue from a recent tumor biopsy 
(preferred) or archival tissue to confirm HER2 status.  A tissue sample is considered a recent sample if it is 
collected from a biopsy performed after the subject’s discontinuation of the last treatment regimen (and most 
recent disease progression).  For subjects who sign this ICF, only serious adverse events (SAEs) directly related 
to the tissue pre-screening procedure (ie, tumor biopsy) should be reported via the SAVER Form. Unless 
documentation of other adverse events (AEs) are required by local law, only SAEs directly related to tumor 
biopsy will be recorded during tissue pre-screening.  The tissue pre-screening may occur any time before the 
Screening Period. 
The Screening Period will start on the day a subject signs the Main ICF and will comprise a maximum 
duration of 28 days.  Rescreening is permitted once during this phase if the subject fails initial Screening.  
During the 28-day Screening Period, subjects’ eligibility will be confirmed.  The activities and/or assessments 
will be performed within 28 days before randomization/registration during the Screening Period and are listed in 
the Schedule of Events.  Within 14 days before randomization/registration, the subjects will undergo medical 
history evaluation, vital signs determination, physical examination, pulse oximetry, height and weight 
measurements, functional status confirmation using the Eastern Cooperative Oncology Group (ECOG) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 17 
performance status (PS), laboratory testing (including blood tests for safety), and electrocardiogram (ECG).  
Eligible subjects will be randomized/registered and enter the Treatment Period. 
The Treatment Period starts on Day 1 of Cycle 1.  Eligible subjects will be randomized to 1 of 2 treatment 
arms in Stage 1:  
- 
Arm 1: T-DXd for injection will be administered intravenously (IV) at a dose of 5.4 mg/kg every 
3 weeks (Q3W) 
- 
Arm 2: T-DXd for injection will be administered IV at a dose of 6.4 mg/kg Q3W 
After Stage 1 enrollment is complete (N=80), eligible subjects will all be registered to T-DXd administered IV 
at a dose of 5.4 mg/kg Q3W in Stage 2 (N=40).  Subjects will receive the assigned dose of T-DXd (5.4 mg/kg 
Q3W or 6.4 mg/kg Q3W) until progression of disease or the subject meets one of the discontinuation criteria.  
Combining both stages of the study, a maximum of 30 subjects per subgroup will be registered onto each of the 
HER2 IHC 2+/ISH+ and RAS-mutant subgroups. A minimum of 20 subjects with RAS-mutant status will be 
enrolled in the study. Once the maximum number of 30 subjects is reached, all subsequent subjects enrolled in 
the study should have HER2 IHC 3+ or RAS wild-type tumor.  
The End of Treatment (EOT) is defined as the date the Investigator decides to discontinue study treatment.  
Subjects who permanently discontinue the study treatment should be scheduled for an EOT visit within +7 days 
following the date study treatment is permanently discontinued.  If the decision to discontinue the subject occurs 
at a regularly scheduled visit, that visit may serve as the EOT visit rather than having the subject return for an 
additional visit. 
The Follow-up Period will start upon permanent discontinuation of T-DXd.  Subjects will be followed 40 days 
(+7 days) after the last study treatment administration or before starting new anticancer treatment, whichever 
comes first.  Subjects who discontinue study drug for any reason other than progressive disease (PD), death, or 
loss to follow-up will be followed every 6 weeks (Q6W) until radiological disease progression or start of new 
anticancer treatment.  If EOT is >40 days after last treatment, then the EOT assessments may take the place of 
the 40-day Follow-up Visit assessments.  Long-term disease follow-up to monitor survival will be documented 
every 3 months (±14 days) for up to 2 years, every 6 months from 3 to 5 years, and annually from 6 to 10 years.  
Survival follow-up contact (either scheduled visit or telephone call) will be performed every 3 months 
(±14 days) from the date of the 40-day Follow-up Visit, until death, withdrawal of consent, loss to follow-up, or 
study closure, whichever occurs first. 
The primary completion date is the date when the last enrolled subject has completed 6 months of follow-up 
treatment or when all subjects have been discontinued from the study and completed the 40-day Follow-up 
Visit, whichever is earlier.  This date is used as the cut-off date for the analysis of the primary efficacy 
endpoint(s) of the study.  All subjects still on treatment and continuing to derive benefit from study drug at the 
primary completion date will continue to follow the study Schedule of Events until the overall End of Study 
(EOS) is reached. 
Overall EOS will occur when: 
 the last subject last visit has occurred or  
 the study is discontinued by the Sponsor for other reasons (administrative, program-level, or class-
related) 
The subject’s EOS is the date of their last study visit/contact. 
Study Duration 
The study start date is the date when the first subject has signed the Main ICF.  A subject is eligible to be 
enrolled into the interventional phase of the study when the Investigator or designee has obtained written ICF 
(both Tissue Pre-Screening and Main), has confirmed all eligibility criteria have been met by the subject, and all 
Screening procedures have been completed. 
Anticipated total duration of the study is approximately 30 months.   
- 
Projected enrollment duration of approximately 18 months 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 18 
- 
Treatment and follow-up duration: 12 months 
The EOS is defined as the date of completion of the last visit or procedure shown in the Schedule of Events in 
the trial globally, or the study is ended by the Sponsor. 
Key Eligibility Criteria 
Key Inclusion Criteria: 
Subjects eligible for inclusion in this study have to meet all inclusion criteria for this study.  Below is a list 
limited to the key inclusion criteria: 
 
Sign and date the Tissue Pre-Screening and Main ICFs, prior to the start of any respective study-specific 
qualification procedures. 
 
Adults aged ≥20 years in Japan, Taiwan, and Korea, or those aged ≥18 years in other countries, at the time 
the ICFs are signed.  (Please follow local regulatory requirements if the legal age of consent for study 
participation is >18 years). 
 
Pathologically-documented, unresectable, recurrent, or metastatic colorectal adenocarcinoma.  Subject must 
have BRAF wild-type cancer and RAS status identified in primary or metastatic site, tested by a Clinical 
Laboratory Improvement Act (CLIA), ISO15189, or equivalent-certified laboratory. 
 
The following therapies should be included in prior lines of therapy:  
o 
Fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated  
o 
Anti-epidermal growth factor receptor (EGFR) treatment, if RAS wild-type and if clinically 
indicated  
o 
Anti-vascular endothelial growth factor (VEGF) treatment, if clinically indicated 
o 
Anti-programmed death-ligand 1 (PD-[L]-1) therapy, if tumor is microsatellite instable (MSI)-
high/deficient mismatch repair (dMMR), or tumor mutational burden (TMB)-high, if clinically 
indicated 
 
Is willing and able to provide an adequate tumor sample for tissue pre-screening to confirm HER2 status by 
central laboratory (most recent tumor tissue preferred). 
 
Confirmed HER2-overexpressing status assessed by central laboratory and defined as IHC 3+ or 
IHC 2+/ISH+. 
 
Presence of at least one measurable lesion assessed by the Investigator per Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1.  Lesions situated in a previously-irradiated area are considered 
measurable if progression has been demonstrated in such lesions after the end of radiotherapy. 
 
ECOG PS of 0 or 1. 
 
Has left ventricular ejection fraction (LVEF) ≥50% within 28 days before randomization/registration. 
 
Has adequate organ function within 14 days before randomization/registration, defined as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count  
100,000/mm3  
(Platelet transfusion is not allowed within 1 week prior to 
Screening assessment) 
Hemoglobin  
≥9.0 g/dL  
(Red blood cell transfusion is not allowed within 1 week 
prior to Screening assessment) 
Absolute neutrophil count (ANC) 
1500/mm3  
(granulocyte-colony stimulating factor [G-CSF] 
administration is not allowed within 1 week prior to 
Screening assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥30 mL/min as calculated using the 
Cockcroft-Gault equation  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 19 
Adequate hepatic function 
Alanine aminotransferase (ALT), 
Aspartate aminotransferase 
(AST) 
 ≤5  upper limit of normal (ULN) 
Total bilirubin 
 ≤1.5  ULN if no liver metastases or <3  ULN in the 
presence of documented Gilbert syndrome (unconjugated 
hyperbilirubinemia) or liver metastases at baseline 
Serum Albumin 
≥2.5 g/dL  
Adequate blood clotting function 
International normalized ratio 
(INR)/Prothrombin time (PT) 
and either partial thromboplastin 
time (PTT) or activated partial 
thromboplastin time (aPTT) 
≤1.5 × ULN  
 
 
 
Has adequate treatment washout period before randomization/registration, defined as: 
Treatment 
Washout Period 
Major surgery 
≥4 weeks 
Radiation therapy, including 
palliative stereotactic radiation to 
chest 
≥4 weeks (palliative stereotactic radiation therapy to other 
areas ≥2 weeks) 
Anticancer chemotherapy 
(immunotherapy [non-antibody-
based therapy]), retinoid therapy 
≥3 weeks (≥2 weeks or 5 half-lives, whichever is longer, 
for small-molecule targeted agents such as 5-fluorouracil-
based agents, folinate agents, weekly paclitaxel; ≥6 weeks 
for nitrosoureas or mitomycin C) 
Antibody-based anticancer 
therapy 
≥4 weeks 
Chloroquine/hydroxychloroquine 
>14 days 
Key Exclusion Criteria: 
Subjects meeting any exclusion criteria for this study will be excluded from this study.  Below is a list limited to 
the key exclusion criteria: 
• 
Medical history of myocardial infarction (MI) within 6 months before randomization/registration, 
symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV).  Subjects with 
troponin levels above ULN at Screening (as defined by the manufacturer), and without any MI-related 
symptoms, should have a cardiologic consultation before randomization/registration to rule out MI. 
• 
Has a corrected QT interval (QTcF) prolongation to >470 msec (female subjects) or >450 msec (male 
subjects) based on the average of the Screening triplicate 12-lead ECGs. 
• 
Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has 
current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
Screening.  
• 
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying 
pulmonary disorder (eg, pulmonary emboli within 3 months of the randomization/registration, severe 
asthma, severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural effusion, 
etc.). 
• 
Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren 
syndrome, 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 subjects who are 
included in the study. 
• 
Prior pneumonectomy. 
• 
Has spinal cord compression or clinically active central nervous system metastases, defined as untreated 
and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated 
symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with 
treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 20 
or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of 
radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and 
randomization/registration. 
• 
Subjects with leptomeningeal carcinomatosis. 
• 
Has multiple primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, 
curatively treated in situ disease, or other solid tumors curatively treated.  
• 
Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in 
the drug product. 
• 
Has a history of severe hypersensitivity reactions to other monoclonal antibodies. 
• 
Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals.  
• 
Has substance abuse or any other medical conditions such as clinically significant cardiac or 
psychological conditions that may in the opinion of the Investigator, interfere with the subject’s 
participation in the clinical study or evaluation of the clinical study results. 
• 
Has known human immunodeficiency virus (HIV) infection. Unless required by local regulations or 
institutional review board (IRB)/ethics committee (EC), an HIV antigen/antibody test is not required prior 
to randomization/enrollment. 
• 
Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral infection 
within 28 days before study randomization/registration. Subjects with past or resolved hepatitis B virus 
(HBV) infection are eligible if hepatitis B surface antigen (HBsAg) negative (-) and antibody to hepatitis 
B core antigen (anti-HBc) positive (+).  Patients positive for hepatitis C virus (HCV) antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA. 
• 
Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet 
resolved to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-
CTCAE) version 5.0, Grade ≤1 or baseline.  Subjects with chronic Grade 2 toxicities may be eligible at 
the discretion of the Investigator and approval of the Sponsor. 
• 
Previous treatment with a DXd-containing antibody-drug conjugate (ADC). 
• 
Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.  Note: Subjects with 
localized fungal infections of skin or nails are eligible. 
• 
Female subject who is pregnant, breastfeeding, or intends to become pregnant during the study. 
Investigational Medicinal Product, Dose, and Mode of Administration 
T-DXd is an investigational agent. The T-DXd drug product containing 100 mg of T-DXd is provided as a 
sterile lyophilized powder in a glass vial (Lyo-DP).  Each glass vial should be reconstituted with 5 mL water for 
injection to a concentration of 20 mg/mL (ie, 100 mg/5 mL). T-DXd will be administered with 5% dextrose as 
an IV infusion.  Each vial is designed for single-use only and is not to be used to treat more than one subject. 
The drug for IV infusion is prepared by dilution of the required volume of the drug product calculated based on 
the subject’s body weight in an infusion bag, by the study site pharmacist. The study treatment will be 
administered as an IV infusion every 3 weeks, initially for approximately 90 minutes, then, if there is no 
infusion-related reaction, for a minimum of 30 minutes thereafter.  
If dose reduction is required, dosing should be reduced by 1 dose level at a time. Up to 2 dose reductions will be 
permitted for subjects. Once the dose of study drug is reduced, no dose re-escalation will be permitted.   
Table 1.1: 
Dose Reduction Levels of Study Treatment  
Treatment Arm 
Starting Dose 
Dose Level -1 
Dose Level -2 
1 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
2 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
T-DXd dose interruption, re-initiation, dose reduction, and/or discontinuation will follow Sponsor dose 
modification guidance in the protocol body.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 21 
Active Ingredient(s)/INN 
Trastuzumab deruxtecan (T-DXd; DS-8201a) is an ADC, that consists of an anti-HER2 antibody, MAAL-9001, 
covalently linked to approximately 8 molecules of MAAA-1162a (GGFG tetra-peptide cleavable linker and a 
topoisomerase I inhibitor [MAAA-1181a]).   
Planned Sample Size 
Approximately 120 subjects will be enrolled in this study.  In Stage 1, the first 80 subjects will be randomized in 
a 1:1 ratio to receive T-DXd at either the 5.4 mg/kg or 6.4 mg/kg dose level.  Then in Stage 2, an additional 40 
subjects will be registered at the 5.4 mg/kg dose to further inform on the efficacy and safety of this dose in 
mCRC.  
In Stage 1, with 40 subjects in each treatment arm, the probability to exclude the objective response rate (ORR) 
benchmark of 20.0% is at least 80% when the true ORR is 41%.  At the end of Stage 2, assuming 80 total 
subjects in the 5.4 mg/kg, the probability to exclude the ORR benchmark of 20.0% is at least 80% when the true 
ORR is 34%.   
With 80 subjects at the 5.4 mg/kg dose level and 40 subjects at the 6.4 mg/kg dose level, if the higher dose true 
ORR is at least 13.75% higher than that of the lower dose, the probability of observing the ORR difference 
between dose levels being 5% or more is at least 80%. 
Assuming 80 subjects at the 5.4 mg/kg dose level and 40 subjects at the 6.4 mg/kg dose level, the 95% 
confidence interval of the ORR difference between dose levels is expected to extend approximately 0.18 from 
the observed difference in proportions to either confidence limit.  
Statistical Analyses 
 
Efficacy Analyses 
The primary efficacy endpoint of ORR per blinded independent central review (BICR) will be calculated at an 
interim and a final analysis. The interim analysis (IA) will be performed when approximately 80 subjects have 
been randomized and had at least 12 weeks of follow-up after randomization or have discontinued 
treatment.  The purpose of this IA is to look at preliminary efficacy and safety signals for both the 5.4 mg/kg 
and 6.4 mg/kg doses of T-DXd in HER2-overexpressing mCRC subjects.  The primary analysis will be 
performed after all 120 subjects have been randomized/registered into the study and had at least 6 months of 
follow-up after initiation of therapy. 
The primary efficacy analyses will be performed for the Full Analysis Set (FAS), according to the treatment and 
the strata they are randomized/registered.  The ORR for each dose level will be estimated along with two-sided 
exact 95% confidence intervals using the Clopper and Peterson method.  The ORR difference between dose 
levels will be presented along with 95% confidence interval of the difference, using a stratified analysis, 
adjusting for the randomization stratification factors. 
Analyses of secondary efficacy endpoints are specified in the Statistical Analysis Plan (SAP).  
 
Health Economic and Outcomes Research Analyses  
Health economic and outcomes research (HEOR) endpoints based on the hospitalization-related data collection 
form and the following PRO questionnaires will be summarized by treatment group: European Organization for 
Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, EORTC QLQ-CR29, 
EuroQol-5 dimensions-5 levels of severity (EQ-5D-5L), Patient Global Impression-Severity (PGIS), Patient 
Global Impression-Change (PGIC), and Patient Global Impression-Treatment Tolerability (PGI-TT). 
The global health status/quality of life (QoL) scale of the EORTC QLQ-C30 questionnaire is the HEOR 
measurement. A score of the global health status/QoL at each assessment will be calculated per 
“EORTC QLQ-C30 Scoring Manual.” Descriptive statistics will be calculated to summarize change from the 
baseline in symptoms, physical functioning, and general health-related QoL (HRQoL) scales in the C30 and 
CR29 study questionnaires at each scheduled assessment time point by dose level.  The number of subjects 
completing each patient questionnaire and the number of missing or incomplete assessments will be provided 
for each scheduled assessment time point by dose level. 
 
Pharmacokinetic Analyses  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 22 
Pharmacokinetics (PK) analyses will be performed using the PK Analysis Set.  Serum concentrations for T-
DXd, total anti-HER2 antibody and MAAA-1181a (DXd) will be listed and summarized using descriptive 
statistics at each time point. Additional analyses are specified in the protocol. 
 
Biomarker Analyses  
Biomarker analysis will be performed using the FAS. 
Descriptive statistics including mean, standard deviation, coefficient of variation, geometric mean, median, 
minimum, and maximum will be computed by evaluation time for biomarkers as specified in the protocol.  If 
possible, change from baseline and percent change from baseline will also be summarized. 
 
Safety Analyses 
Safety endpoints will include SAEs, TEAEs, AEs of special interest (AESIs), discontinuations due to AEs, 
physical examination findings (including ECOG PS), vital sign measurements, standard clinical laboratory 
parameters, ECG parameters, echocardiogram (ECHO)/multigated acquisition (MUGA) findings, and anti-drug 
antibodies (ADAs). TEAEs will be graded according to the NCI-CTCAE version 5.0.  Safety analyses in 
general will be descriptive and will be presented in tabular format with the appropriate summary statistics. 
1.2. 
Study Schema 
Figure 1.1: 
Study Level Flow Diagram 
 
dMMR = deficient mismatch repair; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EGFR = epidermal 
growth factor receptor; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry; ISH = in situ 
hybridization; MSI = microsatellite instable; PD = progressive disease; PD-(L)-1 = programmed death-ligand 1; Q3W = every 3 
weeks; RAS = rat sarcoma viral oncogenes homologue; TMB = tumor mutational burden; VEGF = vascular endothelial growth 
factor. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 23 
1.3. 
Schedule of Events 
Table 1.2: 
Schedule of Events – Tissue Pre-Screening and Screening 
Visit 
Tissue Pre-Screening 
Screening 
CSP Section(s) 
Comment(s) 
Window (Day) 
 
 
 
Procedures 
Any time before Screening 
-28 
to -1 
-14 
to -1  
(or as 
noted) 
Tissue Pre-Screening ICF 
X 
 
 
8.1.1; 8.1.2;  
10.1.2 
A signed and dated Tissue Pre-Screening ICF must be obtained 
before tumor tissue pre-screening assessments. The Tissue 
Pre-Screening ICF can be obtained any time before Screening 
(ie, during previous therapy).   
Tumor Sample for Tissue 
Pre-Screening 
X* 
X** 
 
8.1.2; 8.1.4; 
10.1.2 
Central laboratory testing.  
*At tissue pre-screening, subjects must provide a tumor sample: 
archival tissue (most recent preferred), recent tumor tissue, or a 
new tumor biopsy (if archival tissue is not available). A tissue 
sample is considered a recent sample if it is collected from a 
biopsy performed after the subject’s discontinuation of the last 
treatment regimen and most recent disease progression. 
**If slides are sent in place of a paraffin embedded tissue block at 
Pre-Screening, then additional slides will be required at 
Screening.  
Refer to the Study Laboratory Manual for preparation, number of 
slides required, storage, and shipment procedures. 
Assign SID from IRT 
X 
 
8.1.2  
One SID will be assigned at tissue pre-screening. 
Main ICF 
 
X 
 
8.1.1; 10.1.2 
A signed and dated Main ICF must be obtained before initiating 
all other study-specific procedures or assessments. 
Optional PGx ICF 
 
X 
8.7.2  
A signed and dated PGx ICF must be obtained before sample 
collection.  
Eligibility Assessment  
 
X 
8.1 
Review all inclusion/exclusion criteria to determine eligibility. 
Demographics 
 
 
X 
8.1.6 
Demographic data will include age, sex, country, and self-
reported race/ethnicity where allowed per local regulations. 
Medical History 
 
 
X 
8.1.3;  8.1.5 
Including CRC history. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 24 
Visit 
Tissue Pre-Screening 
Screening 
CSP Section(s) 
Comment(s) 
Window (Day) 
 
 
 
Procedures 
Any time before Screening 
-28 
to -1 
-14 
to -1  
(or as 
noted) 
Vital Signs 
 
 
X 
8.4.4.2 
Blood pressure, pulse rate, respiratory rate, and temperature 
should be taken approximately 5 minutes or more after the subject 
has rested in a recumbent position and prior to laboratory blood 
draws and ECG measurements. 
Height 
 
 
X 
8.4.4.2 
Assessment(s) to be performed within 14 days before 
Cycle 1 Day 1. 
Weight 
 
 
X 
8.4.4.2 
 
SpO2 
 
 
X 
8.4.4.2 
SpO2 will be assessed via pulse oximetry. 
ECOG PS 
 
 
X 
8.4.4.3  
 
Physical Examination 
 
 
X 
8.4.4.1 
 
Ophthalmologic 
Assessments 
 
X 
 
8.4.4.7 
Ophthalmologic assessments including visual acuity testing, slit 
lamp examination, and fundoscopy will be performed at 
Screening. 
ECHO/MUGA 
 
X 
 
8.4.4.5 
ECHO or MUGA assessments to be performed at Screening. Use 
the same test for a subject throughout the study. 
12-lead ECG (in triplicate) 
 
 
X 
8.4.4.4  
 
Hematology and Chemistry 
 
 
X 
8.4.3; 10.2 
Hematology tests to include hemoglobin, hematocrit, platelet 
count, RBC count, WBC count, absolute ± differential (%) WBC 
count: basophils, eosinophils, lymphocytes, monocytes, 
neutrophils. 
Blood chemistry tests to include albumin, ALT, ALP, AST, 
bilirubin (total), BUN/urea, Ca, Cl, creatinine (serum), LDH, Mg, 
K, protein (total), Na, and FSH and estradiol (if applicable) to 
confirm menopausal status. 
Coagulation 
 
 
X 
8.4.3; 10.2 
Coagulation tests will include PT/INR and PTT/aPTT. 
Troponin (preferably high-
sensitivity troponin-T) 
 
 
X 
8.4.3; 10.2 
Collect blood samples for local and central troponin (preferably 
high-sensitivity troponin-T and troponin I or troponin-T).  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 25 
Visit 
Tissue Pre-Screening 
Screening 
CSP Section(s) 
Comment(s) 
Window (Day) 
 
 
 
Procedures 
Any time before Screening 
-28 
to -1 
-14 
to -1  
(or as 
noted) 
Urinalysis (abbreviated) 
 
 
X 
8.4.3; 10.2 
Urinalysis tests to include glucose, microscopy assessments (if 
indicated), occult blood, protein, specific gravity. 
Pregnancy test 
 
 
X 
5.1; 8.4.2.1  
Urine pregnancy test to be done within 72 hours before 
randomization/registration for all female subjects of childbearing 
potential; a positive urine pregnancy test result must immediately 
be confirmed using a serum test. 
HIV Ab Test 
 
X 
 
8.1.7 
Unless required by local regulations or independent IRB/EC, an 
HIV antigen/Ab test is not required prior to 
randomization/enrollment. 
HBsAg, HC Ab 
 
X 
 
5.2; 8.1.8 
Active HBV and/or HCV infection, such as those with serologic 
evidence of viral infection within 28 days before study 
randomization/registration. Subjects with past or resolved HBV 
infection are eligible if HBsAg negative (-) and anti-HBc 
positive (+). Patients positive for HCV Ab are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
Optional Tumor Biopsy 
Sample for Exploratory 
Biomarkers 
 
X 
 
8.7.1.1.1 
Biopsies are optional (strongly recommended).  The detailed 
procedures for collection, handling, and shipping tumor tissue 
samples will be provided in the Study Laboratory Manual. 
Blood Sample for 
HER2ECD 
 
 
X 
8.7.1 
 
Blood Sample for Tumor 
Markers (CEA and 
CA19-9) 
 
 
X 
10.4 
 
Radiographic Tumor 
Assessment 
 
X 
 
8.3.4; 8.4.1.9.1  
Baseline tumor assessment will include the chest, abdomen, and 
pelvis as well as any other sites of disease are required.  
Baseline CT of chest will serve to monitor for ILD/pneumonitis 
required for all subjects. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 26 
Visit 
Tissue Pre-Screening 
Screening 
CSP Section(s) 
Comment(s) 
Window (Day) 
 
 
 
Procedures 
Any time before Screening 
-28 
to -1 
-14 
to -1  
(or as 
noted) 
CT/MRI of the Brain 
 
X 
 
8.3.4 
At baseline, a CT or MRI of the brain is required ONLY if the 
subject has a history of brain metastases and/or symptoms 
suggestive of brain metastases.  If there are no brain metastases at 
the time of Screening, a brain CT or MRI should only be 
performed during the study treatment if symptoms associated 
with brain metastases appear during the study period.  If no 
clinical symptoms are observed, a CT or MRI of the brain is not 
mandatory at Screening.   
Randomization/Registration 
 
 
X 
8.2 
Cycle 1 Day 1 of treatment should occur within 7 days (Days 0-7) 
after randomization/registration.  However, it is permissible for a 
subject to receive the first dose of T-DXd on the same day as 
randomization/registration, if applicable. 
AEs 
 
X 
8.4.1 
 
Concomitant Medications 
 
X 
6.6 
 
Ab = antibody; AE = adverse event; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; BUN = blood urea nitrogen; Ca = calcium; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; cfDNA  = cell-free deoxyribonucleic acid; 
Cl = chloride; CRC = colorectal cancer; CSP = clinical study protocol; CT = computed tomography; EC = Ethics Committee; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FSH = follicle-stimulating hormone; HBcAg = hepatitis B core antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HER2ECD = human epidermal growth factor receptor-2 extracellular domain; HIV = human immunodeficiency virus; ICF = informed consent 
form; ILD = interstitial lung disease; INR = international normalized ratio; IRB = institutional review board; IRT = interactive response technology; K = potassium; LDH = lactate 
dehydrogenase; Mg = magnesium; MRI = magnetic resonance imaging; MUGA = multigated acquisition; Na = sodium; PGx = pharmacogenomic; PS = performance status; PT = 
prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; RNA = ribonucleic acid; SID = subject identification; SpO2 = peripheral oxygen saturation; WBC = 
white blood cell 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 27 
Table 1.3: 
Schedule of Events – Treatment and Follow-up 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Vital Signs 
Xd 
X 
X 
X 
Xd 
X 
Xd 
X 
Xd 
 
X 
X 
 
8.4.4.2 
Blood pressure, 
pulse rate, 
respiratory rate, and 
temperature should 
be taken 
approximately 5 
minutes after the 
subject has rested in 
a recumbent position 
and prior to ECG 
measurements and 
laboratory blood 
draws.   
d Assessment(s) to 
be performed within 
3 days before study 
drug administration. 
Weight 
Xd 
 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
X 
 
8.4.4.2 
d Assessment(s) to 
be performed within 
3 days before study 
drug administration.  
SpO2 
Xd 
X 
X 
X 
Xd 
X 
Xd 
X 
Xd 
 
X 
X 
 
8.4.4.2  
Physical Examination 
Xd 
 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
X 
 
8.4.4.1  
Ophthalmologic 
Assessments 
(if clinically indicated) 
X 
 
 
8.4.4.7 
ECOG PS 
Xd 
 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
X 
 
8.4.4.3; 10.3.3   
d Assessment(s) to 
be performed within 
3 days before study 
drug administration. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 28 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
ECHO/MUGA 
 
 
 
 
 
 
 
 
X 
 
X 
 
 
8.4.4.5 
Use the same test for 
a subject throughout 
the study.  
ECHO or MUGA 
assessments to be 
performed BI on 
Day 1 of Cycle 5, 
and then every 4 
cycles (±7 days) 
thereafter (ie, Cycles 
9, 13, etc.), at EOT, 
and as clinically 
indicated.  
12-lead ECG 
Xd 
 
 
 
 
 
 
 
Xd 
 
X 
 
 
8.4.4.3 
After Cycle 1, single 
ECGs will be taken 
at every fourth cycle 
(ie, Cycles 4, 8, 12, 
etc), unless an 
abnormality is noted, 
then subsequent 
ECGs will be 
performed in 
triplicate in close 
succession 
(approximately 3 
minutes apart).  
ECGs will be 
performed prior to 
blood draws and 
while the subject is 
in a supine/semi-
recumbent position. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 29 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
d Within 3 days 
before study drug 
administration. 
Hematology and 
Chemistry 
Xd 
 
X 
X 
Xd 
 
Xd 
 
Xd 
 
X 
X 
 
8.4.3; 10.2 
 
d Assessment(s) to 
be performed within 
3 days before study 
drug administration.  
If hematology and 
chemistry were done 
within 3 days of 
Cycle 1 Day 1 at 
Screening, then these 
can replace the 
Cycle 1 Day 1 
assessments. 
Coagulation 
 
 
 
 
 
 
 
 
 
 
X 
 
 
8.4.3; 10.2 
Coagulation tests 
will include PT/INR 
and PTT/aPTT. 
Troponin (preferably 
high-sensitivity troponin-
T) 
(if clinically indicated) 
X 
 
 
8.4.3; 10.2 
Collect blood 
samples for local and 
central troponin 
(preferably high-
sensitivity troponin-
T) at EOT and if, at 
any time a subject 
reports signs or 
symptoms 
suggesting CHF, MI, 
or other causes of 
myocyte necrosis.  
Pregnancy Test 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
5.1; 8.4.2.1  
Perform repeat 
pregnancy tests 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 30 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
(urine or serum test 
per institutional 
guideline) on women 
of childbearing 
potential 72 hours BI 
of each cycle, at 
EOT, and at the 40-
day FU visit. 
Optional SARS-CoV-2 
Sample 
X 
 
 
 
 
 
 
 
Xe 
 
X 
 
 
10.6 
If subject provides 
consent, samples 
should be collected 
prior to study drug 
infusion.   
e Starting at Cycle 5 
Day 1 and every 4 
cycles thereafter. 
For subjects with 
suspected or 
confirmed SARS-
CoV-2 infections, 
follow the dose 
modifications in 
Appendix 7 (Section 
10.6). 
Optional PK Sampling for 
CQ/HCQ Administration 
If CQ or HCQ is administered for SARS-CoV-2, additional PK blood 
samples should be collected at the following visits: 
Prior to the first CQ or HCQ dose (Day 1) 
Day 3 or Day 4 of CQ or HCQ treatment, prior to CQ or HCQ dose 
(within 4 hours) 
Last day of the CQ/HCQ treatment, prior to CQ/HCQ dose (within 4 
hours) 
 
 
 
8.6; 10.6 
If subject provides 
consent, samples 
should be collected. 
f A washout period 
of more than 14 days 
is required before 
restarting T-DXd 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 31 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
The day of T-DXd resumption, after the CQ/HCQ washout period, 
(within 8 hours BI of T-DXd).f 
Optional Tumor Biopsy 
Sample for Exploratory 
Biomarkers 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
8.7.1.1  
During study 
treatment, biopsies 
are optional 
(strongly 
recommended).  The 
detailed procedures 
for collection, 
handling, and 
shipping tumor 
tissue samples will 
be provided in the 
Study Laboratory 
Manual. 
Blood Sample for cfRNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8.7.1 
Pretreatment sample 
will be collected 
within 3 days before 
study drug 
administration. 
Blood Samples for cfDNA 
Xd 
 
 
 
Xd 
 
Xd 
 
Xd,g 
 
X 
 
 
8.7.1 
d Assessment(s) to 
be performed within 
3 days before study 
drug administration 
 g cfDNA samples 
will be collected BI 
on Day 1 of Cycles 
1, 2, 3, 4, 7, then 
every 4 cycles, and 
at EOT (+7 days). 
Optional PGx Blood 
Sample 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8.7.2 
Participation in the 
PGx part of the study 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 32 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
is optional for all 
subjects. 
PK Blood Sample 
Xh 
Xi,j 
X 
X 
Xh 
Xi 
Xh 
Xi 
Xh 
Xi 
 
 
 
8.6 
 
Central laboratory 
testing. 
h Specified PK 
samples within 8 
hours BI on Day 1 of 
Cycles 1, 2, 3, 4, and 
6. 
i Specified PK 
samples within 15 
minutes of EOI on 
Day 1 of Cycles 1, 2, 
3, and 4. 
j Specified PK 
samples to be 
collected 5 hours 
(±15 minutes) after 
the start of 
administration on 
Day 1 of Cycle 1. 
Immunogenicity Blood 
Sample (ADA and NAb)p 
Xk 
 
 
 
Xk 
 
 
 
Xk 
 
X 
X 
Xl 
8.7.3 
k Immunogenicity 
samples to be 
collected within 8 
hours BI on Day 1 of 
Cycles 1, 2 and 4, 
and then every 4 
cycles.  
l For subjects with 
positive ADA at the 
FU visit, additional 
serum ADA samples 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 33 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
may be collected 
during long-term 
follow-up that is, 
every 3 months (±14 
days) up to 1 year 
after the last dose of 
the study drug, or 
until the 
immunogenicity 
result becomes 
negative, or until the 
ADA titer becomes 
less than the baseline 
(applicable when 
pre-existing ADA 
was observed), or 
until the subject 
starts another 
therapy for cancer, 
or withdraws consent 
from the study, 
whichever occurs 
first. 
Blood Sample for Tumor 
markers (CEA and CA19-
9) 
 
 
 
 
 
 
Xm 
 
Xm 
 
 
 
 
10.4 
m Sample to be 
collected every 2 
cycles beginning on 
Day 1 of Cycle 3 
(ie, Day 1 of Cycles 
3, 5, 7, 9, etc), These 
samples should be 
collected only if 
these biomarkers are 
informative 
(abnormal), as 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 34 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
assessed by the 
Investigator. 
CT/MRI of the Brain 
X (The first on-study imaging assessment should be performed at 6 weeks [42 
days (+7) days] from Cycle 1 Day 1.) 
 
 
8.3.4 
At baseline, a CT or 
MRI of the brain is 
required ONLY if 
the subject has a 
history of brain 
metastases and/or 
symptoms 
suggestive of brain 
metastases.  When 
the subject has brain 
metastases identified 
at baseline, a CT or 
MRI of the brain is 
required throughout 
the study (at tumor 
assessment time 
points) and EOT. 
Radiographic Tumor 
Assessment  
Xn 
Xn 
 
 
8.3.4 
n Tumor imaging 
should be performed 
every 6 weeks 
(±7 days) from Day 
1 of Cycle 1 or more 
frequently if 
clinically indicated. 
The first on-study 
imaging assessment 
should be performed 
at 6 weeks (42 days 
[+7] days) from 
Cycle 1 Day 1. After 
12 months (365 days 
[±7] days), subjects 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 35 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
who remain on 
treatment will have 
imaging performed 
every 12 weeks 
(±14 days) until 
disease progression 
or start of new 
anticancer treatment.  
Regarding the EOT 
tumor assessment: If 
the previous scan 
was within the last 
6 weeks (within 12 
weeks if the subject 
completed the first 
year of tumor 
assessments), the 
tumor assessment at 
the EOT Visit does 
not need to be 
performed. If the 
Investigator makes a 
clinical diagnosis 
that there has been 
progression, imaging 
examinations should 
be performed as 
promptly as possible, 
and efforts should be 
made to obtain an 
image-based 
assessment of PD. 
Imaging timing 
should follow 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 36 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
calendar days.  (For 
suspected 
ILD/pneumonitis, 
see Section 6.5.2.)  
Allocate ePRO Device and 
ePRO Subject Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
8.5.1.6  
The ePRO device 
must be charged and 
fully functional prior 
to the subject’s 
arrival at the site for 
Cycle 1 Day 1 
(-3 days) to ensure 
that the ePROs can 
be completed at the 
start of the visit. The 
subject should be 
trained on the use of 
the device, including 
the importance of 
completing the 
ePRO questionnaires 
throughout the study 
in accordance with 
the completion 
schedule. 
EORTC QLQ-C30, 
EORTC QLQ-CR29, EQ-
5D-5L, PGIS 
Xd 
 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
X 
X 
8.5.1 
d Assessment(s) to 
be performed within 
3 days before study 
drug administration. 
EORTC QLQ-C30, 
EORTC QLQ-CR29, 
EQ-5D-5L, and 
PGIS to be 
completed at Day 1 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 37 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
of Cycles 1, 2, 3,  
and then every 2 
cycles (ie, Cycle 5, 
7, 9, etc.), EOT, 
40-day FU visit 
(+7 days) and at 
approximately 
6 months and 
12 months 
(±14 days) after the 
40-day FU visit. 
Subjects should 
complete the 
questionnaires 
before any other 
assessments or 
procedures are done. 
PGIC 
 
 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
X 
X 
8.5.1 
d Assessment(s) to 
be performed within 
3 days before study 
drug administration. 
PGI-TT 
 
 
 
 
Xd 
 
Xd 
 
Xd 
 
X 
 
 
8.5.1 
d Assessment(s) to 
be performed within 
3 days before study 
drug administration. 
Administer Study Drug 
(T-DXd) 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
 
6.2.2 
Administer Q3W 
(±2 days) unless 
discontinuation 
criteria are met. 
Healthcare Resource Use 
At each scheduled visit, the site should review clinical notes for any non-study-related hospital 
admissions and visits that have occurred. 
 
8.5.2 
If a subject 
discontinues study 
treatment for reasons 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 38 
 
Day 
Treatment 
Follow-up 
CSP Section(s) 
Comment(s) 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 – 
Cycle x 
EOTa 
40D 
FUb 
LTFUc 
1 
8 
15 
1 
1 
1 
Window  
Procedure 
BI 
 
EOI 
 
±1D 
±1D 
±2D  
±2D 
±2D  
±1D 
+7D 
±14D 
BI 
EOI 
BI 
EOI 
BI 
EOI 
other than RECIST 
(version 1.1) 
progression, the 
HOSPAD eCRF 
module form should 
continue to be 
administered until 
progression has been 
confirmed. 
AEs 
X 
8.4.1 
 
Concomitant Medications 
X 
6.6 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
X 
8.3.7  
 
ADA = anti-drug antibody; AE = adverse event; BI = before infusion; CA19-9 = carbohydrate antigen 19-9; CEA = carcinoembryonic antigen; cfDNA = cell-free 
deoxyribonucleic acid; cfRNA = cell-free ribonucleic acid; CHF = congestive heart failure; CQ = chloroquine; CSP = clinical study protocol; CT = computed tomography; 
CTCAE = Common Terminology Criteria for Adverse Events; EC = Ethics Committee; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative 
Oncology Group; EOI = end of infusion; EORTC QLQ = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EOT = end of treatment; 
ePRO = electronic patient-reported outcome; EQ-5D-5L = EuroQol 5 Dimension 5 Level; FU = follow-up; HCQ = hydroxychloroquine; HOSPAD = Hospital Admission (eCRF 
module); ILD = interstitial lung disease; LTFU = long-term follow-up; MI = myocardial infarction; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NAb = 
neutralizing antibody; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PGI-TT = Patient Global Impression of Treatment Tolerability; 
PGx = pharmacogenomic; PK = pharmacokinetic; PRO = patient-reported outcome; PS = performance status; Q3W = once every 3 weeks; RECIST = Response Evaluation 
Criteria in Solid Tumors; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SpO2 = peripheral oxygen saturation. 
a EOT is the date when the Investigator decides to discontinue study treatment (+7 days). 
b FU is 40 days (+7 days) after the last T-DXd administration or before starting new anticancer treatment, whichever comes first.  If EOT is >40 days (+7 days) of subject’s last 
treatment, then the EOT assessments may take the place of the 40-day FU Visit assessments. 
c Long-term follow-up will occur every 3 months (±14 days). 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 39 
2. 
INTRODUCTION 
2.1. 
Background 
Colorectal cancer (CRC) is the third most common cancer worldwide.  There were 
approximately 1.85 million new cases diagnosed and 880,000 associated deaths worldwide in 
2018.1  Several standard therapies for advanced or metastatic CRC (mCRC) are listed in the 
guidelines.2,3,4  However, many patients with mCRC eventually progress on current standard of 
care treatments.  The treatment benefit of third-line or subsequent therapy is also limited in 
patients who maintain a good performance status (PS) after receiving available treatments. 
Approximately 2% of all CRCs are human epidermal growth factor receptor 2 (HER2)-positive 
and approximately 2% of Kirsten rat sarcoma viral oncogene homologue (KRAS) wild-type CRC 
are HER2 positive.5  Most HER2 amplifications are found in rat sarcoma viral oncogenes 
homologue (RAS)/BRAF wild-type CRCs.6,7  HER2 gene amplification/overexpression is 
considered to be associated with resistance to anti-epidermal growth factor receptor 
(EGFR)-targeted therapy,8,9,10 and HER2 amplification/overexpression is a predictive marker of 
shorter progression-free survival (PFS) after anti-EGFR antibody cetuximab treatment in patients 
with mCRC harboring RAS wild-type and v-raf murine sarcoma viral oncogene homologue B1 
(BRAF) wild-type.  There is a high concordance between HER2 overexpression staining and 
HER2 gene amplification in colorectal adenocarcinomas.11,12 
However, the reported frequency of HER2 amplification and overexpression in CRC varies 
between studies because of differences in examination methods and objective criteria.13  The 
HER2 Amplification for Colorectal Cancer Enhanced Stratification (HERACLES) study 
assessed the antitumor activity of trastuzumab and lapatinib in patients with HER2-positive 
CRC, and found 5% of patients had HER2-positive tumors in human KRAS wild-type CRC.14  In 
reported analyses of 3256 patients enrolled in the Quantitative Assessment of Swallowing after 
Radiation (QUASAR), Fluorouracil, Oxaliplatin, and Irinotecan: Use and Sequencing (FOCUS), 
and Panitumumab, Irinotecan, and Cyclosporin in Colorectal Cancer (PICCOLO) studies, HER2 
overexpression in KRAS/BRAF mutated colorectal cancer tumor was 1.0%.1   
Trastuzumab deruxtecan (T-DXd; DS-8201a) is an antibody-drug conjugate (ADC) composed of 
an anti-HER2 antibody conjugated to a drug-linker carrying a topoisomerase I payload.  In the 
Phase 1 clinical study, DS8201-A-J101, in subjects with advanced HER2-expressing solid 
tumors, T-DXd was well tolerated at repeated doses of up to 8.0 mg/kg intravenously (IV) once 
every 3 weeks (Q3W).  Preliminary data from DS8201-A-J101 and the Phase 2 clinical study 
DS8201-A-J203 (DESTINY-CRC01), in subjects with advanced HER2-expressing CRC studies 
have shown promising preliminary clinical efficacy in this patient population.15   
T-DXd was also studied in the DS8201-A-U201 (DESTINY-Breast01) study in HER2-positive 
metastatic breast cancer previously treated with T-DM1.16,17  
Based on data from DESTINY-Gastric01, T-DXd was granted orphan drug designation in the 
United States for the treatment of patients with GC/gastro-esophageal junction (GEJ) 
adenocarcinoma and Breakthrough Therapy Designation for the treatment of patients with 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 40 
HER2-positive unresectable or metastatic gastric or GEJ adenocarcinoma who have received 2 or 
more prior regimens including trastuzumab based on data from DESTINY-Gastric01.18  
Based on the results of these studies, T-DXd (ENHERTU®) obtained accelerated approval in the 
United States on 20 December 2019 for the treatment of adults with unresectable or metastatic 
HER2-positive breast cancer who received 2 or more prior anti-HER2-based regimens in the 
metastatic setting.19  On 25 March 2020, T-DXd obtained approval under the conditional early 
approval system in Japan for the treatment of patients with HER2-positive unresectable or 
recurrent breast cancer after prior chemotherapy (limit the use to patients who are refractory or 
intolerant to standard treatments). 
2.1.1. 
Investigational Product Trastuzumab Deruxtecan (T-DXd; DS-8201a) 
T-DXd is a novel anti-HER2 ADC, that consists of an anti-HER2 antibody, MAAL-9001, 
covalently linked to approximately 8 molecules of MAAA-1162a (GGFG tetra-peptide cleavable 
linker and a topoisomerase I inhibitor [MAAA-1181a]).  The drug MAAA-1181a (DXd), a 
derivative of exatecan, is released after internalization and leads to apoptosis of the target tumor 
cells via the inhibition of topoisomerase I. MAAL-9001 shares amino acid sequences with 
2 currently approved anti-HER2 agents, trastuzumab and the antibody part of T-DM1, and thus 
T-DXd similarly targets HER2 expressing tumors. 
Due to incorporation of a novel linker, T-DXd achieves a higher drug-to-antibody ratio (DAR) of 
approximately 8 with homogeneous conjugation of DXd compared with all currently approved 
ADCs composed of a DAR of 3 to 4.  Despite the high DAR in T-DXd, the cleavable linker in 
T-DXd is more stable in plasma than T-DM1 to confer a favorable safety profile as observed in 
the nonclinical toxicology rat and monkey studies. 
After binding to HER2 and internalization, T-DXd is cleaved by lysosomal enzymes 
preferentially expressed in tumor 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.  T-DXd 
is expected to exhibit antitumor activity through MAAA-1181a induced apoptosis and the 
antibody-dependent cellular cytotoxic (ADCC) activity of MAAL-9001 which leads to the 
inhibition of Akt phosphorylation. 
As further differentiation from T-DM1, the released cytotoxic drug, MAAA-1181a, is cell 
membrane permeable after it is cleaved from the linker and exhibits a bystander effect.20,21  This 
could allow potent activity even against tumors with HER2 heterogeneity.   
2.2. 
Study Rationale 
HER2 gene amplification is considered to be associated with resistance to EGFR-targeted 
therapy22 and HER2 amplification is a predictive marker of shorter PFS after anti-EGFR 
antibody cetuximab treatment in patients with mCRC.23  Therefore, HER2 is considered to be an 
important target for mCRC, although anti-HER2 combinations are recommended in National 
Comprehensive Cancer Network (NCCN) guidelines for HER2-amplified/KRAS wild-type CRC 
patients, no approved HER2-targeted therapies exist for CRC.  In the third or later-line setting, 
therapies including Stivarga® and Lonsurf® are approved, but with modest efficacy: objective 
response rate (ORR) of Lonsurf® and Stivarga® are up to 1.6%, and PFS is 1.9 to 2.0 months.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 41 
Although HER2 amplification can be found in RAS/BRAF mutant CRC tumors, the clinical 
significance of this and how to effectively target it are unknown.  New treatment options are 
needed for the HER2 positive/RAS-mutant or -wild-type (mt/wt) population.  
In the MyPathway study which evaluated the combination of pertuzumab and trastuzumab in 
HER2 amplified mCRC subjects, 13 RAS-mutant subjects were enrolled and the ORR was 
8% (95% CI: 0.2, 36), median PFS was 1.4 months (95% CI: 1.2, 2.8).24  An unmet medical need 
exists for patients with RAS-mutant mCRC.  Given the current evidence on the potential role of 
the HER2 pathway in mCRC, anti-HER2 treatment approaches are considered for further 
investigation. 
Both 5.4 and 6.4 mg/kg doses of T-DXd have shown clinical efficacy in multiple cancer 
indications.  However, the 5.4 mg/kg dose has not yet been tested in HER2 positive mCRC 
subjects.  This Phase 2, randomized study to evaluate 5.4 mg/kg and 6.4 mg/kg doses in 
HER2-overexpressing mCRC subjects will further characterize the benefit-risk profile of T-DXd 
in this population. 
2.3. 
Benefit and Risk Assessment 
T-DXd has been developed for the treatment of HER2-expressing malignant tumors and has 
demonstrated substantial antitumor activity at a dose of 5.4 mg/kg in studies DS8201-A-J101 and 
DS8201-A-U201 (DESTINY-Breast01).  As of 01 August 2019, the confirmed ORRs by 
independent central review (ICR) were 51.0% (95% CI: 36.6, 65.2) in DS8201-A-J101 and 
60.9% (95% CI: 53.4, 68.0) in DS8201-A-U201 with a sustained duration of response (DoR) 
(median DoR for confirmed responses of 10.8 months [95% CI: 6.7, not evaluable (NE)] in 
DS8201-A-J101 and 14.8 months [95% CI: 13.8, 16.9] in DS8201-A-U201) and a prolonged 
PFS (median PFS by ICR of 13.7 months [95% CI: 8.5, 19.6] in DS8201-A-J101 and 
16.4 months [95% CI: 12.7, NE] in DS8201-A-U201), all of which represent a clinically 
meaningful improvement over available therapies based on historical and real-world experience. 
Preliminary clinical evidence for T-DXd in HER2-overexpressing mCRC comes from 
DS8201-A-J203.  As of 09 August 2019, in DS8201-A-J203 study, mCRC subjects were 
enrolled in 3 cohorts (A: IHC 3+ and IHC 2+/ ISH+; B: IHC 2+/ ISH-; C: IHC 1+).  All subjects 
were RAS wild-type. Patients were treated at 6.4 mg/kg every 3 weeks (Q3W).25  A total of 
53 subjects were enrolled in Cohort A. The confirmed ORR was 45.3% (95% CI: 31.6, 59.6), 
median PFS was 6.9 months (95% CI: 4.1, NE), and median DoR was not yet observed (95% CI: 
4.2, NE) based on ICR.  In the subgroup analysis in Cohort A: 40 subjects had IHC 3+ and 
13 subjects had IHC 2+/ ISH+. The confirmed ORR in these subgroups were 57.5% (23/40) and 
7.7% (1/13), respectively.  However, there were no objective responses observed in subjects 
enrolled in Cohorts B (N=7) and C (N=18).25 
Based on the cumulative review of the safety data, including available nonclinical, clinical, and 
epidemiologic information and scientific literature (published and unpublished) and taking into 
consideration biological plausibility, interstitial lung disease (ILD)/pneumonitis, anaemia, 
neutrophil count decrease including febrile neutropenia, and platelet count decrease are classified 
as important identified risks.  Left ventricular (LV) dysfunction is classified as an important 
potential risk.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 42 
ILD/pneumonitis is an important serious risk of T-DXd and cases with fatal outcomes have been 
reported.  Most ILD/pneumonitis events in the above studies were Grade 1 or Grade 2, were 
manageable by dose modification and by following clinical treatment guidelines for 
drug-induced ILD/pneumonitis.  In DS8201-A-J203, a total of 5 patients (6.4%) experienced 
ILD as adjudicated by an independent committee (two Grade 2; one Grade 2; and two 
Grade 5).25 ILD/pneumonitis requires proper monitoring including early identification, and 
management instituted in a timely fashion.  
T-DXd has demonstrated an overall acceptable safety profile in the treated populations to date.   
In conclusion, the data available on the efficacy and safety of T-DXd supports the overall 
benefit-risk profile remaining favorable for clinical development. 
For current assessments of risks and benefits to subjects, refer to the most current Investigator’s 
Brochure (IB) for T-DXd.26  
2.3.1. 
Benefit/Risk in Regard to SARS-CoV-2 
With the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
comes an increased safety risk for all subjects.  Due to the potential impact of SARS-CoV-2 on 
the lung, the Sponsor has developed a monitoring plan to limit and manage the potential risk of 
SARS-CoV-2 to T-DXd study subjects.  For any subjects with suspected or confirmed 
SARS-CoV-2, study treatment will be interrupted until they fully recover for treatment 
resumption (as outlined in the dose modification guidance; Section 10.6).  All clinical study 
protocols have been updated to include language on dose modification for SARS-CoV-2.  
As the subjects included in this study are at high risk of recurrence, and improved therapies are 
still needed for this population, the Sponsor considers the potential benefit of T-DXd for subjects 
in this study outweighs any potential risks associated with SARS-CoV-2.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 43 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS 
The objectives, definitions of associated endpoints as well as applicable outcome measures are 
described in Table 3.1.  Further requirements for the endpoint analyses and censoring rules, 
where applicable, can be found in Section 9.5.1, Section 9.5.2, Section 9.5.3, and Section 9.5.4. 
Table 3.1: 
Description of Objectives, Outcome Measures, and Endpoints 
Objectives 
Outcome Measures 
Endpoints 
Category 
Primary 
 
 
 
To assess the 
efficacy of T-DXd, 
as measured by the 
confirmed ORR by 
BICR in HER2-
overexpressing 
(defined as IHC 3+ 
or IHC 2+/ISH+) 
mCRC subjects 
treated at the 
5.4 mg/kg and 
6.4 mg/kg doses 
Title: Confirmed ORR 
Description: CR and PR as 
assessed by blinded data 
review and based on RECIST 
version 1.1 
Time frame: 12 weeks after 
the first 80 subjects are 
randomized for the IA and 
6 months after the last subject 
is registered for the primary 
analysis 
The primary efficacy endpoint is 
confirmed ORR, defined as the 
proportion of subjects with CR or 
PR, assessed by BICR based on 
RECIST version 1.1 
Efficacy 
Secondary 
 
 
 
To evaluate the 
clinical efficacy of 
T-DXd by 
confirmed ORR by 
Investigator 
assessment 
Title: Clinical Efficacy 
Description: Evaluation of 
the clinical efficacy of T-DXd 
at 5.4 mg/kg and 6.4 mg/kg 
doses by confirmed ORR by 
Investigator assessment  
Time frame: 12 weeks after 
the first 80 subjects are 
randomized for the IA and 
6 months after the last subject 
is registered for the primary 
analysis 
Confirmed ORR as indicated 
above assessed by Investigator 
assessment based on RECIST 
version 1.1 
 
Efficacy 
To evaluate the 
clinical efficacy of 
T-DXd by DoR 
Title: Clinical Efficacy 
Description: Evaluation of 
the clinical efficacy of T-DXd 
at 5.4 mg/kg and 6.4 mg/kg 
doses by DoR 
Time frame: 12 weeks after 
the first 80 subjects are 
randomized for the IA and 
6 months after the last subject 
is registered for the primary 
analysis 
DoR, defined as time from the 
initial response (CR or PR) by 
BICR and Investigator 
assessment until documented 
tumor progression or death from 
any cause 
Efficacy 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 44 
Objectives 
Outcome Measures 
Endpoints 
Category 
To further evaluate 
the clinical efficacy 
of T-DXd by DCR, 
CBR, PFS and OS 
Title:  Clinical Efficacy 
Description: Further 
evaluation of the clinical 
efficacy of T-DXd at 
5.4 mg/kg and 6.4 mg/kg 
doses by DCR, CBR, PFS, 
and OS 
Time frame: 12 weeks after 
the first 80 subjects are 
randomized for the IA (DCR, 
PFS) and 6 months after the 
last subject is registered for 
the primary analysis (DCR, 
CBR, PFS, OS) 
 
Based on BICR and Investigator 
assessment according to RECIST 
version 1.1 (unless otherwise 
specified):   
 
DCR, defined as the 
proportion of subjects who 
achieved CR, PR, or SD for 
a minimum of 6 weeks 
during study treatment;  
DCR based on BICR and 
DCR based on Investigator 
assessments will both be 
determined  
 
CBR, defined as proportion 
of subjects who achieved 
CR, PR, or SD for at least 6 
months;  CBR based on 
BICR and CBR based on 
Investigator assessments will 
both be determined 
 
PFS, defined as the time 
from date of 
randomization/registration 
until first objective 
radiographic tumor 
progression or death from 
any cause, based on BICR 
and Investigator assessment 
 
OS, defined as the time from 
date of 
randomization/registration 
until death from any cause 
Efficacy 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 45 
Objectives 
Outcome Measures 
Endpoints 
Category 
To further evaluate 
the safety and 
tolerability of 
T-DXd 
Title: TEAEs and other safety 
parameters during the study 
Description: Descriptive 
statistics of safety endpoints 
Time frame: 12 weeks after 
the first 80 subjects are 
randomized for the IA and 
6 months after the last subject 
is registered for the primary 
analysis 
Safety endpoints will include, 
incidence and severity of 
(according to the NCI-CTCAE 
version 5.0): 
 
TEAEs (including SAEs and 
AESIs) 
 
TEAEs associated with 
death 
 
Incidence of dose 
interruptions, dose 
modifications, and 
discontinuations due to AEs 
 
ECOG PS 
 
Vital sign measurements 
 
Clinical laboratory 
parameters (hematologic and 
non-hematologic) 
 
ECG parameters 
 
ECHO/ MUGA 
 
Ophthalmologic assessments 
Safety 
To evaluate HEOR 
endpoints including 
patient-reported 
HRQoL, symptoms, 
and physical 
functioning  
Title: PROs during the study 
Description: EORTC QLQ-
C30 and EORTC QLQ-CR29, 
EQ-5D-5L, PGI-TT, PGIS, 
and PGIC 
Time frame: 6 months after 
the last subject is registered or 
later 
 
PROs include: 
 
Change from baseline in 
EORTC QLQ-C30 and 
EORTC QLQ-CR29 scale 
scores 
 
EQ-5D-5L health state 
utility index 
 
Patient-reported treatment 
tolerability with PGI-TT 
 
Proportion of subjects with 
overall PGIS and PGIC  
HEOR 
To evaluate 
healthcare resource 
utilization for both 
treatment arms 
Title: Healthcare resource use 
during the study 
Description: Healthcare 
resource use 
Time frame: 6 months after 
the last subject is registered or 
later 
Healthcare resource use will be 
captured/collected, including 
inpatient admissions, intensive 
care unit admissions, and length 
of stay in hospital 
Healthcare resource 
use 
To evaluate PK of 
T-DXd 
Title: PK profile 
Description: Serum 
concentrations 
Time frame: 6 months after 
the last subject is registered or 
later 
 
The PK endpoints include 
serum concentrations of 
T-DXd, total anti-HER2 
antibody, and MAAA 
1181a 
PK 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 46 
Objectives 
Outcome Measures 
Endpoints 
Category 
To evaluate 
immunogenicity of 
T-DXd 
Title: Immunogenicity profile 
Description: Incidence of 
ADA and NAb 
Time frame: 6 months after 
the last subject is registered or 
later 
 
The immunogenicity 
endpoint includes incidence 
of ADA and NAb 
Immunogenicity 
Exploratory 
 
 
 
To further evaluate 
the clinical efficacy 
of T-DXd by TTR, 
best percent change 
in the SoD for all 
target lesions, and 
TTD in ECOG PS 
Title:  Clinical Efficacy 
Description: Further 
evaluation of the clinical 
efficacy of T-DXd at 
5.4 mg/kg and 6.4 mg/kg 
doses by TTR, SoD, and TTD 
in ECOG PS 
Time frame: 12 weeks after 
the first 80 subjects are 
randomized for the IA and 6 
months after the last subject is 
registered for the primary 
analysis 
 
 
TTR, defined as the time 
from the date of 
randomization/registration to 
the date of first documented 
objective response (CR or 
PR), based on BICR and 
Investigator assessment 
 
Best percentage change from 
baseline in the SoD for all 
target lesions, based on 
BICR and Investigator 
assessment  
 
TTD in ECOG PS, defined 
as the time from the date of 
randomization/registration to 
the date when ECOG PS 
score of ≥2 is observed for 
the first time 
Efficacy 
To assess the 
relationship between 
changes in tumor 
markers (CEA and 
CA19-9) and 
radiographic 
response to T-DXd 
treatment 
Not applicable 
Changes in CEA and CA19-9 
 
PD 
To evaluate ERBB2 
copy number 
detected in cfDNA 
at baseline as an 
exploratory 
predictive biomarker 
of response 
Not applicable 
ERBB2 copy number at baseline 
and its association with clinical 
outcomes 
 
Biomarker 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 47 
Objectives 
Outcome Measures 
Endpoints 
Category 
To evaluate other 
potential biomarkers 
of resistance or 
clinical benefit to 
study treatment 
Not applicable 
 
Liquid biomarkers (eg, 
cfRNA and cfDNA) and 
its association with 
clinical outcomes 
 
Potential DNA, RNA, and 
protein-based biomarkers 
evaluated by different 
methodologies (eg, 
cfDNA, NGS based 
analysis of DNA and 
RNA, protein-based 
analysis, IHC digital 
pathology analysis etc. of 
tumor and blood samples) 
Biomarker 
To explore an 
exposure/response 
relationship 
Not applicable  
 
T-DXd PK concentration 
versus selected safety and 
efficacy endpoints 
PK, Safety, and 
Efficacy 
ADA = anti-drug antibody; AE = adverse event; AESI = adverse event of special interest; BICR = blinded 
independent central review; CA19-9 = carbohydrate antigen 19-9; CBR = clinical benefit rate; 
CEA = carcinoembryonic antigen; cfDNA = cell-free deoxyribonucleic acid; cfRNA = cell-free ribonucleic acid; 
CR = complete response; DCR = disease control rate; DNA = deoxyribonucleic acid; DoR = duration of response; 
ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; EORTC = European Organization for Research and Treatment of Cancer; 
EQ-5D-5L = EuroQol-5 dimensions-5 levels of severity; ERBB2 = erb-b2 receptor tyrosine kinase 2; 
HEOR = Health Economics and Outcomes Research; HER2=Human epidermal growth factor receptor 2; 
HRQoL = health-related quality of life; IA = interim analysis; IHC = immunohistochemistry; ISH = in situ 
hybridization; MAAA-1181a = released drug; mCRC = metastatic colorectal cancer; MUGA = multigated 
acquisition; NAb = neutralizing antibodies; NCI-CTCAE = National Cancer Institute-Common Terminology 
Criteria for Adverse Events; NGS = next-generation sequencing; ORR = objective response rate; OS = overall 
survival; PFS = progression-free survival; PGIC = Patient Global Impression-Change; PGIS = Patient Global 
Impression-Severity; PGI-TT = Patient Global Impression-Treatment Tolerability; PK = pharmacokinetics; 
PR = partial response; PRO = patient-reported outcome; PS = performance status; QLQ = Quality of Life 
Questionnaire; RECIST = Response Evaluation Criteria in Solid Tumors; RNA = ribonucleic acid; SAE = serious 
adverse event; SD = stable disease; SOC = standard of care; SoD = sum of diameters; TEAE = treatment-emergent 
adverse event; TTD = time to deterioration; TTR = time to response. 
3.1. 
Rationale for Selection of Primary and Secondary Endpoints 
The primary and key secondary efficacy endpoints selected will evaluate evidence of drug 
anti-tumor activity.  ORR is defined as the proportion of subjects with complete or partial 
response (PR) as defined by RECIST version 1.1 in this study.  ORR is a direct measure of drug 
antitumor activity, which can be evaluated in the current study.  Because ORR is directly 
attributable to drug effect, it is an appropriate measure of efficacy.27  
DoR in subjects with confirmed response is an important secondary endpoint of the study.  A 
durable response is clinically meaningful in cancer patients and is an important measure to 
supplement ORR. 
PFS represents the time interval from randomization/registration to disease progression or death, 
and provides a direct evidence of the activity of an investigational treatment in delaying tumor 
growth.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 48 
4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a global, multicenter, randomized, 2-arm, parallel, Phase 2 study to evaluate 2 doses of 
T-DXd (5.4 mg/kg Q3W or 6.4 mg/kg Q3W) in subjects with locally advanced, unresectable, or 
metastatic HER2-overexpressing CRC (IHC 3+ or IHC 2+/ISH+) in 2 stages.  The treatment 
assignment will remain unknown to the study subjects, Investigators, study site personnel (except 
the unblinded pharmacist and other unblinded staff members as deemed necessary for site 
operations to maintain the blind), central imaging readers, and the ILD Adjudication Committee 
(AC).  The Sponsor and the contract research organization (CRO) are not blinded to the 
treatment assignment of the subjects.  This study is planned to be conducted in approximately 
70 study sites, including but not limited to the Americas, Asia-Pacific, and Europe.  The subject 
population is described in Section 5. 
The study start date is the date when the first subject has signed the main informed consent form 
(ICF).  A subject is eligible to be enrolled into the interventional portion of the study when the 
Investigator or designee has obtained written (main) consent, has confirmed all eligibility criteria 
have been met by the subject, and all Screening procedures have been completed. 
Randomization/registration is defined as the time point at which the Investigator has obtained the 
subject’s randomization/registration code through the interactive response technology (IRT) 
system and study drug dose has been assigned (5.4 mg/kg Q3W or 6.4 mg/kg Q3W). 
4.1.1. 
Design Overview 
Approximately 850 subjects will be pre-screened for tumor tissue via a central laboratory to 
enroll approximately 120 subjects with HER2-overexpressing CRC of BRAF wild-type and 
either RAS wild-type or mutant tumor type, previously treated with standard therapy. 
Eighty subjects will be randomized in a 1:1 ratio through the IRT to 5.4 mg/kg Q3W or 
6.4 mg/kg Q3W of T-DXd at Stage 1.  Randomization will be stratified by the following factors: 
1. Eastern Cooperative Oncology Group (ECOG) PS (0 or 1) 
2. HER2 status (IHC 3+ or IHC 2+/ISH+) 
3. RAS status (wild-type or mutant) 
The treatment assignment will remain unknown to the study subjects, Investigators, study site 
personnel (except the unblinded pharmacist), central imaging readers, and the ILD AC.  The 
Sponsor and the CRO are not blinded to the treatment assignment of the subjects. 
After enrollment is completed in Stage 1, forty subjects will be registered to the 5.4 mg/kg arm at 
Stage 2.  An interim analysis (IA) is planned when at least 80 subjects have been randomized in 
Stage 1 of the study and have been followed for at least 12 weeks or have discontinued from the 
study. 
The study will be divided into the following periods: Tissue Pre-Screening Period, Screening 
Period, Treatment Period, End of Treatment (EOT), and Follow-up Period. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 49 
 The Tissue Pre-Screening Period will start on the day of obtaining a signed and 
dated written Tissue Pre-Screening ICF from the subject prior to collecting tissue 
from a recent tumor biopsy (preferred) or archival tissue to confirm HER2 status.  A 
tissue sample is considered a recent sample if it is collected from a biopsy performed 
after the subject’s discontinuation of the last treatment regimen (and most recent 
disease progression).  For subjects who sign this ICF, only serious adverse events 
(SAEs) directly related to the tissue pre-screening procedure (ie, tumor biopsy) 
should be reported via the SAVER Form.  Unless documentation of other adverse 
events (AEs) are required by local law, only SAEs directly related to tumor biopsy 
will be recorded during tissue pre-screening.  The tissue pre-screening may occur any 
time before the Screening Period. 
 The Screening Period will start on the day a subject signs the Main ICF and will 
comprise a maximum duration of 28 days.  Rescreening is permitted once during this 
phase if the subject fails initial Screening.  During the 28-day Screening Period, 
subjects’ eligibility will be confirmed.  The activities and/or assessments will be 
performed within 28 days before randomization/registration during the Screening 
Period are listed in Table 1.2.  Within 14 days before randomization/registration, the 
subjects will undergo medical history evaluation, vital signs determination, physical 
examination, pulse oximetry (peripheral oxygen saturation [SpO2]), height and 
weight measurements, functional status confirmation using the ECOG PS, laboratory 
testing (including blood tests for safety), and 12-lead electrocardiograms (ECG) in 
triplicate.  Eligible subjects will be randomized/registered and enter the Treatment 
Period. 
 The Treatment Period starts on Day 1 of Cycle 1.  Eligible subjects will be 
randomized to 1 of 2 treatment arms in Stage 1:  
 Arm 1: T-DXd for injection will be administered IV at a dose of 5.4 mg/kg Q3W 
 Arm 2: T-DXd for injection will be administered IV at a dose of 6.4 mg/kg Q3W 
 After Stage 1 enrollment is complete (N=80), eligible subjects will be registered to 
T-DXd administered IV at a dose of 5.4 mg/kg Q3W in Stage 2 (N=40).  Subjects 
will receive the assigned dose of T-DXd (5.4 mg/kg Q3W or 6.4 mg/kg Q3W) until 
progression of disease or the subject meets one of the discontinuation criteria 
(Section 7.1).  Combining both stages of the study, a maximum of 30 subjects per 
subgroup will be registered onto each of the HER2 IHC 2+/ISH+ and RAS-mutant 
subgroups.  A minimum of 20 subjects with RAS-mutant status will be enrolled in the 
study.  Once the maximum number of 30 subjects is reached, all subsequent subjects 
enrolled in the study should have HER2 IHC 3+ or RAS wild-type tumor. 
 The EOT is defined as the date the Investigator decides to discontinue study 
treatment.  Subjects who permanently discontinue the study treatment should be 
scheduled for an EOT visit within +7 days following the date study treatment is 
permanently discontinued.  If the decision to discontinue the subject occurs at a 
regularly scheduled visit, that visit may serve as the EOT visit rather than having the 
subject return for an additional visit. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 50 
 The Follow-up Period will start upon permanent discontinuation of T-DXd.  
Subjects will be followed 40 days (+7 days) after the last study treatment 
administration or before starting new anticancer treatment, whichever comes first. 
Subjects who discontinue study drug for any reason other than PD, death, or loss to 
follow-up will be followed every 6 weeks (Q6W) until radiological disease 
progression or start of new anticancer treatment.  If EOT is >40 days after last 
treatment, then the EOT assessments may take the place of the 40-day Follow-up 
Visit assessments.  Long-term disease follow-up to monitor survival will be 
documented every 3 months (±14 days) for up to 2 years, every 6 months from 3 to 
5 years, and annually from 6 to 10 years.  Survival follow-up contact (either 
scheduled visit or telephone call) will be performed every 3 months (±14 days) from 
the date of the 40-day Follow-up Visit, until death, withdrawal of consent, loss to 
follow-up, or study closure, whichever occurs first. 
The subject population is described in Section 5.  A flow diagram of study activities is presented 
in Figure 1.1. 
4.1.2. 
End of Study 
The primary completion date is the date when the last enrolled subject has completed 6 months 
of follow-up treatment or when all subjects have been discontinued from the study and 
completed the 40-day Follow-up Visit, whichever is earlier.  This date is used as the cut-off date 
for the analysis of the primary efficacy endpoint(s) of the study.  All subjects still on treatment 
and continuing to derive benefit from study drug at the primary completion date will continue to 
follow the study schedule of assessments (Table 1.2) until the overall End of Study (EOS) is 
reached. 
Overall EOS will occur when the last subject last visit has occurred or the study is discontinued 
by the Sponsor for other reasons (administrative, program-level, or class-related). 
The subject’s EOS is the date of their last study visit/contact. 
4.1.3. 
Dose Regimen 
Eligible subjects will be randomized to 1 of 2 treatment arms in Stage 1:  
 Arm 1: T-DXd for injection will be administered IV at a dose of 5.4 mg/kg Q3W 
 Arm 2: T-DXd for injection will be administered IV at a dose of 6.4 mg/kg Q3W 
After Stage 1 enrollment is complete, eligible subjects will be registered to the arm that T-DXd 
for injection will be administered IV at a dose of 5.4 mg/kg Q3W in Stage 2. 
Subjects will continue to receive T-DXd if they experience clinical benefit or until unacceptable 
toxicity/symptomatic deterioration attributed to PD (ie, pain secondary to disease or 
unmanageable ascites, etc.), after an integrated assessment of both radiographic data and clinical 
status by the Investigator.  See Table 6.1 for complete details on dose regimen. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 51 
4.1.4. 
Duration 
Duration of Treatment and Subject Participation 
Subjects will receive T-DXd until discontinuation criteria are met (see Section 7.1) or in the 
absence of disease progression as assessed by Investigators, death, pregnancy, withdrawal of 
subject consent, loss to follow-up, study closure, physician decision, AE, protocol deviation, or 
other reasons (see details in Section 7.2).  
Overall Study Duration 
Enrollment is planned to occur over approximately 18 months.  The anticipated total duration of 
the study is expected to be 30 months.   
See Section 4.1 for the definition of study start and Section 4.1.2 for the definition of the overall 
EOS. 
Study Drug Continuation After the End of Study 
Not applicable. 
4.2. 
Rationale for Study Design 
This Phase 2 study design is based on Study DS8201-A-J203 which demonstrated the clinical 
efficacy of T-DXd in HER2 overexpressing mCRC subjects at the 6.4 mg/kg dose.  Both 
5.4 mg/kg and 6.4 mg/kg doses of T-DXd have shown clinical efficacy in multiple cancer 
indications.  However, the 5.4 mg/kg dose has not been tested in HER2 overexpressing mCRC.  
Therefore, it is important to further characterize the benefit-risk profile for both doses in this 
study. 
The study design of Stage 1 will implement both blinding (with respect to study subjects and 
Investigators) and randomization to minimize bias in the trial conduct and to allow unbiased 
assessment of 5.4 mg/kg and 6.4 mg/kg doses.  Moreover, randomization will be stratified by 
important and potential prognostic/predictive factors which include ECOG PS (0 or 1), 
HER2 status (IHC 3+ or IHC 2+/ISH+), RAS status (wild-type or mutant), in order to reduce the 
risk of prognostic imbalance between treatment groups. 
4.3. 
Justification for Dose 
The dose selection of 5.4 mg/kg and 6.4 mg/kg in this study was based on the efficacy, safety, 
tolerability, and PK data of T-DXd from prior clinical studies in subjects with breast cancer, 
colorectal cancer, and other solid tumors.   
The T-DXd dose of 5.4 mg/kg has been evaluated in the DS8201-A-J101 study and a 
Phase 2 study (DS8201-A-U201) in subjects with HER2-positive, unresectable, and/or metastatic 
breast cancer.  The dose of 5.4 mg/kg has shown robust efficacy with confirmed ORR of 58.3% 
(137/235; 95% CI: 51.7% 64.7%) in subjects with metastatic breast cancer.  From a safety 
perspective, a numeric trend for better safety profile was observed at the 5.4 mg/kg dose 
compared with higher doses (≥6.4 mg/kg) in subjects with breast cancer.  The T-DXd dosing 
regimen of 5.4 mg/kg Q3W has also received approval in the United States and Japan for the 
treatment of adult patients with unresectable or metastatic HER2-positive breast cancer and is 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 52 
also being evaluated in ongoing global Phase 3 studies in subjects with metastatic HER2-positive 
breast cancer and also in subjects with HER2 expressing non-small cell lung cancer (NSCLC) in 
an ongoing study (DS8201-A-U204).   
The systemic exposure (area under the concentration-time curve [AUC] in the dosing cycle 
during Cycle 1 or at steady state) of intact T-DXd and DXd at 6.4 mg/kg dose in colorectal 
cancer patients were comparable to values observed in metastatic breast cancer patients at 
5.4 mg/kg (for intact T-DXd) and 6.4 mg/kg (for DXd) doses, respectively.  In subjects with 
breast cancer, DXd exposures were correlated with incidence of the safety endpoints, such as 
AE-related dose reduction or drug interruption, AEs Grade ≥3, SAE, anaemia, neutropenia, or 
thrombocytopenia.  In these analyses, approximately 2% to 7% higher incidence of these safety 
endpoints was estimated at DXd exposures associated with 6.4 mg/kg dose compared with 
5.4 mg/kg dose in subjects with breast cancer.  These data suggest potentially lower incidence of 
these safety events expected at DXd exposures predicted at 5.4 mg/kg dose of T-DXd in subjects 
with colorectal cancer.  In addition, the exposure-response analysis for ORR in subjects with 
colorectal cancer predicted about 5% lower ORR rate at 5.4 mg/kg dose compared with the 
6.4 mg/kg dose.   
In the dose escalation portion (Part 1) of the first-in-human Study DS8201-A-J101, no dose-
limiting toxicities were observed, and the maximum tolerated dose (MTD) was not reached in 
the evaluated dose range of 0.8 to 8.0 mg/kg.  Based on the efficacy and safety data in Part 1, the 
5.4 mg/kg and 6.4 mg/kg doses exhibited clinical activity with a qualitatively similar safety 
profile, and therefore were selected for the dose expansion portion (Part 2) of Study 
DS8201-A-J101 in subjects with breast cancer, colorectal cancer, and other solid tumors; 
subjects with colorectal cancer (N =20) received only 6.4 mg/kg dose of T-DXd.  T-DXd dose of 
6.4 mg/kg has shown activity in HER2-expressing colorectal cancer subjects with confirmed 
ORR of 5% (1/20) and median DoR of 13 months and median (95% CI) PFS of 4 (2.7, 5.6) 
months following a median treatment duration of 8.1 months (range: 0.7 to 29 months) at the 
time of data cut (data cut-off date: 01 Feb 2019).  
The T-DXd dose of 6.4 mg/kg is also being evaluated in the ongoing Phase 2 Study 
DS8201-A-J203 in subjects with HER2-expressing advanced colorectal cancer.  Promising 
efficacy was also observed based on the data (data cut-off date: 9 Aug 2019) from this ongoing 
study with median treatment duration of 4.8 months (median; range: 3.9 to 5.8 months) at the 
time of data cut.  In subjects with HER2-expressing advanced colorectal cancer (IHC 3+ or IHC 
2+/ISH+) following treatment with T-DXd dose of 6.4 mg/kg, confirmed ORR by ICR was 
45.3% (24/53; 95% CI: 31.6% - 59.6%) with median DoR not reached (95% CI: 4.2 months to 
NE) and the median PFS was 6.9 months (95% CI: 4.1 months to NE).  
These findings along with the observed efficacy and safety data in subjects with HER2 
expressing colorectal cancer in the Studies DS8201-A-J101 and DS8201-A-J203 support the 
selection of 5.4 mg/kg and 6.4 mg/kg doses to further characterize the benefit-risk profile of 
T-DXd in HER2 overexpressing CRC subjects.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 53 
5. 
STUDY POPULATION 
Adult subjects with a diagnosis of locally advanced, unresectable, or metastatic HER2 
overexpressing colorectal cancer with BRAF wild-type status. 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for randomization/registration into 
the study: 
1. Sign and date the Tissue Pre-Screening and Main ICFs, prior to the start of any respective 
study-specific qualification procedures. 
2. Adults aged ≥20 years in Japan, Taiwan, and Korea, or those aged ≥18 years in other 
countries, at the time the ICFs are signed.  (Please follow local regulatory requirements if 
the legal age of consent for study participation is >18 years). 
3. Pathologically-documented, unresectable, recurrent, or metastatic colorectal 
adenocarcinoma.  Subject must have BRAF wild-type cancer and RAS status identified in 
primary or metastatic site, tested by a Clinical Laboratory Improvement Act (CLIA), 
ISO15189, or equivalent-certified laboratory. 
4. The following therapies should be included in prior lines of therapy:  
a. Fluoropyrimidine, oxaliplatin, and irinotecan, unless contraindicated  
b. Anti-EGFR treatment, if RAS wild-type and if clinically indicated  
c. Anti-VEGF treatment, if clinically indicated 
d. Anti-PD-(L)-1 therapy, if tumor is MSI-high/deficient mismatch repair (dMMR), or 
tumor mutational burden (TMB)-high, if clinically indicated 
5. Is willing and able to provide an adequate tumor sample for tissue pre-screening to 
confirm HER2 status by central laboratory (most recent tumor tissue preferred). 
6. Confirmed HER2-overexpressing status assessed by central laboratory and defined as 
IHC 3+ or IHC 2+/ISH+. 
7. Presence of at least one measurable lesion assessed by the Investigator per RECIST 
version 1.1.  Lesions situated in a previously-irradiated area are considered measurable if 
progression has been demonstrated in such lesions after the end of radiotherapy. 
8. ECOG PS of 0 or 1. 
9. Has LVEF ≥50% within 28 days before randomization/registration. 
10. Has adequate organ function within 14 days before randomization/registration, defined 
as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count 
100,000/mm3  
(Platelet transfusion is not allowed within 
1 week prior to Screening assessment) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 54 
Parameter 
Laboratory value 
Hemoglobin 
≥9.0 g/dL  
(Red blood cell transfusion is not allowed 
within 1 week prior to Screening assessment) 
Absolute neutrophil count (ANC) 
1500/mm3  
(Granulocyte-colony stimulation factor [G-CSF] 
administration is not allowed within 1 week 
prior to Screening assessment) 
Adequate renal function 
Creatinine 
Creatinine clearance ≥30 mL/min as calculated 
using the Cockcroft-Gault equation 
(Section 10.3.1) 
Adequate hepatic function 
Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) 
 ≤5 × upper limit of normal (ULN) 
Total bilirubin  
≤1.5 × ULN if no liver metastases or <3 × ULN 
in the presence of documented Gilbert 
syndrome (unconjugated hyperbilirubinemia) or 
liver metastases at baseline 
Serum Albumin 
≥2.5 g/dL  
Adequate blood clotting function 
International normalized ratio 
(INR)/Prothrombin time (PT) and 
either partial thromboplastin time 
(PTT) or activated partial 
thromboplastin time (aPTT) 
≤1.5 × ULN  
11. Has adequate treatment washout period before randomization/registration, defined as: 
Treatment 
Washout Period 
Major surgery 
≥4 weeks 
Radiation therapy, including 
palliative stereotactic radiation to 
chest 
≥4 weeks (palliative stereotactic radiation 
therapy to other areas ≥2 weeks) 
Anticancer chemotherapy 
(immunotherapy [non-antibody-
based therapy]), retinoid therapy 
≥3 weeks (≥2 weeks or 5 half-lives, whichever 
is longer, for small-molecule targeted agents 
such as 5-fluorouracil-based agents, folinate 
agents, weekly paclitaxel; ≥6 weeks for 
nitrosoureas or mitomycin C) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 55 
Treatment 
Washout Period 
Antibody-based anticancer therapy 
≥4 weeks 
Chloroquine/hydroxychloroquine 
>14 days 
12. If the subject is a woman of childbearing potential, she must have a negative urine 
pregnancy test within 72 hours before randomization/registration; a positive urine 
pregnancy test result must immediately be confirmed using a serum test.  The subject 
must also be willing to use highly effective birth control, as detailed in Section 10.3.4, 
upon randomization/registration, during the Treatment Period, and for 7 months, 
following the last dose of study drug.  A woman is considered of childbearing potential 
following menarche and until becoming postmenopausal (no menstrual period for a 
minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy).  
a. Non-childbearing potential is defined as premenopausal female subjects with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months 
of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous 
follicle-stimulating hormone [FSH] >40 mIU/mL and estradiol <40 pg/mL 
[<147 pmol/L] is confirmatory).  Female subjects on hormone replacement therapy 
(HRT) and whose menopausal status is in doubt will be required to use one of the 
contraception methods outlined for women of childbearing potential if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status prior to randomization/registration.  For most 
forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and 
the blood draw; this interval depends on the type and dosage of HRT.  Following 
confirmation of their postmenopausal status, they can resume use of HRT during the 
study without use of a contraceptive method. 
13. If male, the subject must be surgically sterile or willing to use highly effective birth 
control (Section 10.3.4) upon randomization/registration, during the Treatment Period, 
and for 4 months following the last dose of study drug. 
14. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 4 months after the final study drug administration.  Preservation 
of sperm should be considered prior to randomization/registration in this study. 
15. Female subjects 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. 
16. Is willing and able to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions. 
17. Life expectancy is ≥3 months. 
5.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 56 
1. Medical history of myocardial infarction (MI) within 6 months before 
randomization/registration, symptomatic congestive heart failure (CHF) (New York 
Heart Association Class II to IV).  Subjects with troponin levels above ULN at Screening 
(as defined by the manufacturer), and without any MI-related symptoms, should have a 
cardiologic consultation before randomization/registration to rule out MI. 
2. Has a corrected QT interval (QTcF) prolongation to >470 msec (female subjects) or 
>450 msec (male subjects) based on the average of the Screening triplicate 
12-lead ECGs. 
3. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current 
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at 
Screening.  
4. Lung-specific intercurrent clinically significant illnesses including, but not limited to, any 
underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the 
randomization/registration, severe asthma, severe chronic obstructive pulmonary disease 
[COPD], restrictive lung disease, pleural effusion, etc.). 
5. Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, 
Sjögren syndrome, 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 electronic case report form (eCRF) for subjects who are included in the 
study. 
6. Prior pneumonectomy. 
7. Has spinal cord compression or clinically active central nervous system metastases, 
defined as untreated and symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms.  Subjects with clinically inactive brain 
metastases may be included in the study.  Subjects with treated brain metastases that are 
no longer symptomatic and who require no treatment with corticosteroids or 
anticonvulsants may be included in the study if they have recovered from the acute toxic 
effect of radiotherapy.  A minimum of 2 weeks must have elapsed between the end of 
whole brain radiotherapy and randomization/registration. 
8. Subjects with leptomeningeal carcinomatosis. 
9. Has multiple primary malignancies within 3 years, except adequately resected 
non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors 
curatively treated. 
10. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
11. Has a history of severe hypersensitivity reactions to other monoclonal antibodies. 
12. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.  
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 
subject’s participation in the clinical study or evaluation of the clinical study results. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 57 
14. Has known human immunodeficiency virus (HIV) infection.  Unless required by local 
regulations or institutional review board (IRB)/ethics committee (EC), an HIV 
antigen/antibody test is not required prior to randomization/enrollment. 
15. Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of 
viral infection within 28 days before study randomization/registration.  Subjects with past 
or resolved hepatitis B virus (HBV) infection are eligible if hepatitis B surface antigen 
(HBsAg) negative (-) and antibody to hepatitis B core antigen (anti-HBc) positive (+). 
Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA. 
16. Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to the National Cancer Institute-Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 5.0, Grade ≤1 or baseline.  Subjects with 
chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and 
approval of the Sponsor.  
17. Previous treatment with a DXd-containing ADC. 
18. Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.  Note: 
Subjects with localized fungal infections of skin or nails are eligible. 
19. Female subject who is pregnant, breastfeeding, or intends to become pregnant during the 
study. 
20. Psychological, social, familial, or geographical factors that would prevent regular 
follow-up. 
21. Otherwise considered inappropriate for the study by the Investigator. 
5.3. 
Screening Failures, Rescreening, and Subject Replacement 
Rescreening is permitted once for any subject who fails to meet reversible or transient eligibility 
criteria upon initial screening.  The rescreening must be performed within the Screening Period.  
The subject identifier (SID) number must remain the same at the time of rescreening.  The initial 
Screening information and the reason why the subject was ineligible for the initial evaluation 
will be recorded on the Screening Log.   
For subjects that had an initial tumor sample sent but where the central laboratory reports that 
there was an analytical failure (ie, quality control samples fail, tissue with quality issues 
[including no staining, no tumor, or equivocal cases]) then the site can send additional tissue, 
archival or by performing a new tumor biopsy.  NOTE: This is not a second attempt at 
prescreening, this is part of the initial/same prescreening procedure.  
Randomized/registered subjects will not be replaced. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 58 
6. 
STUDY TREATMENT 
See Figure 1.1 for treatment sequence. 
6.1. 
Study Drug Description 
Table 6.1 describes the formulation, dose, regimen, duration, packaging, and labeling of T-DXd. 
Table 6.1: 
Study Drug Dosing Information 
Study Drug Name 
Trastuzumab deruxtecan  
(T-DXd; DS-8201a) 
Dosage Formulation 
T-DXd for injection 100 mg will be provided as a 
lyophilized powder containing 100 mg of T-DXd in a 
single-use glass vial.27 
Dosage Level(s) 
5.4 mg/kg or 6.4 mg/kg 
Route of Administration 
Intravenous (IV) 
Dosing Regimen 
One IV infusion every 3 weeks (Q3W) on Day 1 of 
each 21-day (±2 days) cycle 
Duration 
Intermittent dosing, 21 days per cycle 
Packaging 
T-DXd for injection 100 mg will be labeled and 
packaged in compliance with regulatory requirements  
Labeling 
The packaging will clearly display the name of the 
study drug, the lot number, storage condition, and other 
required information in accordance with local 
regulations 
 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug 
6.2.1. 
Preparation, Handling, and Disposal 
T-DXd for IV infusion is prepared by dilution of the required volume of the study treatment 
calculated based on the subject’s body weight.  The preparation of study drug will be conducted 
in accordance with the Pharmacy Instruction provided by the Sponsor.   
Procedures for proper handling and disposal should be followed in compliance with the standard 
operating procedures (SOP) of the site. 
6.2.2. 
Administration 
The initial dose of study treatment will be infused for approximately 90 minutes.  If there is no 
infusion-related reaction, after the initial dose, the next doses of study treatment will be infused 
for a minimum of 30 minutes (approximately ±5 minutes).  Following which, the study treatment 
may be administered as an IV infusion over 30 to 90 minutes every 21 days (±2 days).  The 
subject’s weight at Screening (baseline) will be used to calculate the initial dose.  If during the 
course of treatment the subject’s weight changes by ±10% of the baseline weight, the subject’s 
dose will be recalculated based on the subject’s updated weight. For weight changes <10%, 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 59 
dose-calculation adjustments should follow local guidelines.  Refer to the pharmacy instructions 
for detailed information about administration of study treatment. 
T-DXd should only be administered by a physician or healthcare professional experienced in the 
administration of cytotoxic chemotherapy.  Medicinal products to treat allergic/anaphylactic 
infusion reactions, as well as emergency equipment, should be available for immediate use. 
6.2.3. 
Storage 
T-DXd must be stored in a secure, limited access storage area under the recommended storage 
conditions noted on the label.  If storage conditions are not maintained per specified 
requirements, the Sponsor or CRO should be contacted. 
T-DXd for injection 100 mg must be stored at 2°C to 8°C (protected from light) for lyophilized 
powder.  
See the Pharmacy Manual and Pharmacy Instruction for storage conditions of the infusion 
solution. 
6.2.4. 
Drug Accountability 
When a drug shipment is received, the Investigator or designee will check the amount and 
condition of the drug against the shipping documentation, check for appropriate local language in 
the label, check drug expiration date, and acknowledge receipt in the IRT system.  
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment.  The original shipment documentation will be retained at the study 
site. 
The Investigator is responsible for study drug accountability, reconciliation and record 
maintenance (ie, Receipt of Shipment Form, dispensation/return record, and certificate of 
destruction/return receipt). 
A Drug Accountability Record will be provided for study treatment.  The record must be kept 
current and should contain all of the following: 
 Dates and quantities of drug received  
 Subject’s SID and/or initials or supply number (as applicable)  
 The date and quantity of study treatment dispensed and remaining (if from individual 
subject drug units)  
 The initials of the dispenser  
At the study closure, as per local laws and/or directed by Sponsor, all unused study treatment 
will be returned or destroyed as per local laws or site policy and only after the study monitor has 
completed a final inventory.  As applicable, the study site must file a copy of the appropriate 
institution policy within their Investigator Site File and provide a copy to the Sponsor.  At the 
study closure, a final study treatment reconciliation statement must be completed by the 
Investigator or designee and provided to the Sponsor.  See the Pharmacy Manual for details.  
Unused drug supplies may be destroyed by the Investigator when approved in writing by 
Sponsor and Sponsor has received copies of the study site’s drug handling and disposition SOPs 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 60 
and it is assured that the Sponsor will receive copies of the certificate of destruction which is 
traceable to the study treatment. 
All investigational product inventory forms must be made available for inspection by a Sponsor 
authorized representative or designee and regulatory agency inspectors.  
6.3. 
Measure to Minimize Bias: Randomization and Blinding 
6.3.1. 
Method of Treatment Allocation 
6.3.1.1. 
Stage 1 
Randomization to either 5.4 mg/kg Q3W or 6.4 mg/kg Q3W will occur in Stage 1 of the study. 
Prior to randomization of a subject, all Screening procedures and eligibility criteria must be met, 
and a signed main informed consent obtained. 
Subjects will be randomized into 1 of the 2 treatment arms (T-DXd at 5.4 mg/kg Q3W or 
6.4 mg/kg Q3W) in a 1:1 ratio.  The randomization will be stratified by the following 
3 stratification factors: 
 ECOG PS (0 or 1)  
 HER2 status (IHC 3+ or IHC 2+/ISH+)  
 RAS status (wild-type or mutant) 
Randomization will be managed through the IRT for subjects meeting all eligibility criteria.  The 
directions on how to use the system will be provided in the IRT Reference Manual. 
The system will assign a unique SID number and treatment arm for that subject 
(ie, Arm 1 vs Arm 2).  Cycle 1 Day 1 of treatment should occur within 7 days (Days 0-7) after 
randomization/registration.  However, it is permissible for a subject to receive the first dose of 
T-DXd on the same day as randomization/registration, if applicable. 
The assignment of the subjects is blinded to the site through the roles and permissions document 
in the IRT.  The randomization schedule will be developed by a third party vendor. 
6.3.1.2. 
Stage 2 
For Stage 2, subjects will be registered onto the 5.4 mg/kg Q3W treatment arm only. 
Combining both stages of the study, a maximum of 30 subjects per subgroup will be registered 
onto each of the HER2 IHC 2+/ISH+ and RAS-mutant subgroups. 
6.3.2. 
Blinding 
The treatment assignment will remain unknown to the study subjects, Investigators, study site 
personnel (except the unblinded pharmacist and other unblinded staff members as deemed 
necessary for site operations to maintain the blind), central imaging readers, and the ILD AC.  
The Sponsor is not blinded to the treatment assignment of the subjects, nor the CRO except 
central imaging vendor.  
The randomization schedule will be kept securely. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 61 
6.3.3. 
Emergency Unblinding Procedure 
In the case of a rare emergency where, in the opinion of the Investigator, discontinuation of study 
drug is not sufficient and study treatment must be unblinded to evaluate a further course of 
medical treatment, the following procedures will apply: 
This option may be used ONLY if the subject’s well-being requires knowledge of the subject’s 
treatment dose assignment.  The occurrence of an SAE should not precipitate the immediate 
unblinding of the investigational product dose.  The Investigator must contact the Sponsor prior 
to unblinding a subject’s treatment assignment.  However, to prevent delays to the Investigator or 
medical personnel responding to a potentially emergent situation, unblinding of the study 
treatment will not be dependent upon the Investigator receiving approval from the Sponsor (ie, 
the Investigator will be able to obtain the code break information independent of the Sponsor).  If 
a subject’s treatment assignment is unblinded, the Sponsor must be notified immediately. 
In the event of emergency unblinding, the subject will be informed about their treatment 
assignment.  Information about the treatment assignment must be restricted to designated study 
site staff/personnel who are providing immediate care to the subject.  Any documentation of the 
treatment assignment must be maintained separately (ie, a secured file).  When an emergency 
unblinding has occurred, an automatic notification (via e-mail) will be sent to the Investigator 
and selected Daiichi Sankyo study personnel from the IRT vendor.  The notification will not 
contain any unblinding information.  This will trigger the follow-up process to document the 
unblinding by completing the Emergency Unblinding by Investigator Form (to be provided to the 
Sponsor by study personnel upon receipt of IRT notification) and submission to Daiichi Sankyo 
Clinical Safety and Pharmacovigilance; please refer to the form for completion instructions. 
Once the study treatment has been unblinded for a specific subject, the study treatment should be 
discontinued for the subject, and the subject should exit the study treatment phase.  The EOT and 
follow-up assessments for the subjects will be performed as defined in the protocol. 
6.4. 
Treatment Compliance 
T-DXd will be administered by IV only to subjects participating in the study and under the 
supervision of clinical study personnel at the site.  Therefore, treatment compliance will be 
guaranteed as long as the subject attends each visit for administration of the study drug.  Start 
and stop date/times of injection and amount of drug administered must be recorded in the eCRF. 
6.5. 
Guidelines for Dose Modification 
The Investigator will evaluate which toxicities are attributable to T-DXd and adjust the dose as 
recommended below.  All dose modifications (interruption, reduction, and/or discontinuation) 
should be based on the worst preceding toxicity (NCI-CTCAE version 5.0).  Specific criteria for 
interruption, re-initiation, dose reduction and/or discontinuation of T-DXd are listed in Table 6.3, 
which is applicable only to treatment-emergent AEs (TEAEs) that are assessed as related to use 
of T-DXd by the Investigator(s) unless otherwise instructed.  A TEAE is defined as an AE that 
occurs, having been absent before the first dose of study drug, or has worsened in severity or 
seriousness after the initiating the study drug until 47 days after last dose of the study drug.  For 
non-drug-related TEAEs, follow standard clinical practice.  Appropriate clinical experts should 
be consulted as deemed necessary.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 62 
All dose interruptions or modifications must be recorded in the eCRF.  If study drug is 
interrupted, missed doses will not be made up.   
In the event of a dose interruption occurring prior to completion of a PK/immunogenicity blood 
sampling in the study, Investigators should contact the Sponsor’s Medical Monitor for guidance 
regarding scheduling of these procedures. 
Prophylactic or supportive treatment for expected toxicities, including management of study 
drug-induced AEs will be as per the Investigator’s discretion and institutional guidelines.  
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) 
should be performed at intervals no greater than 7 days until the AE is determined to be 
resolving or subject is discontinued at the EOT. 
Note: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified below in 
Table 6.3.  
6.5.1. 
Dose Reduction Guidelines 
If dose reduction is required, dosing should be reduced by 1 dose level at a time.  Up to 2 dose 
reductions will be permitted for subjects (Table 6.2).  If toxicity continues after the permitted 
dose reductions, the subject will be withdrawn from the study treatment if further toxicity 
meeting the requirement for dose reduction occurs. 
Once the dose of T-DXd has been reduced because of toxicity, all subsequent cycles should be 
administered at that lower dose level unless further dose reduction is required.  Once the dose of 
T-DXd is reduced, no escalation is permitted. 
Table 6.2: 
Dose Reduction Levels of T-DXd 
Treatment Arm 
Starting Dose 
Dose Level −1 
Dose Level −2 
1 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
2 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
If toxicity continues after 2 dose reductions, the subject will be withdrawn from the study 
treatment.  T-DXd dose increases are not allowed in the study. 
6.5.2. 
Dose Interruption and Modification / Toxicity Management Guidelines for 
T-DXd 
Specific criteria for T-DXd dose interruption, re-initiation, dose reduction, and/or 
discontinuation in case of TEAEs that are considered related to the use of T-DXd by the 
Investigator are presented in Table 6.3, which is applicable only to TEAEs that are assessed as 
related to use of T-DXd by the Investigator(s).  A TEAE is defined as an AE that occurs, having 
been absent before the first dose of study drug, or has worsened in severity or seriousness after 
initiating the study drug until 47 days after last dose of the study drug.  For non-drug-related 
TEAEs or if nothing is noted in Table 6.3, standard practice guidelines for management of AEs 
should be followed.  Appropriate experts should be consulted as deemed necessary.  The 
Investigator may consider dose interruptions or T-DXd discontinuation based on other events not 
listed in Table 6.3 according to the subject’s condition.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 63 
There will be no dose modifications for Grade 1 or Grade 2 TEAEs unless specified in Table 6.3.  
For Grade 3 or Grade 4 events, monitoring (including local laboratory tests when appropriate) 
should be performed frequently and at an interval no greater than 7 days.   
A dose can be delayed for up to 28 days (49 days from the last infusion date) from the planned 
date of administration.  If a subject is assessed as requiring a dose delay of longer than 28 days, 
the subject will be withdrawn from the study treatment. 
A subject for whom T-DXd dosing is temporarily withheld for any reason may have future 
cycles scheduled based on the date of the last study drug dose. 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF.  Please 
refer to Section 10.6 for additional information on dose modification related to SARS-CoV-2. 
Table 6.3: 
Dose Modification Guidelines for T-DXd 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
No toxicity 
Maintain dose and schedule 
Infusion-Related Reaction 
Grade 1 (Mild transient reaction; infusion 
interruption not indicated; intervention not 
indicated) 
 
If infusion-related reaction (such as fever and chills, with 
and without nausea/vomiting, pain, headache, dizziness, 
dyspnea, hypotension) is observed during administration, 
the infusion rate should be reduced by 50% and subjects 
should be closely monitored. 
 
If no other reactions appear, the subsequent infusion rate 
could be resumed at the initial planned rate. 
Grade 2 (Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, antihistamines, 
nonsteroidal anti-inflammatory drugs 
[NSAIDs], narcotics, intravenous [IV] 
fluids); prophylactic medications indicated 
for ≤24 hrs) 
 
Administration of T DXd should be interrupted and 
symptomatic treatment started (eg, antihistamines, 
nonsteroidal anti-inflammatory drugs [NSAIDs], narcotics, 
IV fluids). 
 
If the event resolves or improves to Grade 1, infusion can 
be re started at a 50% reduced infusion rate. 
 
Subsequent administrations should be conducted at the 
reduced rate. 
Grade 3 or 4 (Prolonged or life-threatening 
consequences, urgent intervention indicated) 
 
Administration of T DXd should be discontinued 
immediately and permanently. 
 
Urgent intervention indicated.  Antihistamines, steroids, 
epinephrine, bronchodilators, vasopressors, intravenous 
fluid therapy, oxygen inhalation etc., should be 
administered. 
Hematologic Toxicity 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3  
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 
Delay dose until resolved to ≤ Grade 2,  
 
Reduce dose 1 level 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 64 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
Febrile Neutropenia (absolute neutrophil 
count <1 × 109/L, fever >38.3°C or a 
sustained temperature of ≥38°C for more 
than one hour) 
Delay dose until resolved,  
 
Reduce dose by 1 level 
Lymphocyte Count Decreaseda 
Grade 1 to Grade 3 lymphopenia 
No dose modification 
Grade 4 (<0.2 × 109/L) 
Delay dose until resolved to ≤ Grade 2: 
 
If resolved in ≤14 days from day of onset, maintain dose 
 
If resolved in >14 days from day of onset, reduce dose 1 
level 
Anaemia 
Grade 3 (Hemoglobin [Hb] <8.0 g/dL); 
transfusion indicated 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
Life-threatening consequences; urgent 
intervention indicated 
Delay dose until resolved to ≤ Grade 2, then reduce dose 1 level 
Platelet Count Decreased 
Grade 3 (platelets <50 - 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 (platelets <25 × 109/L) 
Delay dose until resolved to ≤ Grade 1, then reduce dose 1 level 
Cardiac Toxicity 
Symptomatic congestive heart failure (CHF) 
Discontinue subject from study treatment 
Decrease in left ventricle ejection fraction 
(LVEF) 10 20% (absolute value), but LVEF 
>45% 
Continue treatment with T DXd 
LVEF 40% to ≤45% and decrease is <10% 
(absolute value) from baseline 
 
Continue treatment with T DXd 
 
Repeat LVEF assessment within 3 weeks 
LVEF 40% to ≤45% and decrease is 10-20% 
(absolute value) from baseline 
 
Interrupt T DXd dosing 
 
Repeat LVEF assessment within 3 weeks 
 
If LVEF has not recovered to within 10% (absolute value) 
from baseline, discontinue subject from study treatment 
 
If LVEF recovers to within 10% from baseline, resume 
treatment with study drug 
LVEF <40% or >20% (absolute value) drop 
from baseline 
 
Interrupt T DXd dosing 
 
Repeat LVEF assessment within 3 weeks 
 
If LVEF <40% or >20% drop from baseline is confirmed, 
discontinue subject from study treatment 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 65 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
Electrocardiogram QT prolonged 
Grade 3 (Average QTc> 500 ms or >60 ms 
change from baseline) 
Delay dose until resolved to ≤ Grade 1 (corrected QT ≤480 ms), 
determine if another medication the subject was taking may be 
responsible and can be adjusted or if there are any changes in 
serum electrolytes that can be corrected, then if attributed to T 
DXd, reduce dose 1 level 
Grade 4 (Torsade de pointes or polymorphic 
ventricular tachycardia or signs/symptoms of 
serious arrhythmia) 
Discontinue subject from study treatment 
Pulmonary Toxicity 
If a subject develops radiographic changes potentially consistent 
with interstitial lung disease (ILD)/pneumonitis or develops an 
acute onset of new or worsening pulmonary or other related 
signs/symptoms such as dyspnea, cough, or fever, rule out 
ILD/pneumonitis.  
If the adverse event (AE) is confirmed to have an etiology other 
than ILD/pneumonitis, follow the management guidance outlined 
in the “Other Non-Laboratory Adverse Events” dose 
modification section below. 
If the AE is suspected to be ILD/pneumonitis, treatment with 
study drug should be interrupted pending further evaluations. 
Evaluations should include: 
 
High resolution computed tomography (CT) 
 
Pulmonologist consultation (Infectious Disease consultation 
as clinically indicated) 
 
Blood culture and complete blood count (CBC). Other blood  
tests could be considered as needed 
 
Consider bronchoscopy and bronchoalveolar lavage if 
clinically indicated and feasible 
 
Pulmonary function tests and pulse oximetry (SpO2) 
 
Arterial blood gases if clinically indicated 
 
One blood sample collection for pharmacokinetic (PK) 
analysis as soon as ILD/pneumonitis is suspected, if feasible. 
Other tests could be considered, as needed. 
If the AE is confirmed to be ILD/pneumonitis, follow the 
ILD/pneumonitis management guidance as outlined below. 
All events of ILD/pneumonitis regardless of severity or 
seriousness will be followed until resolution including after drug 
discontinuation. 
Grade 1 
The administration of T DXd must be interrupted for any 
ILD/pneumonitis events regardless of grade.  
 
Monitor and closely follow-up in 2 to 7 days for onset of 
clinical symptoms and pulse oximetry. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 66 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
 
Consider follow-up imaging in 1-2 weeks (or as clinically 
indicated). 
 
Consider starting systemic steroids (eg, at least 0.5 
mg/kg/day prednisone or equivalent) until improvement, 
followed by gradual taper over at least 4 weeks. 
 
If worsening of diagnostic observations despite initiation of 
corticosteroids, then follow Grade 2 guidelines.* 
For Grade 1 events, T DXd can be restarted only if the event is 
fully resolved to Grade 0: 
 
If resolved in ≤28 days from day of onset, maintain dose 
 
If resolved in >28 days from day of onset, reduce dose 1 
level 
However, if the event Grade 1 ILD/pneumonitis occurs beyond 
cycle day 22 and has not resolved within 49 days from the last 
infusion, the drug should be discontinued. 
* If subject is asymptomatic, then subject should still be 
considered as Grade 1 even if steroid treatment is given. 
Grade 2 
Permanently discontinue subject from study treatment. 
 
Promptly start and treat with systemic steroids (eg, at least 
1.0 mg/kg/day prednisone or equivalent) for at least 14 days 
or until complete resolution of clinical and chest CT 
findings, then followed by a gradual taper over at least 4 
weeks. 
 
Monitor symptoms closely. 
 
Re-image as clinically indicated. 
 
If worsening or no improvement in clinical or diagnostic 
observations in 5 days: 
o 
Consider increasing dose of steroids (eg, 2 
mg/kg/day prednisone or equivalent) and 
administration may be switched to intravenous (eg, 
methylprednisolone). 
o 
Reconsider additional work-up for alternative 
etiologies as described above. 
o 
Escalate care as clinically indicated. 
Grade 3 and 4 
Permanently discontinue subject from study treatment. 
 
Hospitalization required. 
 
Promptly initiate empiric high-dose methylprednisolone IV 
treatment (eg, 500-1000 mg/day for 3 days), followed by at 
least 1.0 mg/kg/day of prednisone (or equivalent) for at least 
14 days or until complete resolution of clinical and chest CT 
findings, then followed by a gradual taper over at least 4 
weeks. 
 
Re-image as clinically indicated. 
 
If still no improvement within 3 to 5 days: 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 67 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
o 
Reconsider additional work-up for alternative 
etiologies as described above. 
o 
Consider other immunosuppressants and/or treat per 
local practice. 
Ocular 
Grade 3 
Delay dose until resolved to ≤ Grade 1: 
 
If resolved in ≤7 days from day of onset, maintain dose 
 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 
Blood creatinine increased 
Grade 3 (>3.0 to 6.0 × upper limit of normal 
[ULN]) 
Delay dose until resolved to ≤ Grade 2 or baseline, then reduce 
dose 1 level 
Grade 4 (>6.0 × ULN) 
Discontinue subject from study treatment 
Hepatic Toxicity 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) with simultaneous total bilirubin 
(TBL) 
AST/ALT >3.0 × ULN with simultaneous 
TBL >2.0 × ULN 
Delay study medication until drug-induced liver injury can be 
ruled out.  
If drug-induced liver injury is ruled out, the subject should be 
treated accordingly, and resumption of study drug may occur 
after discussion between the Investigator and Sponsor.  
If drug-induced liver injury cannot be ruled out from diagnostic 
work-up, permanently discontinue study treatment. 
Monitor AST/ALT and TBL twice weekly until resolution or 
return to baseline. 
Aspartate aminotransaminase (AST) or alanine aminotransaminase (ALT) 
Grade 2 (>3.0 - 5.0 × ULN if baseline was 
normal; >3.0 - 5.0 × baseline if baseline was 
abnormal) 
No action for Grade 2 AST/ALT  
Grade 3 (>5.0 - 20.0 × ULN if baseline was 
normal; >5.0 - 20.0 × baseline if baseline 
was abnormal) 
In subjects without liver metastases and 
subjects with liver metastases and baseline 
level ≤3 × ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ 
Grade 1 if baseline ≤ 3 × ULN, otherwise delay dose until 
resolved to ≤ baseline, then: 
• 
If resolved in ≤7 days from day of onset, maintain dose 
• 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 3: (>8.0 - 20.0 × ULN if baseline was 
normal; >8.0 - 20.0 × baseline if baseline 
was abnormal) 
In subjects with liver metastases, if the 
baseline level was >3 × ULN 
Repeat testing within 3 days. Delay dose until resolved to ≤ 
baseline level, then: 
• 
If resolved in ≤7 days from day of onset, maintain dose 
• 
If resolved in >7 days from day of onset, reduce dose 1 level 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 68 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
Grade 4 (>20.0 × ULN if baseline was 
normal; >20.0 × baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Total Bilirubin 
Grade 2 (>1.5 - 3.0 × ULN if baseline was 
normal; >1.5 - 3.0 × baseline if baseline was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, delay dose until resolved to ≤ Grade 1: 
• 
If resolved in ≤7 days from day of onset, maintain dose 
• 
If resolved in >7 days from day of onset, reduce dose 1 level    
If documented Gilbert’s syndrome or liver metastases at baseline 
at baseline, continue study treatment 
Grade 3 (>3.0 - 10.0 × ULN if baseline was 
normal; >3.0 - 10.0 × baseline if baseline 
was abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, repeat testing within 3 days.  Delay dose until resolved 
to ≤ Grade 1: 
• 
If resolved in ≤7 days from day of onset, reduce dose 1 level 
• 
If resolved in >7 days from day of onset, discontinue T DXd   
If documented Gilbert’s syndrome or liver metastases at baseline 
at baseline, repeat testing within 3 days. Delay dose until 
resolved to < Grade 2: 
• 
If resolved in ≤7 days from day of onset,  reduce dose 1 level 
• 
If resolved in >7 days from day of onset, discontinue T DXd 
Grade 4 (>10.0 × ULN if baseline was 
normal; >10.0 × baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Blood Alkaline Phosphatase Increased 
Grade 3 (>5.0 - 20.0 × ULN if baseline was 
normal; >5.0 - 20.0 × baseline if baseline 
was abnormal) 
or 
Grade 4 (>20.0 × ULN if baseline was 
normal; >20.0 × baseline if baseline was 
abnormal) 
No modification unless determined by the Investigator to be 
clinically significant or life-threatening 
Gastrointestinal 
Nausea 
Grade 3  
Delay dose until resolved to ≤ Grade 1  
• 
If resolved in ≤7 days from day of onset, maintain dose 
• 
If resolved in >7 days from day of onset, reduce dose 1 level 
Diarrhoea/Colitis 
Grade 3 
Delay dose until resolved to ≤ Grade 1 
• 
If resolved in ≤3 days from day of onset, maintain dose 
• 
If resolved in >3 days from day of onset, reduce dose 1 level 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 69 
Worst Toxicity National Cancer Institute-
Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0 Grade 
(unless otherwise specified) 
Management Guidelines for T DXd 
Grade 4 
Discontinue subject from study treatment 
Other Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline level:  
• 
If resolved in ≤7 days from day of onset, maintain dose 
• 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 
Other Non-Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline:  
• 
If resolved in ≤7 days from day of onset, maintain dose 
• 
If resolved in >7 days from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 
a There will be no dose modifications for Grade 1 to Grade 3 lymphopenia. 
Note: All dose modifications should be based on the worst preceding toxicity. 
In addition, Investigators may consider dose reductions or discontinuations of T-DXd according 
to the subject’s condition and after discussion with the Sponsor’s Medical Monitor or designee. 
6.6. 
Prior and Concomitant Medications 
Therapies used from the time the subject signs the Main ICF for study participation to the 
40-day Follow-up Visit (+7 days) after the last administration of T-DXd will be recorded in the 
eCRF.  Prophylactic therapies (including any required premedications), prior therapies, and all 
concomitant therapies will be recorded in the eCRF. 
All therapies received by subjects within 28 days prior to randomization will be recorded as prior 
therapies.  Concomitant therapies include all prescription, over-the-counter, and herbal remedies.  
In addition, details of prior neoadjuvant therapy and radiotherapy (if applicable) will be recorded 
in the eCRF. 
6.6.1. 
Prohibited Therapies/Products 
The following medications/ treatment and procedures will be prohibited during the Treatment 
Period. The Sponsor must be notified if a subject receives any of these during the study. 
 Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, 
antibody, retinoid, or anticancer hormonal treatment (concurrent use of hormones for 
noncancer-related conditions [eg, insulin for diabetes and HRT] is acceptable). 
 Other investigational therapeutic agents. 
 Radiotherapy (except for palliative radiation to known metastatic sites as long as it 
does not affect assessment of response and it does not interrupt treatment for more 
than the maximum time specified in the dose modification section). 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 70 
 Radiotherapy to the thorax. 
 Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing AEs (inhaled steroids or 
intra-articular steroid injections are permitted in this study). 
 Subjects with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study. 
 Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during 
the study treatment. Refer to Section 10.6 for further details. 
6.6.2. 
Permitted Therapies/Products 
The following therapies/products are permitted during study treatment. 
 Hematopoietic growth factors may be used for prophylaxis or treatment based on the 
clinical judgment of the Investigator. 
 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. 
 Based on the currently available clinical safety data, it is recommended that subjects 
receive prophylactic anti-emetic agents prior to infusion of T-DXd and on subsequent 
days.  Antiemetics such as 5-hydroxytryptamine receptor (5-HT3) antagonists or 
Neurokinin-1 (NK1) receptor antagonists and/or steroids (eg, dexamethasone) should 
be considered and administered in accordance with the prescribing information or 
institutional guidelines. 
6.6.3. 
Restricted Products 
 Use of tobacco products, e-cigarettes and vaping is strongly discouraged but not 
prohibited.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 71 
7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION 
FROM THE STUDY 
7.1. 
Discontinuation of Study Drug 
The primary reason for the permanent discontinuation of T-DXd treatment administration must 
be recorded.  Reasons for treatment discontinuation include: 
 Death 
 AE 
 Progressive disease (PD) per RECIST version 1.1 assessed by the Investigator 
 Clinical progression (definitive clinical signs of disease progression, but a recent 
radiographic assessment did not meet the criteria for PD according to RECIST 
version 1.1) 
 Withdrawal of consent by subject (to discontinue study drug); NOTE: In this 
section this is only withdrawal for treatment with study drug and is NOT the same 
thing as a complete withdrawal from the study.  Discuss with the subject that they 
will remain in the study (ie, continue with study visits and assessments, including 
survival follow-up). 
 Physician decision 
 Lost to follow-up (see Section 7.3 for details on when a subject is considered lost to 
follow-up) 
 Pregnancy 
 Protocol deviation 
 Study termination by Sponsor 
 Emergency unblinding 
 Other 
After study drug is permanently discontinued for any reason other than death or lost to 
follow-up, the subject will be treated as clinically indicated by the Investigator or referring 
physician.  If there is evidence that the subject is receiving benefit from treatment even though 
the subject has met a criterion for discontinuation as listed above, the subject may remain on 
study treatment after discussion with and approval from the Sponsor Medical Monitor except for 
the following cases:  
Discontinuation due to drug-related TEAE which required 49 days dose delay from the last 
infusion date 
 Discontinuation due to more than 2 dose reductions required  
The Investigator must discuss with the subject that their decision to permanently discontinue the 
study drug means the subject still agrees to continue into the Follow-up Period for onsite or 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 72 
modified follow-up visits.  Subjects will be followed for disease progression, if applicable, and 
survival at regularly scheduled intervals (see Table 1.2). 
7.1.1. 
Procedures for Discontinuation from Study Drug 
If a subject is discontinued from the study drug: 
 The reason(s) for discontinuation and the last dose date should be documented in the 
subject’s medical record and eCRF; 
 Due to an AE, the Investigator will follow the subject until the AE has resolved or 
stabilized; 
 An EOT evaluation should be performed as described in the Schedule of Events 
(SoE) (Table 1.3); 
 A safety follow-up evaluation should be performed approximately 40 (+7) days after 
the last dose of study drug as described in the SoE (Table 1.3); 
 If subject has not discontinued for “PD,” continue tumor assessments until 
progression or start of new therapy, if applicable, and survival as described in the SoE 
(Table 1.3); 
 Long-term follow-up evaluations will be performed to assess survival as described in 
the SoE (Table 1.3). 
The Investigator will complete and report the observations as thoroughly as possible up to the 
date of discontinuation, including the date of last dose.  All procedures and tumor assessments 
specified for the EOT visit will be conducted.  See Table 1.2 for specific EOT procedures. 
If a subject does not agree to continue to come to the study site, then a modified follow-up must 
be arranged to ensure the continued collection of endpoints and safety information.  Options for 
modified follow-up are noted below. 
7.1.2. 
Modified Follow-up Options 
The following modified follow-up options can be offered to the subject who does not agree to 
study visits at the study site. 
 Study personnel contacting the subject by telephone (may be quarterly, bi-annually, 
annually, or only at EOS) 
 Study personnel contacting an alternative person (eg, family member, spouse, partner, 
legal representative, physician, or other healthcare provider) 
 Study personnel accessing and reviewing the subject’s medical information from 
alternative sources (eg, doctor’s notes, hospital records) 
Dates of the modified follow-up contact(s) should be recorded.  See Section 7.2 for definition of 
withdrawal by subject from the study (ie, withdrawal of consent). 
7.2. 
Subject Withdrawal/Discontinuation from the Study 
Subjects may discontinue from the study for any of the following reasons: 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 73 
 Death 
 Withdrawal by Subject (from the study)  NOTE: This indicates that the subject 
withdraws consent and refuses to undergo any further study procedures or be 
followed for long-term survival 
 Lost to Follow-up (see Section 7.3 for details on when a subject is considered Lost to 
Follow-up) 
 Study Termination by Sponsor 
 Other 
If the reason for study discontinuation is the death of the subject, the options for categorizing the 
primary cause of death are PD or AE.  If reason of death is unknown every effort should be made 
to obtain the primary cause of death.  Only one AE will be recognized as the primary cause of 
death. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation (ie, from the interventional portion and follow-up): 
 Attendance at study visits per protocol 
 Study personnel contacting the subject by telephone 
 Study personnel contacting an alternative person 
 Study personnel accessing and reviewing the subject’s medical information from 
alternative sources 
If the subject refuses all of the above methods of follow-up, the Investigator should personally 
speak to the subject to ensure the subject understands all of the potential methods of follow-up.  
If the subject continues to refuse all potential methods of follow-up, the Investigator will 
document this as a withdrawal of consent (from the interventional portion and follow-up). 
7.2.1. 
Withdrawal Procedures 
If a subject is withdrawn from both the interventional and follow-up portions of the study: 
 The Investigator will complete and report the observations as thoroughly as possible 
up to the date of withdrawal including the date of last dose, date of last contact, and 
the reason for withdrawal; 
 And disclosure of future information is also withdrawn, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent; 
 The subject may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records; 
 Study site personnel may use local, regional, and national public records (in 
accordance with local law) to monitor vital status. 
See SoE (Table 1.3) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 74 
7.3. 
Lost to Follow-up 
Subjects will be considered lost to follow-up if he/she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  Before a subject is deemed lost to follow-up, the 
Investigator or designee will make every effort to regain contact with the subject (where 
possible, 3 telephone calls, texts, emails, and if necessary, a certified letter to the subject’s last 
known mailing address or local equivalent methods).  These contact attempts should be 
documented. 
If direct contact with the subject is not possible the site must make every effort to collect survival 
status from public records (eg, obituaries, death certificates, etc) in accordance with local laws. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 75 
8. 
STUDY PROCEDURES 
See the SoEs in Table 1.2 and Table 1.3 for Tissue Pre-Screening, Screening, Treatment, EOT, 
and follow-up study procedures. 
8.1. 
Eligibility Assessment 
Review the subject's demographics, medical and CRC disease history, vital signs, and results of 
tests (eg, physical examination, ECHO/multigated acquisition [MUGA], ECG, ECOG PS, 
laboratory assessments) and compare against the eligibility criteria (Section 5.1 and Section 5.2).  
See Section 5.3 for rescreening.  
8.1.1. 
Informed Consent 
Before a subject’s participation in the study, it is the Investigator’s responsibility to obtain freely 
given consent, in writing, from the subject after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
procedures or any study drugs are administered.  Subjects should be given the opportunity to ask 
questions and receive responses to their inquiries and should have adequate time to decide 
whether or not to participate in the study.  The written ICF should be prepared in the local 
language(s) of the potential subject population.  See Section 10.1.2 for additional details. 
8.1.2. 
Qualifying Tumor Tissue Specimen 
To determine eligibility, subjects must have CRC that has confirmed HER2 overexpression as 
determined according to the gastric American Society of Clinical Oncology-College of American 
Pathologists (ASCO-CAP) guideline scoring algorithm28 evaluated at a central laboratory. 
Note: Subjects may continue on prior therapy (if applicable) while HER2 testing takes place.  
Please refer to the Study Laboratory Manual for required tumor sample specifications and 
shipping instructions.  
The following procedures will be conducted: 
 Obtain a signed and dated written Tissue Pre-Screening ICF from the subject prior to 
collecting tissue. 
 Obtain adequate archival, recent tumor tissue sample, or new tumor biopsy for HER2 
testing.   
 If slides are sent in place of a paraffin embedded tissue block at Pre-Screening, then 
additional slides will be required at Screening.  
 Refer to Study Laboratory Manual for preparation, number of slides required, storage, 
and shipment procedures.  
 Send the samples to the central laboratory to confirm HER2 status. 
 Assign SID from IRT. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 76 
8.1.3. 
Colorectal Cancer History 
Subject’s CRC history will be obtained by the Investigator or a qualified designee.  RAS status in 
primary or metastatic site(s) must be tested by a CLIA, ISO15189, or equivalent certified 
laboratory.  Subjects are required to have at least KRAS and BRAF status determined locally. 
8.1.4. 
HER2-overexpression Status 
Subjects must have HER2 overexpressing status confirmed by a central laboratory to be enrolled 
in the study.  HER2 expression will be determined by investigational IHC and ISH assays and 
test results will be determined by trained pathologists. HER2 overexpressing status will be based 
on pre-screening results and defined as an IHC score of 3+ or 2+ and positive by ISH (defined as 
a ratio of ≥2.0 for the number of HER2 gene copies to the number of signals for CEP17) 
confirmed by a central laboratory prior to study enrollment.  If sufficient material from the 
archival tissue, recent tumor tissue, or new tumor biopsy is not available for submission, central 
HER2 determination for eligibility may be performed on residual tumor tissue from the time of 
definitive surgery.  See also Section 8.1.2. 
8.1.5. 
General Medical History and Baseline Conditions 
Subject’s medical history will be obtained by the Investigator or a qualified designee. 
Untoward medical occurrence (including clinically relevant laboratory values that are not 
symptoms of CRC/vital signs that are out of range) that were diagnosed or known to exist prior 
to the main consent date will be recorded on the General Medical History and Baseline 
Conditions eCRF, not the AE eCRF.  Record the start date of any medical occurrence that started 
after the Main ICF was signed and is ongoing at the time of the first dose of T-DXd on the 
General Medical History and Baseline Conditions eCRF. 
8.1.6. 
Demographics 
Review the subject’s demographics against the eligibility criteria.  Demographic data will 
include age, sex, country, and self-reported race/ethnicity where allowed per local regulations. 
8.1.7. 
Human Immunodeficiency Virus Antibody Test 
As required by local regulations or independent IRB/EC, perform an HIV antigen/antibody test 
prior to randomization/enrollment.   
8.1.8. 
Hepatitis Screening 
Perform hepatitis B/C serology.  Subjects positive for HCV antibody are eligible only if 
polymerase chain reaction is negative for HCV RNA. 
8.2. 
Randomization/Registration 
For Stage 1, after all Screening procedures are performed, results of Screening tests are 
available, and subjects are confirmed to continue to meet all eligibility criteria, eligible subjects 
will be randomized in a 1:1 ratio into 1 of 2 treatment groups (T-DXd 5.4 mg/kg Q3W versus 
T-DXd 6.4 mg/kg Q3W). 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 77 
Randomization will be stratified by following factors:  
 ECOG PS of 0 or 1 
 HER2 status: IHC 3+ or IHC 2+/ISH+ 
 RAS status (wild-type versus mutant) 
For Stage 2, after all Screening procedures are performed, results of Screening tests are 
available, and subjects are confirmed to continue to meet all eligibility criteria, eligible subjects 
will be registered into the T-DXd 5.4 mg/kg Q3W treatment group. 
Combining both stages of the study, a maximum of 30 subjects (per subgroup) will be registered 
onto each of the IHC 2+/ISH+ and RAS-mutant subgroups. A minimum of 20 subjects with 
RAS-mutant status will be enrolled in the study.  
Cycle 1 Day 1 of treatment should occur within 7 days (Days 0-7) after 
randomization/registration.  However, it is permissible for a subject to receive the first dose of 
T-DXd on the same day as randomization/registration, if applicable. 
8.3. 
Efficacy Assessments 
8.3.1. 
Primary Efficacy Endpoint 
Efficacy assessments will be based on tumor assessments to be performed at Screening and every 
6 weeks while the subject remains on study drug.  The primary efficacy endpoint is ORR, 
defined as the proportion of subjects with a best overall response (BOR) of confirmed CR or 
confirmed PR, assessed by blinded independent central review (BICR) based on RECIST version 
1.1.  Refer to Section 8.3.4 and Section 10.4 for details regarding RECIST for radiological tumor 
assessments.  
8.3.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include the following:  
 Confirmed ORR assessed by the Investigator based on RECIST version 1.1 
 DoR, defined as time from the initial response (complete response [CR] or PR) until 
document tumor progression based on RECIST version 1.1 or death from any cause 
 Disease control rate (DCR), defined as the proportion of subjects who achieved CR, 
PR, or stable disease (SD) for a minimum of 6 weeks during study treatment 
 Clinical benefit rate (CBR), defined as proportion of subjects achieved CR, PR, or SD 
for at least 6 months 
 PFS, defined as the time from date of randomization until first objective radiographic 
tumor progression or death from any cause 
 OS defined as the time from date of randomization until death from any cause 
8.3.3. 
Exploratory Efficacy Endpoints (Including QoL and Biomarker) 
Exploratory efficacy endpoints include the following: 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 78 
 Time to response (TTR); defined as time from the date of randomization/registration 
to the date of first documented objective response (CR or PR) based on BICR and 
Investigator assessment 
 Best percentage change from baseline in sum of diameters (SoD) for all target lesions 
based on BICR and Investigator assessment 
 Time to deterioration (TTD) in ECOG PS 
 Change from baseline in EORTC QLQ-C30 and EORTC QLQ-CR29 scale scores 
 EQ-5D-5L health state utility index 
 Patient-reported treatment tolerability with PGI-TT 
 Proportion of patients with overall PGIS and PGIC  
 Healthcare resource use will be captured/collected, including inpatient admissions, 
intensive care unit admissions, and length of stay in hospital 
 Changes in carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 
(CA19-9) 
 ERBB2 copy number at baseline and its association with clinical outcomes 
 Other potential biomarkers of resistance or clinical benefit to study treatment 
8.3.4. 
Radiographic Tumor Assessments 
At baseline, a computed tomography (CT) or MRI of the brain is required ONLY if the subject 
has a history of brain metastases and/or symptoms suggestive of brain metastases.  If there are no 
brain metastases at the time of Screening, a brain CT or MRI during the study treatment should 
only be performed if symptoms associated with brain metastases appear during the study period.   
If no clinical symptoms are observed, a CT or MRI of the brain is not mandatory at Screening or 
during the study period.  A CT or MRI of the brain is required throughout the study (at tumor 
assessment time points) and EOT when the subject has brain metastases identified at baseline. 
Radiographic tumor assessments will include all known or suspected disease sites.  Scans of the 
chest, abdomen, pelvis, and any other sites of disease are required and may be performed at any 
time, as clinically indicated, and according to the Investigator and details recorded in the eCRF.  
The CT scans should be performed with contrast agents unless contraindicated for medical 
reasons, follow the local label/package insert/SMPC or institutional guidelines for allergic 
reactions to contrast agents.   
Computed tomography and/or MRI (spiral CT or MRI with ≤5 mm cuts) of chest, abdomen, and 
pelvis should be used for tumor assessment unless another modality of disease assessment is 
necessary for the lesions. The same assessment modality should be used throughout the study for 
all assessments for each subject, unless prior approval is obtained from Sponsor or its designee. 
Unscheduled tumor assessments may be performed if disease progression is suspected. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 79 
Baseline tumor assessment should be performed within 28 days of randomization/registration.  
The first on-study imaging assessment should be performed at 6 weeks (42 days [+7] days) from 
Cycle 1 Day 1. 
Subsequently, antitumor activity will be assessed every 6 weeks (±7 days) from Cycle 1 Day 1 in 
the first 12 months.  After 12 months (365 days [±7] days), subjects who remain on treatment 
will have imaging performed every 12 weeks (±14 days) until disease progression or start of new 
anticancer treatment.   
Imaging should continue to be performed until disease progression is identified by the 
Investigator or notification by the Sponsor, whichever occurs first.  
Regarding the EOT tumor assessment: If the previous scan was within the last 6 weeks (within 
12 weeks if the subject completed the first year of tumor assessments), the tumor assessment at 
the EOT Visit does not need to be performed.  If the Investigator makes a clinical diagnosis that 
there has been progression, imaging examinations should be performed as promptly as possible, 
and efforts should be made to obtain an image-based assessment of PD. 
All supplemental imaging must be submitted to the central imaging vendor. 
Imaging timing should follow calendar days.   
Imaging time points will be projected from the previous examination date and should not be 
adjusted for delays in cycle starts.  In addition, radiological tumor assessments will also be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration) and at the 
time of withdrawal from the treatment (if not done in the previous 4 weeks).   
Tumor measurements are performed as per RECIST version 1.1 (Section 10.4).  See also 
Table 1.2 for the SoE. 
8.3.5. 
Response Assessment 
Assess the subject based upon the local laboratory results using the Response Criteria 
(Section 10.4). 
8.3.6. 
Subsequent Anticancer Treatments 
Subsequent anticancer treatments taken since the EOT and their outcomes must be monitored 
and recorded in the eCRF until the end of the study. 
8.3.7. 
Survival Follow-up 
All subjects should be followed for survival at least every 3 months (±14 days) after 
discontinuing study drug.  Survival monitoring will continue until the end of the study.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 80 
8.4. 
Safety Assessments 
8.4.1. 
Adverse Event 
8.4.1.1. 
Method to Detect Adverse Events 
The definitions of an AE or SAE can be found in Section 10.5.  Adverse events may be directly 
observed, reported spontaneously by the subject or by questioning the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally authorized representative) at each 
study visit.  Subjects should be questioned in a general way, without asking about the occurrence 
of any specific symptoms.  The Investigator must assess all AEs to determine seriousness, 
severity, and causality.  The Investigator and any qualified designees are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE and 
remain responsible for following AEs that are serious, considered related to the study drug or 
study procedures, or that caused the subject to discontinue T-DXd. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study drug discontinuation, lead to dose reduction, require 
corrective treatment, or constitute an AE in the Investigator’s clinical judgment.  
Additional relevant information regarding the AEs of special interest (AESIs) ILD and 
LV dysfunction for the T-DXd clinical program, regardless of seriousness is to be collected 
through the targeted questionnaires within the clinical study database. 
For broad surveillance of LV dysfunction, relevant AEs under the MedDRA SMQs of Cardiac 
Failure is included for enhanced data collection; additional data for these AEs are collected via 
TQs of heart failure.  
For broad surveillance of ILD/pneumonitis, a set of predefined list of PTs eligible for 
adjudication as described in the Event Adjudication Site Manual, will be utilized for enhanced 
data collection. 
8.4.1.2. 
Time Period for Collecting Adverse Events, Including AESIs and Serious 
Adverse Events 
All SAEs occurring after the subject signs the Main ICF and up to 40 (+7) days after the last 
dose of study medication (ie, the Follow-up Period), whether observed by the Investigator or 
reported by the subject, will be recorded on the AE eCRF.  All SAEs will be followed until 
resolution, stabilization, the event is otherwise explained, or the subject is lost to follow-up. 
All non-serious AEs occurring after the subject has signed the Main ICF until up to 40 (+7) days 
after the last dose of study medication will be recorded on the AE eCRF. 
Exacerbation of a pre-existing medical condition and symptom after the first dose of T-DXd 
including increase in severity of the symptom will be recorded as an AE on the AE eCRF, unless 
it is a condition of CRC. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 81 
8.4.1.3. 
Reporting Procedure for Investigators 
All AEs (including AESIs and SAEs) will be reported in the AE eCRF.  All AEs (serious and 
non-serious) must be reported with the Investigator’s assessment of seriousness, severity, and 
causality to T-DXd. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
8.4.1.4. 
Disease-Specific AEs and SAEs 
Disease progression/worsening of CRC will not be recorded as an AE on the AE eCRF.  
However, events associated with disease progression may be recorded as AEs. 
Death due to disease progression should be recorded on the Death eCRF. 
8.4.1.5. 
Treatment-Emergent Adverse Events 
A TEAE is defined as an AE that occurs, having been absent before the first dose of study drug, 
or has worsened in severity or seriousness after the initiating the study drug until 47 days after 
last dose of the study drug.  SAEs with an onset or worsening 48 days or more after the last dose 
of study drug, if considered related to the study treatment, are also TEAEs.    
8.4.1.6. 
Serious Adverse Events Reporting 
The following types of events should be reported by the Investigator in the electronic data 
capture (EDC) within 24 hours of awareness: 
 SAEs (Section 10.5.2) 
 Hepatic events (both serious and non-serious) meeting the laboratory criteria of a 
potential Hy’s Law criteria (as defined in Section 8.4.1.7). 
 All potential ILD/pneumonitis cases should be reported within 24 hours, including 
both serious and non-serious potential ILD/pneumonitis cases (potential 
ILD/pneumonitis is described by the Event Adjudication Site Manual). 
 Overdose defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important.  An “excessive 
and medically important” overdose includes any overdose in which either an SAE, a 
non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject. 
 Overdose is always serious. By definition an overdose is medically important, 
which meets the seriousness criterion of important medical event. An overdose 
can occur with or without an AE. AEs can either be serious or non-serious. 
Details of the overdose including T-DXd dosage, clinical course, associated AEs, 
and outcome must be captured in the Narrative form of the Case Report Form 
(CRF) within EDC 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 82 
Details summarizing the course of the SAE, including its evaluation, treatment, and outcome 
should be provided.  Specific or estimated dates of AE onset, treatment, and resolution should be 
included.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the SAE report.  For fatal events, the SAE report should 
state whether an autopsy was or will be performed and should include the results if available.  
Source documents (including medical reports) will be retained at the study site and should not be 
submitted to the Sponsor for SAE reporting purposes. 
For subjects who sign the Tissue Pre-Screening ICF, only SAEs directly related to tissue pre-
screening procedure (ie, tumor biopsy) should be reported via the SAVER Form since EDC is 
not available at this timing. 
If using EDC for SAE reporting: Complete the eCRF within 24 hours of awareness.  In the event 
that the eCRF is unavailable, report SAEs by faxing or emailing the SAVER Form to 
Sponsor/CRO using the provided fax transmittal form and the appropriate fax number provided 
for your country or e-mail address.  Once EDC becomes available, please enter SAEs reported 
on the SAVER Form into the eCRF as soon as possible.  Please refer to the eCRF Completion 
Guide for additional instructions. 
Contact your study monitor for any questions on SAE reporting.  See Section 8.4.1 for details on 
the time period for collecting SAEs. 
8.4.1.6.1. Reporting Requirement to Sites and Regulatory Authorities 
Sponsor and/or CRO will inform Investigators and regulatory authorities of any suspected 
unexpected serious adverse reactions (SUSARs) occurring in study sites or other studies of 
T-DXd, as appropriate per institutional and/or local reporting requirements. 
Sponsor and/or CRO will comply with any additional local safety reporting requirements.  The 
Investigator will assess if an AE is to be considered “unexpected” based on the “Reference 
Safety Information” section in the current IB.26  
8.4.1.6.2. Follow-up for AEs and SAEs 
The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other healthcare 
professionals. 
Urgent safety queries must be followed up and addressed promptly.  The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of receipt of the information.  Follow-up 
information and response to non-urgent safety queries should be combined for reporting to 
provide the most complete data possible within each follow-up report. 
8.4.1.7. 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product 
that is considered both excessive and medically important.  All occurrences of overdose must be 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 83 
reported to (CRO or Sponsor) within 24 hours of awareness.  Overdose involving a subject will 
be reported via eCRF. 
An “excessive and medically important” overdose includes any overdose in which either an 
SAE, a non-serious AE, or no AE occurs and is considered by the Investigator as clinically 
relevant, ie, poses an actual or potential risk to the subject. 
Occupational exposures must be reported via the SAVER Form. 
8.4.1.8. 
Combined Elevations of Aminotransferases and Bilirubin 
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law criteria defined 
as an elevated (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]) 
≥3 × ULN and an elevated TBL >2 × ULN, regardless if it is due to disease progression per 
Investigator assessment, that may occur at different time points during the study conduct, should 
always be reported to the Sponsor.29  These events must be reported either by eCRF, with the 
Investigator’s assessment of seriousness, severity, causality, and a detailed narrative.  These 
events should be reported within 24 hours of Investigator’s awareness of the event regardless of 
seriousness.  A targeted questionnaire will be available as an eCRF to collect relevant additional 
information for these potential cases. 
If the subject discontinues study drug due to liver enzyme abnormalities, the subject will have 
additional clinical and laboratory evaluations as described in Section 10.2 in order to determine 
the nature and severity of the potential liver injury. 
8.4.1.9. 
Adverse Events of Special Interest 
For the T-DXd clinical program, based on the available pre-clinical data, review of the 
cumulative literature, reported toxicities for the same class of agents and biological plausibility, 
ILD and LV dysfunction are considered to be AESIs. 
8.4.1.9.1. Interstitial Lung Disease/Pneumonitis 
Clinical Summary 
Interstitial lung disease/pneumonitis is considered an important identified risk based on a 
comprehensive cumulative review of the available safety data from the clinical development 
program as well as the results of potential ILD/pneumonitis cases reviewed by the independent 
ILD AC, available data from recent epidemiology/literature, biological plausibility, and safety 
information from drugs of similar class.  Refer to the current IB for a summary of preliminary 
clinical study data. 
Management Guidance 
ILD/pneumonitis should be ruled out if a subject develops radiographic changes potentially 
consistent with ILD/pneumonitis or develops an acute onset of new or worsening pulmonary or 
other related signs/symptoms such as dyspnea, cough, or fever.  If the AE is confirmed to have 
an etiology other than ILD/pneumonitis, follow the management guidance outlined in the 
designated “Other Non-Laboratory Adverse Events” dose modification section of the study 
protocol (Table 6.3).  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 84 
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. Evaluations should include high resolution CT, pulmonologist 
consultation (infectious disease consultation as clinically indicated), blood culture and complete 
blood count (CBC) (other blood tests could be considered as needed), bronchoscopy and 
bronchoalveolar lavage if clinically indicated and feasible should be considered, pulmonary 
function tests and pulse oximetry (SpO2), arterial blood gases if clinically indicated, and one 
blood sample collection for PK analysis as soon as ILD/pneumonitis is suspected, if feasible.  
Other tests could be considered, as needed.  
If the AE is confirmed to be ILD/pneumonitis, follow the management guidance outlined in the 
designated “Pulmonary Toxicity” dose modification section of the study protocol (Table 6.3).  
All events of ILD/pneumonitis regardless of severity or seriousness will be followed until 
resolution including after drug discontinuation. 
Independent ILD Adjudication Committee (AC) 
An independent ILD AC for the T-DXd program is responsible for reviewing all cases of 
potential ILD/pneumonitis. To ensure adequate and relevant independent evaluation, systematic 
additional data collection will be conducted for all cases that will be brought for adjudication. 
These additional data collection will cover a more in-depth relevant medical history (eg, 
smoking, radiation, COPD and other chronic lung conditions), diagnostic evaluation, treatment, 
and outcome of the event.  This data collection will be triggered based on a set of predefined list 
of PTs eligible for adjudication as defined in the Event Adjudication Site Manual.  
8.4.1.9.2. Left Ventricular Dysfunction 
Clinical Summary 
Left ventricular dysfunction in association with T-DXd is considered to be important potential 
risk based on the available pre-clinical data, literature, and available safety information for drugs 
of similar class. Refer to the current IB for a summary of preliminary clinical trial data. 
Management Guidance 
Left ventricular ejection fraction will be measured by either ECHO or MUGA scan.  All 
ECHOs/MUGAs will be evaluated by the Investigator or delegated physician for monitoring 
cardiac function. 
Troponin will be measured at Screening, EOT, and as needed based on subject-reported cardiac 
signs or symptoms suggesting CHF, MI, or other causes of cardiac myocyte necrosis.  If an ECG 
is abnormal, follow institutional guidelines. 
Electrocardiograms will be performed and standard ECG parameters will be measured, including 
RR, PR, QT intervals, and QRS duration. All ECGs must be evaluated by Investigator or 
delegated physician for the presence of abnormalities.  Whether or not the ECG measurement is 
performed, date performed, results, and findings for each parameter is to be recorded in the 
eCRF.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 85 
8.4.2. 
Pregnancy 
Sponsor must be notified of any female subject or partner of a male subject who becomes 
pregnant while receiving or within 7 months (or 4 months for a female partner of a male subject) 
of discontinuing the T-DXd. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  If a pregnancy is reported, the Investigator should inform the Sponsor 
within 24 hours of learning of the pregnancy. 
This information is important for both drug safety and public health concerns.  It is the 
responsibility of the Investigator, or designee, to report any pregnancy in a female subject or 
partner of a male subject using the Exposure In Utero (EIU) Reporting form.  Please contact your 
study monitor to receive the EIU Reporting Form upon learning of a pregnancy.  The 
Investigator should make every effort to follow the female subject or partner of a male subject 
(upon obtaining written consent from partner) until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  Any adverse pregnancy outcome, either serious or non-serious, 
should be reported in accordance with study procedures.  If the outcome of the pregnancy meets 
the criteria for immediate classification as an SAE (ie, post-partum complications, spontaneous 
or induced abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted 
fetus), the Investigator should follow the procedures for reporting SAEs. 
8.4.2.1. 
Pregnancy Test 
For women of childbearing potential (as defined in Section 5.1): document the results of a 
negative urine or serum (per institutional guidelines) pregnancy test.   
For eligibility, if not performed as a part of routine care within 72 hours of 
randomization/registration, a pregnancy test must be performed with the results available prior to 
randomization/registration (see Table 1.2).  
Thereafter, repeat pregnancy test (urine or serum per institutional guidelines) must be performed 
72 hours before infusion at each cycle, at EOT visit, and at the 40-day Follow-up Visit.  
A positive urine pregnancy test must immediately be confirmed using a serum test.   
8.4.3. 
Clinical Laboratory Evaluations 
The clinical laboratory tests including hematology, coagulation, blood chemistry, and urinalysis 
will be performed.  Blood samples for troponin, preferably high-sensitivity troponin-T, will be 
collected at Screening, EOT, and as clinically indicated.  Refer to Section 10.2 for the complete 
list of laboratory parameters.  All laboratory values must be appraised by the Investigator as to 
clinical significance and used to take appropriate clinical management measures.  All abnormal 
laboratory values considered clinically significant by the Investigator should be recorded on the 
AE page of the eCRF.  If the abnormal laboratory value constitutes an SAE, the SAE should be 
reported in the CRF and other relevant procedures must be followed (see Section 5). 
Abnormal laboratory values (NCI-CTCAE Grade 3 or 4) occurring during the clinical study will 
be followed until repeat test results return to normal (or baseline), stabilize, or are no longer 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 86 
clinically relevant.  New or worsened clinically relevant abnormalities should be recorded as 
AEs on the AE eCRF. 
8.4.4. 
Other Safety 
8.4.4.1. 
Physical Examinations 
Physical examinations will be performed for each subject according to the SoE (Table 1.2 and 
Table 1.3).  A complete physical examination should include a height (obtained once during 
Screening) and weight measurement, and an evaluation of the head, eyes, ears, nose, and throat 
and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurological systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.  At subsequent visits 
(or as clinically indicated), limited, symptom-directed physical examinations should be 
performed.  Changes from baseline abnormalities should be collected in the subject’s study 
record.  New or worsened clinically relevant abnormalities should be recorded as AEs on the AE 
eCRF. 
8.4.4.2. 
Vital Signs 
Vital signs will be measured and recorded for every subject according to the SoE (Table 1.2 and 
Table 1.3).  Vital signs will include the measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressures, and temperature.   
Vital signs will be measured after the subject has rested in a recumbent position for 5 minutes or 
more and prior to laboratory blood draws and ECG measurements. 
8.4.4.3. 
ECOG Performance Status 
Assess and record the subject’s ECOG PS (see Section 10.3.3) according to the SoE (Table 1.2 
and Table 1.3).  Further, TTD on ECOG PS will be assessed.  Deterioration is defined as a 
decrease of 1 score in ECOG PS. 
8.4.4.4. 
Electrocardiograms 
Standard supine/semi-recumbent 12-lead ECGs will be taken before blood draws and will be 
performed at the time points described in the SoE (Table 1.2 and Table 1.3).  The ECG will be 
measured after the subject has rested in a recumbent position for 5 minutes or more.   
If an abnormality is noted, ECGs should then be performed in triplicate.  When taken in 
triplicate, ECGs should be taken in close succession (approximately 3 minutes apart).  The full 
set of triplicates should be completed in less than 15 minutes.   
Standard ECG parameters will be measured, including heart rate, RR, PR, QT intervals, and 
QRS duration.  All ECGs must be evaluated by the Investigator or delegated physician for the 
presence of abnormalities.  
QTc intervals will be calculated at each time point according to Fridericia’s formula. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 87 
8.4.4.5. 
Multigated Acquisition Scan or Echocardiogram 
Multigated acquisition/ECHO scan must be performed according to the SoE (Table 1.2 and 
Table 1.3) and as clinically indicated.  The same test must be used for the subject throughout the 
study.  
Subjects must have a LVEF ≥50% within 28 days before randomization/registration to be 
eligible for the study. 
8.4.4.6. 
Pulmonary Assessments 
Pulmonary assessments, including CT and additional assessments (as outlined in the SoE), ILD 
management algorithm, and pulse oximetry (SpO2), will be performed as described in the SoE 
(Table 1.2 and Table 1.3).  
8.4.4.6.1. Monitoring for ILD/Pneumonitis 
To further understand the risk of ILD/pneumonitis in the CRC population treated with T-DXd, 
close monitoring of the underlying potential risk of ILD/pneumonitis is needed (see 
Section 8.4.1.9.1).  
All potential cases of ILD will be adjudicated by the independent ILD AC (blinded review). The 
Sponsor will continue to closely monitor the enrolled subjects and the enrollment will continue 
as planned (Section 8.4.1.9.1).  
8.4.4.7. 
Ophthalmological Examinations 
Ophthalmologic assessments including visual acuity testing, slit lamp examination, and 
fundoscopy will be performed as per the SoE (Table 1.2 and Table 1.3) and as clinically 
indicated. 
8.5. 
Health Economics and Outcomes Research 
8.5.1. 
Patient-Reported Outcomes 
Patient-reported outcome measures will be used to examine the impact of treatment on 
symptoms, functioning, health-related quality of life (HRQoL) and overall health status, 
patient-perceived treatment tolerability, and benefit/risk from the patients’ perspective.  PROs 
have become increasingly important in evaluating the efficacy and tolerability of study 
treatments in clinical studies as part of the overall benefit/risk evaluation.30  The PROs included 
in this study are as follows and will be administered in this order: 
 EORTC QLQ-C30 
 EORTC QLQ-CR29 
 EQ-5D-5L 
 Patient Global Impression-Treatment Tolerability (PGI-TT) 
 Patient Global Impression-Severity (PGIS) 
 Patient Global Impression-Change (PGIC) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 88 
The following questionnaires will be administered as per the SoE (Table 1.3) to evaluate the 
health economic and outcomes research (HEOR) endpoints:  
8.5.1.1. 
EORTC QLQ-C30 and EORTC QLQ-CR29 
The QLQ-C30 is a QoL instrument for cancer patients developed in 1987 by EORTC. Since then 
it has undergone several revisions and its current version is 3.0. 
The QLQ-C30 is composed of both multi-item scales and single-item measures. These include 
5 functional scales, 3 symptom scales, a global health status/QoL scale, and 6 single items. Each 
of the multi-item scales includes a different set of items and no item occurs in more than 1 scale. 
All of the scales and single-item measures range in score from 0 to 100. A high scale score 
represents a higher response level. 
Thus, a high score for a functional scale represents a high/healthy level of functioning, a high 
score for the global health status/QoL represents a high QoL, but a high score for a symptom 
scale/item represents a high level of symptomatology/problems. 
Due to limitations inherent in its generic focus, the EORTC QLQ-C30 is supplemented by 
disease-specific modules such as the EORTC QLQ-CR29, which are designed to be administered 
in addition to the core questionnaire. The EORTC QLQ-CR29 is a specific questionnaire for 
CRC. 
Changes from baseline over time will be assessed in the global QoL scale, each of the 
functioning scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, 
nausea/vomiting, and pain), 6 single-item scales (dyspnea, sleep disturbance, appetite loss, 
constipation, diarrhoea, and financial impact) of the EORTC QLQ-C30 and in each of the 
subscales (urinary frequency, blood and mucus in stool, stool frequency, and body image) of the 
EORTC QLQ-CR29.  
Further details on the scoring of these scales, including missing items, will be provided in the 
statistical analysis plan (SAP). 
8.5.1.2. 
EuroQol-5 Dimensions-5 Levels of Severity 
Study subjects will be asked to complete the EQ-5D-5L questionnaire as per the SoE (Table 1.3). 
The EQ-5D-5L is self-administered and consists of 2 parts, the EQ-5D-5L descriptive system, 
and the EQ-visual analogue scale (VAS). The descriptive system comprises 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each dimension 
has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme 
problems.31  The respondent is asked to indicate his/her health state by ticking (or placing a 
cross) in the box against the most appropriate statement in each of the 5 dimensions. This 
decision results in a 1-digit number expressing the level selected for that dimension. The digits 
for 5 dimensions can be combined in a 5-digit number describing the respondent’s health state. 
The numerals 1 to 5 have no arithmetic properties and should not be used as a cardinal score.  
The EQ-VAS records the respondent’s self-rated health on a 20 cm vertical, VAS with endpoints 
labeled “the best health you can imagine” and “the worst health you can imagine.” This 
information can be used as a quantitative measure of health as judged by the individual 
respondents.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 89 
8.5.1.3. 
Patient Global Impression-Treatment Tolerability 
The PGI-TT item is included to assess how a patient perceives the overall tolerability of the 
study treatment over the past 7 days. This is a single-item questionnaire, and patients will rate the 
bother associated with any treatment-related symptoms using response options ranging from 
“Not at all” to “Very much”. 
8.5.1.4. 
Patient Global Impression-Severity 
The PGIS item is included to assess how a patient perceives the overall severity of cancer 
symptoms over the past 7 days. This is a single-item questionnaire, and patients will choose the 
response that best describes the severity of their overall cancer symptoms with options ranging 
from “No Symptoms” to “Very Severe”. 
8.5.1.5. 
Patient Global Impression-Change 
The PGIC item is included to assess how a patient perceives their overall change in health status 
since the start of study treatment. This is a single-item questionnaire, and patients will choose 
from response options ranging from “Much Better” to “Much Worse”. 
8.5.1.6. 
Administration of Patient-Reported Outcome Measures 
The PRO measures will be self-administered by subjects using an electronic (ePRO) device 
provided at the site in accordance with the SoE (Table 1.3). PROs will be provided in the 
language of the country in which it will be administered. It will take approximately 20 to 
30 minutes for subjects to complete the questionnaires. 
The following instructions should be followed when collecting PRO data via an electronic 
(ePRO) device: 
 The research nurse or appointed site staff must explain to subjects the value and 
relevance of study participation and inform them that these questions are being asked 
to find out, directly from them, how they feel. The research nurse or appointed site 
staff should also stress that the information is not routinely shared with study staff. 
Therefore, if subjects have any medical problems, they should discuss them with the 
doctor or research nurse separately from the PRO assessment. 
 It is vital that the PRO-reporting is initiated at the baseline visit (Cycle 1 Day 1), as 
specified in the SoE (Table 1.3) to capture the effect of study treatment. The tablet 
must be charged and fully functional prior to the subject’s arrival at the site for Cycle 
1 Day 1 (-3 days) to ensure that the PROs can be completed at the start of the visit. 
 The subject should be trained on the use of the device, including the importance of 
completing the ePRO questionnaires throughout the study in accordance with the 
completion schedule. 
 All questionnaires must be completed using an electronic device; paper 
questionnaires are not allowed in this study. It is therefore very important to set up the 
device in advance of the subject’s first treatment visit, ideally at least the day before, 
to ensure the device is functioning properly and to identify and address any technical 
issues prior to the visit. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 90 
 PRO questionnaires must be completed before treatment administration and ideally 
before any discussions of health status to avoid biasing the subject’s responses to the 
questions. As feasible, site staff should also ensure PRO questionnaires are completed 
prior to other study procedures, such as collection of laboratory samples, to further 
minimize bias. 
 PRO questionnaires must be completed by the subject in a quiet and private location 
and the subject given enough time to complete the PRO questionnaires at their own 
speed. 
 The research nurse or appointed site staff must remind subjects that there are no right 
or wrong answers and avoid introducing bias by not interpreting or clarifying items. 
 The subject should not receive help from relatives, friends, or clinic staff to answer 
the PRO questionnaires. If a subject uses visual aids (eg, glasses or contact lenses) for 
reading and does not have them when he or she visits the site, the subject will be 
exempted from completing the PROs at the visit. 
 Site staff must not read or complete the PRO questionnaires on behalf of the subject. 
If the subject is unable to read the questionnaire (eg, is blind, illiterate or not fluent in 
the available language), that subject should be exempted from completing PRO 
questionnaires but may still participate in the study. Subjects exempted in this regard 
should be flagged appropriately by the site staff in the source documents and the 
Review of PRO/Questionnaire/Diary eCRF. 
 Site staff must administer questionnaires available in the language that the subject 
speaks and understands. For example, questions should not be read in the available 
language and then translated into another language for the subject. 
Finally, the research nurse or appointed site staff will review the completion status of 
questionnaires during site visits and document the reason(s) why a subject could not complete 
assessments in the eCRF. The research nurse or appointed site staff must monitor compliance 
since minimizing missing data is a key aspect of study success. 
8.5.2. 
Hospitalization-Related Endpoints (Healthcare Resource Use) 
The impact of treatment and disease on healthcare resource use (including inpatient admissions, 
intensive care unit admissions, and length of stay in hospital) will be captured/collected in this 
study on an event-driven basis. The Hospital Admission (HOSPAD) module in eCRF will be 
used to collect information on key healthcare resource use that a subject receives that is not part 
of the study. The data may be used to support health technology assessments and payer-related 
submissions.  
At each scheduled visit, the site should review clinical notes for any non-study-related hospital 
admissions and visits that have occurred. Where any visits have occurred, the site should 
complete the HOSPAD.  If a subject discontinues study treatment for reasons other than 
RECIST version 1.1 progression, the HOSPAD form should continue to be administered until 
progression has been confirmed. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 91 
Time to hospitalization will be assessed. Each hospitalization event will prompt the completion, 
by the site, of a detailed hospitalization eCRF containing the following components: 
 Date of admission to hospital 
 Date of discharge from hospital 
 Primary reason for hospitalization 
 Discharge status from hospital (died, discharged home, discharged to home health 
care, discharged to nursing home care, discharged to long-term care, other) 
 Use of intensive care unit (ICU) services in hospital (Yes/No) 
 If yes, date of admission to ICU 
 If yes, date of discharge from ICU 
8.6. 
Pharmacokinetic (PK) Assessment(s) 
Blood samples for PK analyses will be obtained at the time points specified in the SoE 
(Table 1.3) and in Table 8.4. In addition, if feasible, a blood sample should be collected for PK 
analysis as soon as possible when a subject is suspected of having ILD/pneumonitis. 
Table 8.4: 
Blood Sampling for Pharmacokinetic Analysis 
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (-8 to 0 hours)  
EOI: Within 15 minutes after EOI 
5 hours after the start of drug administration (±15 minutes) 
Day 8 
7 days after the start of drug administration (±1 day) 
Day 15 
14 days after the start of drug administration (±1 day) 
(Day 22) 
If the schedule on Day 1 of the next cycle is delayed for 3 days or more, including if 
the subject cannot continue onto the next cycle, collect blood sample 21 days after 
the start of drug administration (±2 days).  If the next schedule is not delayed, 
sampling at this point is not necessary 
Cycles 2, 3, 
and 4 
Day 1 
BI (-8 to 0 hours) 
EOI: Within 15 minutes after EOI 
Cycle 6 
Day 1 
BI (-8 to 0 hours)  
BI = before infusion; EOI = end of infusion  
In case of chloroquine or hydroxychloroquine administration for SARS-CoV-2 infection, 
additional PK serum samples should be collected at the following time points for T-DXd treated 
subjects (Table 8.5).  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 92 
Table 8.5: 
Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment 
Day of Chloroquine or Hydroxychloroquine 
Administration 
Sampling Time Point 
Day 1 
Prior to chloroquine or hydroxychloroquine dose  
Day 2 or 3 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 hours) 
End of treatment 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 hours) 
Prior to re-initiation of T-DXd 
BI (within 8 hours) 
BI = before infusion 
At each time point, blood will be collected for T-DXd, total anti-HER2 antibody, and DXd 
PK analysis.  The actual time of study drug administration and the exact time of blood sampling 
for PK analysis must be recorded on the eCRF, including for samples collected in case of 
chloroquine or hydroxychloroquine administration.  The date and time of chloroquine or 
hydroxychloroquine administration should also be recorded in case of their administration to 
study subjects.  
Details for blood sampling, processing, storage, and shipment to central laboratory for 
PK samples will be provided in the Study Laboratory Manual. 
Serum concentrations of T-DXd, total anti-HER2 antibody, and DXd will be measured using 
validated assays at the bioanalytical laboratory.  Serum concentrations of T-DXd and/or total 
anti-HER2 antibody may be measured using the same samples for purpose immunogenicity 
assessment. 
8.7. 
Pharmacodynamic Assessment(s) 
In this study, biomarker analyses will be used to investigate the effect of the T-DXd at the 
molecular and cellular level and to determine how changes in the markers may relate to exposure 
and clinical outcomes.  The sample collection information should be recorded on the eCRF 
page(s) and central laboratory requisition form(s).  Detailed instructions for the collection, 
handling, and shipping of biomarker samples are outlined in the Study Laboratory Manual.   
8.7.1. 
Pharmacodynamic Assessments in Blood Samples and Tumor Specimens 
Pharmacodynamic biomarkers will be analyzed with the intent of monitoring the anti-tumor 
impact of treatment with T-DXd.   
A pretreatment blood sample will be collected for cell-free RNA (cfRNA) analysis within 3 days 
before study drug administration.  
The peripheral pharmacodynamic biomarker is cell-free DNA (cfDNA).  Blood samples will be 
collected for cfDNA analysis in the plasma for HER2 amplification and mutations at the time 
points specified in Table 8.6.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 93 
Table 8.6: 
Cell-Free Deoxyribonucleic Acid Sampling Time Points 
Cycle 
Sampling Time Point (Acceptable Range) 
Day 1 of Cycles 1, 2, 3, 4, and 7 
Within 3 days before administration 
Every 4 cycles from Cycle 7 (eg, Cycle 11, 
15, 19, 23, 27, etc.) 
Within 3 days before administration 
End of Treatment 
The date when the Investigator decides on discontinuation of the 
study treatment (+7 days)   
8.7.1.1. 
Optional Tumor Biopsy Sample 
Collection of tumor specimens is critical to assess the pharmacodynamic effect of T-DXd.  The 
tumor biopsy (optional) collected at baseline, on treatment and EOT as per Table 1.2 will be used 
to assess the HER2 status using IHC and/or ISH, mRNA expression profile, and DNA analysis 
using NGS technology and/or other methods.   
8.7.1.1.1. Exploratory Translational Biomarker Analysis 
Samples for biomarker testing will be collected from subjects at the time points specified in 
Table 1.2 and Table 1.3.  In this study biomarker analyses of tumor and blood samples collected 
from subjects will be used to investigate the effect of T-DXd at the molecular and cellular level 
as well as to determine how changes in the markers may relate to exposure and clinical 
outcomes.  
Both tumor and blood-based biomarker samples will be used to analyze DNA, RNA, and/or 
protein measurement to identify predictors of sensitivity or resistance to T-DXd and evaluate 
biomarker changes upon treatment. Samples will be analyzed using appropriate technologies 
including, but not limited to: RNA seq, exome or targeted DNA sequencing, IHC, and/or mass 
spectrometry.  Detailed instructions for the collection, handling, and shipping of biomarker 
samples are outlined in the Study Laboratory Manual. 
The remaining samples (tumor tissues, blood, and plasma) may be stored for up to 15 years.  
8.7.2. 
Optional Pharmacogenomic (Inherited Genetic) Analysis 
An optional single blood sample for pharmacogenomics analysis will be collected from each 
subject, who consented to this test, on Day 1 of Cycle 1, and where allowed per local regulations.  
Participation in this part of the study is optional for all subjects. 
Pharmacogenomic samples may be analyzed for genes involved in absorption, distribution, 
metabolism, elimination, safety, and efficacy of T-DXd.  Additionally, samples may be analyzed 
for genes involved in T-DXd related signaling pathways, or to examine diseases or physiologic 
processes related to T-DXd, such as ILD/pneumonitis. 
Genetic analyses will not be performed on blood samples collected for PK or safety assessments.  
Subject confidentiality will be maintained. 
If subjects agree to the test, the remaining DNA will be stored, as outlined in Section 8.7.2.1 for 
performing future pharmacogenetic analysis.  Otherwise, all remaining DNA samples will be 
destroyed. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 94 
Detailed instructions for the collection, handling, and shipping of samples are outlined in the 
Study Laboratory Manual. 
8.7.2.1. 
Optional Banking of Specimens for Inherited Genetic Analysis 
Procedures for the long-term preservation (banking) of blood and/or DNA specimens extracted 
from subjects' blood samples for each subject that consented are described in the Study 
Laboratory Manual. 
The banked samples may be analyzed for genes involved in absorption, distribution, metabolism, 
elimination, safety, and efficacy of T-DXd.  Additionally, samples may be analyzed for genes 
involved in T-DXd related signaling pathways, or to examine diseases or physiologic processes 
related to T-DXd.  DNA samples will not be immortalized or sold to anyone.  This information 
may be useful in increasing the knowledge of differences among individuals in the way they 
respond to the study drug, as well as helping in the development of new drugs or improvement of 
existing drugs. 
Storage and Disposal of Specimens 
Banked DNA samples will be stored for a maximum of 15 years after the finalization of the 
clinical study report (CSR) for this protocol.  These specimens will be kept for pharmacogenetic 
analysis in case new genomic or genetic information is obtained in the future regarding the 
response (PK or pharmacodynamic) to T-DXd, or in case serious adverse drug reactions are 
noted in a clinical study and pharmacogenetic analysis is to be conducted for investigation into 
the cause. 
During the storage period, the samples will be coded with labels having no personal information 
and will not be immortalized or sold to anyone.  Subjects will have the right to withdraw consent 
and have their sample destroyed at any time.  However, the data will not be discarded if analysis 
has been completed before the subject withdraws consent. 
Disclosure of the Results of Future Pharmacogenetic Analysis 
Because the nature and value of future pharmacogenetic analysis cannot be known at this time, 
any results obtained from research involving pharmacogenetic samples will not be disclosed to 
the subject or Investigators now or in the future. 
8.7.3. 
Immunogenicity 
Blood samples for immunogenicity (anti-drug antibody [ADA] and NAb) assessments will be 
collected at the time points specified in the SoE (Table 1.2).  A blood sample will be drawn at 
each time point.  Serum concentrations of T-DXd and/or total anti-HER2 antibody may be 
measured using the same samples as for the purpose of immunogenicity assessment.   
For subjects with positive ADA at the FU visit, additional serum ADA samples may be collected 
during long-term follow-up that is, every 3 months (±14 days) up to 1 year after the last dose of 
the study drug, or until the immunogenicity result becomes negative, or until the ADA titer 
becomes less than the baseline (applicable when pre-existing ADA was observed), or until the 
subject starts another therapy for cancer, or withdraws consent from the study, whichever occurs 
first. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 95 
Details for ADA serum sampling, processing, storage, and shipment for ADA samples will be 
provided in the Study Laboratory Manual. 
The ADA testing will be performed using a validated ADA assay following tiered assay steps 
including Screening, confirmatory, and titer determination testing.  Samples confirmed positive 
will be analyzed by NAb assay. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 96 
9. 
STATISTICAL CONSIDERATIONS  
9.1. 
General Statistical Considerations 
The data cut-off date for the primary analysis will occur at least 6 months after the last subject 
has been enrolled or when all subjects have discontinued from the study, whichever is earlier.  
All data collected up to the data cut-off date will be included in the primary analyses.  Data from 
all sites will be pooled for analyses.  
The final analysis of the study will occur after all subjects have discontinued from the study and 
have completed the 40-day Follow-up Visit.  Data collected beyond the primary analysis data 
cut-off will be presented as appropriate in a CSR addendum if deemed necessary. 
Descriptive statistics on continuous variables will include the number of observations, mean, 
standard deviation, median, and minimum and maximum values (as well as geometric mean and 
geometric coefficient of variation for PK variables, if applicable).  Categorical variables will be 
summarized using frequency counts and percentages.  Graphical representation of data will be 
employed when appropriate. 
An IA of efficacy and safety for both the 5.4 mg/kg and 6.4 mg/kg doses of T-DXd will be 
performed when all subjects in Stage 1 (ie, the randomized portion of the trial) have been 
randomized and had at least 12 weeks of follow-up after initiation of therapy or have 
discontinued treatment. No formal direct comparison will be made between both treatment arms.  
The purpose of this IA is to look at preliminary efficacy and safety signals within the IHC 
2+/ISH+ and RAS-mutant subgroups.  It is not the intent to modify the study design based on the 
IA results.  
In general, the baseline value for an efficacy variable is the last non-missing value before 
randomization. The baseline value for a safety variable is the last non-missing value before the 
first dose of study treatment. Summary for change from baseline and percent change from 
baseline will include only subjects with both baseline and post-baseline assessments.  Missing 
data will not be imputed for data analysis, unless specifically noted otherwise. 
9.2. 
Statistical Hypothesis 
The primary objective of this study is to evaluate confirmed ORR of T-DXd in HER2 
overexpressing mCRC subjects treated at 5.4 mg/kg and 6.4 mg/kg doses.  The evaluation of the 
study results will be based primarily on the estimation. 
9.3. 
Sample Size Determination 
The sample size in this study is determined on the basis of the probability evaluation that the 
95% Clopper-Pearson CI exceeds and excludes the ORR benchmark of 20.0%. This benchmark 
is the lower bound of the 95% CI (ORR 32.0; 95% CI: 20.0 to 45.0) in pertuzumab plus 
trastuzumab arm in the MyPathway phase 2a open-label trial, that was investigated for patients 
with HER2-amplified metastatic colorectal cancer.24  
Approximately 120 subjects will be enrolled in this study.  In Stage 1, the first 80 subjects will 
be randomized in a 1:1 ratio to receive T-DXd at either 5.4 mg/kg or 6.4 mg/kg dose level.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 97 
Then, in Stage 2, an additional 40 subjects will be registered at the 5.4 mg/kg dose to further 
inform on the efficacy and safety of this dose in mCRC. 
In Stage 1, with 40 subjects in each treatment arm, the probability to exclude the ORR 
benchmark of 20.0% is at least 80% when the true ORR is 41%.  At the end of Stage 2, assuming 
80 total subjects in the 5.4 mg/kg, the probability to exclude the ORR benchmark of 20.0% is at 
least 80% when the true ORR is 34%.  Details of the probability evaluation under different true 
ORR values are shown in Table 9.1. 
The resulting 95% CIs using exact (Clopper-Pearson) method under several scenarios of 
observed ORR are provided in Table 9.2, indicating that with 80 subjects at 5.4 mg/kg and 30% 
observed ORR, the 95% CI excludes the benchmark of 20.0% ORR.  With 40 subjects at 
6.4 mg/kg and 35% observed ORR, the 95% CI excludes the benchmark of 20.0% ORR. 
With 80 subjects at the 5.4 mg/kg dose level and 40 subjects at the 6.4 mg/kg dose level, if the 
higher dose true ORR is at least 13.75% higher than that of the lower dose, the probability of 
observing the ORR difference between dose levels being 5% or more is at least 80%. 
Assuming 80 subjects at the 5.4 mg/kg dose level and 40 subjects at the 6.4 mg/kg dose level, the 
95% confidence interval of the ORR difference between dose levels is expected to extend 
approximately 0.18 from the observed difference in proportions to either confidence limit.  
Table 9.1: 
The Probability that the Resulting Clopper-Pearson 95% CI will Exclude the 
Benchmark of 20.0% ORR 
True ORR (%) 
Probability evaluated for N=80 
(%) 
Probability evaluated for N=40 
(%) 
30 
54.2 
29.7 
31 
61.8 
34.7 
32 
68.9 
39.9 
33 
75.2 
45.2 
34 
80.8 
50.6 
40 
97.6 
78.9 
41 
98.4 
82.4 
50 
99.9 
98.1 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 98 
Table 9.2: 
Confidence Interval with 40 and 80 Subjects Under Scenarios of Observed 
Objective Response Rate 
Sample size at a dose 
level 
Dose level 
Observed ORR (%) 
95% CI using exact method 
(%) 
80 
5.4 mg/kg 
 
30 
(20.3, 41.3) 
35 
(24.7, 46.5) 
40 
(29.2, 51.6) 
45 
(33.8, 56.5) 
50 
(38.6, 61.4) 
55 
(43.5, 66.2) 
60 
(48.4, 70.8) 
40 
6.4 mg/kg 
30 
(16.6, 46.5) 
35 
(20.6, 51.7) 
40 
(24.9, 56.7) 
45 
(29.3, 61.5) 
50 
(33.8, 66.2) 
55 
(38.5, 70.7) 
60 
(43.3, 75.1) 
CI = confidence interval; ORR = objective response rate 
Calculations were made using R package of binom 
9.4. 
Population for Analysis Sets 
Analysis Sets 
 The Full Analysis Set (FAS) will include all subjects for whom study treatment has 
been assigned by randomization.  Following the Intent-to-Treat principle, subjects 
will be analyzed according to the treatment and strata they have been assigned to 
during the randomization process. 
 The Safety Analysis Set will include all subjects who received at least one dose of 
study treatment.  Subjects will be analyzed according to the study treatment received, 
where treatment received is the randomized/assigned study drug if the subject took at 
least one dose of the randomized/assigned study drug; otherwise the first treatment 
received will be used. 
 The Response Evaluable Set (RES) will include all subjects in FAS who received at 
least one dose of study treatment and had measurable target lesions as assessed by 
BICR at baseline. 
 The PK Analysis Set will include all enrolled subjects who received at least one dose 
of study drug and had measurable serum concentrations of T-DXd. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 99 
9.5. 
Statistical Analysis 
The SAP will be developed and finalized before IA database finalization and will describe the 
subject populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints. 
9.5.1. 
Efficacy Analyses 
Table 3.1 lists the primary and secondary endpoints and their corresponding definitions of all 
endpoints.  Additional details for the analysis and censoring rules are noted in the following 
sections.  Detailed censoring rules for the applicable secondary efficacy endpoints will be 
specified in the SAP. 
Efficacy analyses will be performed for FAS and RES.  Point estimates will be accompanied 
with 2-sided 95% CIs, unless specified otherwise. 
9.5.1.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is confirmed ORR, defined as the sum of CR and PR rate, 
assessed by the BICR based on RECIST version 1.1. 
The primary analysis of ORR will be performed for FAS.  The ORR for each dose level will be 
estimated along with the two-sided 95% confidence intervals (Clopper-Pearson).  In addition, the 
ORR difference between dose levels will be estimated using a stratified analysis, where the 
strata-adjusted ORR difference is computed, and each stratum is weighted according to the 
inverse of variance. The 95% confidence interval will also be computed. 
9.5.1.2. 
Secondary Efficacy Analyses 
The secondary endpoint of confirmed ORR by Investigator assessment based on RECIST 
version 1.1 will be analyzed using the same method as for the primary efficacy endpoint.   
Duration of Response, defined as time from the initial response (CR or PR), until documented 
tumor progression or death from any cause, will be summarized using Kaplan-Meier approach 
for each dose level. 
Disease Control Rate is defined as the proportion of subjects who achieve CR, PR, or SD during 
study treatment.  Disease Control Rate based on BICR and DCR based on Investigator 
assessments will both be determined.  
Clinical Benefit Rate is defined as the proportion of subjects who achieved CR or PR or had SD 
for at least 6 months per RECIST version 1.1.  Clinical Benefit Rate based on BICR and DCR 
based on Investigator assessments will both be determined.  Disease Control Rate and CBR will 
be analyzed in the same approach as ORR. 
Progression-free Survival, defined as the time from date of randomization/registration until first 
objective radiographic tumor progression or death from any cause based on BICR and 
Investigator assessments, will be analyzed using the Kaplan-Meier approach.   

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 100 
Likewise, OS, defined as the time from date of randomization/registration until death from any 
cause, will also be similarly analyzed.  The censoring rules for PFS and OS will be detailed in 
the SAP. 
9.5.1.3. 
Exploratory Analyses 
Time to Response, defined as the time from the date of randomization/registration to the date of 
the first documentation of objective response (CR or PR), will be summarized using descriptive 
statistics, for each dose level.  
Best percent change from baseline in the sum of the diameters for all target lesions will be 
summarized with descriptive statistics by dose level. 
Time to Deterioration in ECOG PS is defined as the time from the date of 
randomization/registration to the date when ECOG PS score of ≥2 is observed for the first time, 
with censoring occurring at the date of the last ECOG PS assessment if no deterioration is 
observed. Time To Deterioration in ECOG PS will be summarized using Kaplan-Meier approach 
for each dose level. 
For the following subgroups, analyses using the same methods as for the FAS will be performed, 
provided that a minimum number (10) subjects in at least one treatment arm are available: 
 Lines of prior systemic therapy for advanced disease (2, 3, ≥4) 
 Age (<65, ≥65 yrs.) 
 Sex (female, male) 
 ECOG PS (0 or 1)  
 HER2 status (IHC 3+ or IHC 2+/ISH+)  
 RAS status (wild-type or mutant) 
 Region: United States, European Union, Asia-Pacific  
 Primary tumor site (right, left/rectum) 
 Number of metastatic sites (<2, ≥2) 
 Prior treatment with irinotecan or other topoisomerase I inhibitors (Yes or No) 
 Prior treatment with HER2 targeted regimen 
 Prior treatment with any anti EGFR antibody  
 Prior treatment with any VEGF antibody  
 Prior treatment with regorafenib or TAS-102 (Yes or No) 
 Prior treatment with anti-PD-(L)-1 inhibitor 
 Presence of liver metastases at baseline (Yes or No) 
 Renal impairment at baseline (within normal range, and mild/moderate impairment) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 101 
9.5.1.4. 
Multiplicity Adjustment 
The evaluation of the study results will be based primarily on the estimation.  Multiplicity 
adjustment is not applicable. 
9.5.2. 
Safety Analyses 
Safety analyses involving safety data (ie, extent of exposure, TEAEs, clinical laboratory results, 
ECG, vital signs and physical examinations) will be performed on the Safety Analysis Set 
according to the actual treatment received by subjects. No inferential statistical analysis is 
planned for safety data, unless otherwise specified. Descriptive statistics will be calculated for 
quantitative safety data and frequency counts and percentages will be compiled for classification 
of qualitative safety data. All percentages will be calculated based on the number of subjects in 
the Safety Analysis Set, unless otherwise indicated. If the number of subjects with available data 
does not allow for the reliable estimation of variability at a scheduled time point, no summary 
statistics will be presented for that time point, unless otherwise indicated.  Unless otherwise 
noted, baseline values will be the last non-missing assessment collected prior to first dose of 
study treatment. 
Safety analyses, primarily summaries by description statistics of safety variables, will be 
performed by dose level. 
Adverse Events 
A TEAE is defined as an AE that occurs, having been absent before the first dose of study drug, 
or has worsened in severity or seriousness after the initiating the study drug until 47 days after 
last dose of the study drug.  SAEs with an onset or worsening 48 days or more after the last dose 
of study drug, if considered related to the study treatment, are also TEAEs.   
Adverse events will be coded using MedDRA and graded using NCI-CTCAE version 5.0.  The 
number and percentage of subjects reporting TEAEs will be tabulated by system organ class, 
preferred term, relationship to the study drug, and the worst NCI-CTCAE grade and dose level.  
Similarly, the number and percentage of subjects reporting serious TEAEs will be tabulated by 
dose level, as well as TEAEs leading to discontinuation of the study treatment. 
A by-subject AE (including TEAE) data listing including but not limited to the verbatim terms, 
SOC, PT, NCI-CTCAE grade, and relationship to study drug will be provided.  Deaths, other 
SAEs, AESIs, and other significant AEs, including those leading to discontinuation of the study 
treatment, will be listed. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for the clinical laboratory test results and changes from 
baseline by dose level at each scheduled time of evaluation.  In addition, mean change from 
baseline will be presented by dose level for the maximum and minimum post-treatment values 
and the values at the EOT visit. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 102 
2-way frequency tabulation for baseline and the worst post-treatment value according to 
NCI-CTCAE grade, will be provided for clinical laboratory tests. 
A listing of abnormal clinical laboratory test results deemed of clinical significance or of Grade 3 
or 4 will be provided. 
ECG 
Descriptive statistics will be provided for the ECG measurements by scheduled time of 
evaluation and by treatment group, as well as for the change from baseline.  In addition, the 
number and percentage of subjects with ECG interval values meeting the criteria will be 
tabulated (eg, QTc ≤450 ms, >450 to ≤480 ms, >480 ms to ≤500 ms, and >500 ms).  Maximum 
change from baseline will be tabulated (≤30 ms, >30 to ≤60 ms, >60 ms).  The QT intervals will 
be corrected for heart rate by Fridericia’s formula (ie, QTcF). 
A listing of ECG data will be provided. 
Vital Signs 
Descriptive statistics will be provided for the vital signs measurements by scheduled time of 
evaluation and by dose level, as well as for the change from baseline.  The baseline value is 
defined as the last non-missing value before the initial administration of study treatment.  A 
listing of vital sign data will be provided. 
Other 
Concomitant medications will be coded using the World Health Organization drug reference 
dictionary (WHODrug).  Number and percentage of subjects taking concomitant medications 
will be summarized.  Concomitant medications will also be listed. 
All other safety data (eg, physical examination findings including ECOG PS, ECHO/MUGA, 
and ophthalmologic findings) will be listed. 
9.5.3. 
HEOR Analysis 
To assess patient HRQoL, the following PROs questionnaires will be administered: 
 A cancer specific PRO (EORTC QLQ-C30) along with tumor-specific modules 
(EORTC QLQ-CR29) to assess patient-reported tolerability and clinical benefit. 
 A generic health status questionnaire, the EQ-5D-5L module including EQ-VAS to 
assess patient-reported health utility for health economic evaluations. 
 Three global anchors (PGIS, PGIC, and PGI-TT) will be included to estimate 
meaningful change thresholds for EORTC QLQ-C30 and EORTC QLQ-CR29. 
Descriptive statistics will be calculated to summarize change from baseline in symptoms, 
physical functioning, and general HRQoL scales in the EORTC QLQ-C30 and EORTC 
QLQ-CR29 study questionnaires at each scheduled assessment time point by dose level.  The 
number of subjects completing each patient questionnaire and the number of missing or 
incomplete assessments will be provided for each scheduled assessment time point by dose level. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 103 
9.5.4. 
Other Analyses 
The following other analyses are planned in this study. 
Pharmacokinetics 
Pharmacokinetics analyses will be performed using the PK Analysis Set. 
Descriptive statistics will be provided for serum concentration data of T-DXd, DXd, and total 
anti-HER2 antibody at each time point for each dose level of T-DXd. PK parameters (Cmax, 
Tmax, AUC, [AUClast (area under the concentration time-curve from time 0 to the last 
measurable concentration)], and AUC0-21d [area under the concentration time-curve from time 
0 to 21 days]) of T-DXd, total anti-HER2 antibody and DXd may also be determined using 
non-compartmental analysis after the first dose and summarized using descriptive statistics by 
dose level if data allows. 
Serum concentration data of T-DXd, and DXd from this study may be analyzed using population 
PK modeling approach.  In addition, exposure-response relationships between serum exposures 
of T-DXd, and/or DXd with key efficacy and safety endpoints may also be evaluated. For the 
population PK and exposure-response analyses, data from this study may be combined with other 
T-DXd studies and results reported separately from the CSR.  
Immunogenicity Analyses 
Immunogenicity will be assessed through characterization of incidence and titer of ADA. The 
number and percentage of subjects positive for ADA at baseline (prior to the first administration 
of T-DXd) and during the study after start of administration of T-DXd will be determined.  The 
ADA titer values will be summarized by time point and dose level using descriptive statistics.  
The treatment-emerging ADA incidence will be calculated by dose level.  Treatment-emergent 
ADA positive subject will be defined as subjects who are ADA negative at baseline and become 
ADA positive post-treatment, or who are ADA positive at baseline and post-treatment, but have 
an increase in ADA titer from baseline to post-treatment, or those who have missing ADA data 
at baseline but become ADA positive post-treatment.  The number and percentage of subjects 
positive for NAb of T-DXd by dose level will also be determined. 
Biomarker 
Biomarker analysis will be performed using the FAS. 
Descriptive statistics including mean, standard deviation, coefficient of variation, geometric 
mean, median, minimum, and maximum will be computed by evaluation time for biomarkers 
listed in Section 8.7.1.1.1.  If possible, change from baseline and percent change from baseline 
will also be summarized.  Summaries and analyses for exploratory biomarkers will be 
documented in a separate analysis plan and will be reported outside the CSR in a separate report. 
9.6. 
Interim Analysis 
Efficacy and safety IA for both the 5.4 mg/kg and 6.4 mg/kg doses of T-DXd will be performed 
when all subjects in Stage 1 (40 subjects for each dose) have been randomized and had at least 
12 weeks of follow-up after initiation of therapy or have discontinued treatment.  It is not the 
intent to modify the study design based on the IA results. During the study, individual subject 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 104 
data will be reviewed on an ongoing basis and aggregate safety data will be monitored by the 
study team across the duration of the trial. The data review and analysis will be based on the 
available Investigator reported data in the clinical database at the respective time on a monthly 
basis. 
In addition, pharmacokinetic and exposure-response analyses may also be performed at the time 
of the IA. 
For each dose, the primary efficacy endpoint of ORR will be summarized using descriptive 
statistics including 2-sided exact 95% confidence interval (Clopper-Pearson).  Other efficacy 
endpoints based on response rates will be summarized by dose using the same methodology as 
the primary efficacy endpoint.  For time to event endpoint such as PFS, Kaplan-Meier estimates 
of median and their corresponding 95% CIs using Brookmeyer and Crowley method will be 
provided.  Safety data related to AEs will be summarized using descriptive statistics.  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 105 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS 
10.1. 
Appendix 1 Regulatory and Ethical Considerations 
10.1.1. 
Regulatory Compliance 
The study protocol, the Investigator Brochure, available safety information, recruitment 
procedures (eg, advertisements), subject information and consent form, any subject written 
instructions to be given to the subject, information about payments and compensation available 
to the subjects, and documentation evidencing the Investigator’s qualifications should be 
submitted to the independent IRB or EC for ethical review and approval according to local 
regulations, prior to the study start.  The written approval should identify all documents reviewed 
by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP.  Written approval of all protocol amendments and changes to any of 
the above listed documents must be obtained from the IRB or EC. 
The Investigator should notify the IRB or EC of deviations from the protocol or SAEs occurring 
at the study site and other AE reports received from the Sponsor/CRO, in accordance with local 
procedures. 
The Sponsor will appoint a Coordinating Investigator.  Among other possible duties, the 
Coordinating Investigator will be responsible for reviewing the final CSR and testifying to the 
accuracy of the description of the study conduct.  Because the Coordinating Investigator should 
have personal knowledge of the conduct of the study, he or she will normally be chosen from 
among those Investigators who have enrolled and treated at least one subject.  However, where 
an Investigator has special knowledge of the field or of the study, the Coordinating Investigator 
can be chosen prior to enrollment of the first subject.  In all cases, the Coordinating Investigator 
must be chosen prior to locking the database. 
Compliance Statement, Ethics, and Regulatory Compliance 
This study will be conducted in compliance with the protocol, the ethical principles that have 
their origin in the Declaration of Helsinki, the International Council for Harmonization of 
Technical Requirements for Pharmaceuticals for Human Use (ICH) consolidated Guideline E6 
for Good Clinical Practice (GCP) (CPMP/ICH/135/95), and applicable regulatory requirement(s) 
including the following: 
 European Commission Directive (2001/20/EC Apr 2001) and/or; 
 European Commission Directive (2005/28/EC Apr 2005) and/or; 
 US Food and Drug Administration (FDA) GCP Regulations: Code of Federal 
Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 (27 Mar 1997) 
and/or; 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 106 
 The Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical 
Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, and 
Cosmetics No. 1 (25 Nov 2014); 
 Other applicable local regulations. 
In addition, the Investigator will inform the Sponsor in writing within 24 hours of any urgent 
safety measures taken by the Investigator to protect the study subjects against any immediate 
hazard, and of any suspected/actual serious GCP non-compliance that the Investigator becomes 
aware of. 
Supply of New Information Affecting the Conduct of the Study 
When new information becomes available that may adversely affect the safety of subjects or the 
conduct of the study, the Sponsor will inform all Investigators involved in the clinical study, 
ECs/IRBs, and regulatory authorities of such information, and when needed, will amend the 
protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the EC/IRB.  The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised Main ICF. 
10.1.2. 
Informed Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The ICFs and any revision(s) should be 
approved by the EC/IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICFs should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICFs 
should be retained in accordance with institutional policy, and a copy of the signed ICFs should 
be provided to the subject.  The date and time (if applicable) that informed consent was given 
must be recorded in the eCRF. 
If the subject cannot read, then according to ICH GCP Guideline, Section 4.8.9, an impartial 
witness should be present during the entire informed consent discussion.  This witness should 
sign the ICFs after the subject has consented to their participation.  By signing the ICFs, the 
witness attests that the information in the ICFs and any other written information was adequately 
explained to and apparently understood by the subject and that informed consent was freely 
given by the subject. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 107 
A separate special consent for inherited genetic analysis will be obtained from subjects in 
accordance with health authorities in their particular region/country. 
Suggested model text for the ICFs for the study and any applicable subparts (PK, 
pharmacodynamic, etc) is provided in the Sponsor’s ICF templates for the Investigator to prepare 
the documents to be used at his or her study site.  Updates to applicable forms will be 
communicated via letter from the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA). 
10.1.3. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
For European Union (EU) study sites, the Sponsor will observe the rules laid down in the 
European Data Protection Directive 95/46/EC on the protection of individuals with regard to the 
processing of personal data and the free movement of such data. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique SID 
as designated by the Sponsor.  Documents that are not for submission to the Sponsor or the CRO 
(eg, signed ICF) should be kept in strict confidence by the Investigator. 
In compliance with ICH GCP Guidelines, it is required that the Investigator and institution 
permit authorized representatives of the company, of the regulatory agency(s), and the 
independent IRB/EC direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  The Investigator is obligated to inform the 
subject that his/her study-related records will be reviewed by the above named representatives 
without violating the confidentiality of the subject. 
10.1.4. 
Data Integrity and Quality Assurance 
Monitoring and Inspections 
The CRO monitor and regulatory authority inspectors are responsible for contacting and visiting 
the Investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the study (eg, eCRFs, source data, and other pertinent documents). 
The verification of adherence to the protocol; completeness, accuracy, and consistency of the 
data; and adherence to ICH GCP and local regulations on the conduct of clinical research will be 
accomplished through a combination of onsite visits by the monitor and review of study data 
remotely.  The frequency of the monitoring visit will vary based on the activity at each study 
site.  The monitor is responsible for inspecting the eCRFs and ensuring completeness of the 
study essential documents.  The monitor should have access to subject medical records and other 
study-related records needed to verify the entries on the eCRFs.  Detailed information is 
provided in the monitoring plan. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 108 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the Investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor.  Audit of study site facilities (eg, pharmacy, drug storage 
areas, laboratories) and review of study-related records will occur in order to evaluate the study 
conduct and compliance with the protocol, ICH GCP, and applicable regulatory requirements.  
The Investigator should respond to audit findings. 
In the event that a regulatory authority informs the Investigator that it intends to conduct an 
inspection, the Sponsor shall be notified immediately. 
Data Collection 
An eCRF must be completed for each subject who signs an ICF and undergoes any Screening 
procedure.  If a subject is not treated, the reason must be recorded on the eCRF.  All data 
collected during the study will be recorded in this individual, subject-specific eCRF.  Instructions 
will be provided for the completion of the eCRF and any corrections made will be automatically 
documented via an “audit trail.” 
The eCRF should be kept current to enable the study monitor to review the subject’s status 
throughout the course of the study.  Upon completion of the subject’s eCRF, it will be reviewed 
and signed off by the Investigator via the EDC system’s electronic signature.  This signature will 
indicate that the Investigator inspected or reviewed the data in the subject-specific eCRF, the 
data queries, and the site notifications and agrees with the eCRF content. 
Data Management 
Each subject will be identified in the database by a unique SID. 
To ensure the quality of clinical data across all subjects and study sites, a Sponsor or CRO 
Clinical and Data Management review will be performed on subject data according to 
specifications developed by the Sponsor.  Data will be vetted both electronically by programmed 
data rules within the application and manually.  Queries generated by rules and raised by 
reviewers will be generated within the EDC application.  During this review, subject data will be 
checked for consistency, completeness, and any apparent discrepancies. 
Data received from external sources such as central laboratories will be reconciled to the clinical 
database. 
All AEs will be coded using MedDRA.  Serious AEs in the clinical database will be reconciled 
with the safety database. 
All concomitant medications and prior cancer therapies will be coded using the World Health 
Organization Drug Reference (WHODrug) Dictionary. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 109 
Data that may potentially unblind the treatment assignment (ie, study drug serum concentrations 
and study drug preparation/accountability data) will be handled with special care during the data 
cleaning and review process.  These data will be handled in such a way that, prior to unblinding, 
any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available.  If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent audits. 
10.1.5. 
Committees 
An independent ILD AC for the T-DXd program is responsible for reviewing all cases of 
potential ILD/pneumonitis. To ensure adequate and relevant independent evaluation, systematic 
additional data collection will be conducted for all cases that will be brought for adjudication. 
These additional data collection will cover a more in-depth relevant medical history (eg, 
smoking, radiation, COPD and other chronic lung conditions), diagnostic evaluation, treatment, 
and outcome of the event.  This data collection will be triggered based on a set of predefined list 
of PTs eligible for adjudication as described in the Event Adjudication Site Manual. 
10.1.6. 
Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to whom 
he/she has delegated study duties.  All persons authorized to obtain informed consent and make 
entries and/or corrections on eCRFs will be included on the Signature List. 
Investigators will maintain a confidential Screening Log of all potential study candidates that 
includes limited information of the subjects, date, and outcome of the Screening process. 
Investigators will be expected to maintain an Enrollment Log of all subjects enrolled in the study 
indicating their assigned study number. 
Investigators will maintain a confidential subject identification code list.  This confidential list of 
names of all subjects allocated to study numbers on enrolling in the study allows the Investigator 
to reveal the identity of any subject when necessary. 
Source documents are original documents, data, and records from which the subject’s eCRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, diaries, microfiches, X-rays, and correspondence. 
Records of subjects, source documents, monitoring visit logs, data correction forms, eCRFs, 
inventory of study drug, regulatory documents (eg, protocol and amendments, EC/IRB 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (site specific Trial Master 
File).  Source documents include all recordings and observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the 
clinical study.  These records will be retained in a secure file for the period required by local 
laws or regulations or study site policy.  Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to provide further instruction. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 110 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (site specific Trial Master File) of all study-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting source 
documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the independent IRB/EC and the Sponsor. 
 Records related to the study drug including acknowledgment of receipt at study site, 
accountability records, and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All essential documentation will be retained by the Investigator until at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years have lapsed since the 
formal discontinuation of clinical development of the investigational drug.  These documents 
should be retained for a longer period, however, if required by the applicable laws or regulatory 
requirements or by an agreement with the Sponsor.  It is the responsibility of the Sponsor to 
inform the Investigator/Institution as to when these documents no longer need to be retained. 
Subjects’ medical files should be retained in accordance with applicable legislation and in 
accordance with the maximum period of time permitted by the hospital, institution, or private 
practice.  
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor in writing of the new responsible 
person and/or the new location. 
10.1.7. 
Finances 
Prior to starting the study, the Principal Investigator and/or Institution will sign a clinical study 
agreement with DS/CRO.  This agreement will include the financial information agreed upon by 
the parties. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity, and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 111 
10.1.8. 
Publication, Public Disclosure Policy, and Data Sharing 
The Sponsor is committed to meeting the highest standards of publication and public disclosure 
of information arising from clinical studies sponsored by the company.  The Sponsor will 
comply with US, EU, and Japanese policies for public disclosure of the clinical study protocol 
and clinical study results, and for sharing of clinical study data.  The Sponsor will follow the 
principles set forward in “Good Publication Practice for Communicating Company-Sponsored 
Medical Research (GPP3)”, and publications will adhere to the “Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals” 
established by the International Council of Medical Journal Editors (ICMJE). 
In order to ensure compliance with the public disclosure policies and the ICMJE 
recommendations, and to protect proprietary information generated during the study, all 
publications (manuscripts, abstracts, or other public disclosure) based on data generated in this 
study must be reviewed and approved in writing by the Sponsor prior to submission.  
The data from this study may be shared with or used by third parties, including commercial 
partners. 
10.1.9. 
Protocol Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by the 
Sponsor and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the ECs/IRBs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. 
The Sponsor must be notified in writing of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, missed study visits) within 24 hours and in accordance 
with the clinical study agreement between the parties. 
The Investigator, or person designated by the Investigator, should document and explain any 
deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or study treatment, and had at least one 
administration of study drug, data should be collected for safety purposes. 
If applicable, the Investigator should notify the EC/IRB of deviations from the protocol in 
accordance with local procedures. 
10.1.10. 
Study and Site Closure 
The Sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the Sponsor.  Study sites will be closed upon study completion.  A 
study site is considered closed when all required documents and study supplies have been 
collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 112 
 Failure of the Investigator to comply with the protocol, the requirements of the 
EC/IRB or local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further study intervention development 
10.1.11. 
Product Complaints 
A product complaint is any dissatisfaction with a product that may be attributed to the identity, 
quality, durability, reliability, or safety of the product.  Individuals who identify a potential 
product complaint situation should immediately report the event.  Whenever possible, the 
associated product should be maintained in accordance with the label instructions pending 
further guidance from a quality representative form the Sponsor. 
For product complaints, refer to the Pharmacy Manual for instructions and details. 
10.2. 
Appendix 2: Central and/or Local Laboratory 
The clinical laboratory tests listed in Table 10.1 are to be performed in this study. 
Table 10.1: 
Clinical Laboratory Tests 
Test 
Analytes 
 
Blood Chemistry 
albumin 
alanine aminotransferase (ALT) 
alkaline phosphatase (ALP) 
aspartate aminotransferase (AST) 
bilirubin (total) 
blood urea nitrogen (BUN)/urea 
calcium (Ca) 
chloride (Cl) 
creatinine (serum) 
 
lactate dehydrogenase (LDH) 
magnesium (Mg) 
potassium (K) 
protein (total) 
sodium (Na) 
FSH and estradiol during Screening (if 
applicable) to confirm menopausal status 
Troponin 
high-sensitivity troponin-T (central or local 
laboratory) 
troponin I or troponin-T (local laboratory) 
 
Hematology 
hemoglobin 
hematocrit 
platelet count 
red blood cell (RBC) count 
white blood cell (WBC) count 
 
absolute ± differential (%) WBC count: 
basophils  
eosinophils 
lymphocytes 
monocytes 
neutrophils 
Coagulation 
prothrombin time (PT)- international normalized ratio (INR) 
partial thromboplastin time (PTT)  
activated partial thromboplastin time (aPTT) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 113 
Test 
Analytes 
 
Urinalysis 
(abbreviated) 
glucose 
microscopy assessments, if indicated 
occult blood 
protein 
specific gravity 
 
10.3. 
Appendix 3: Reference Standards 
10.3.1. 
Cockcroft-Gault Equation 
The estimated creatinine clearance (CrCl; mL/min) will be calculated using the Cockcroft-Gault 
equation based on [actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds):32  
Conventional – serum creatinine in mg/dL: 
 
CLcr (mL/min) = 
{× 0.85 for females} 
 
International System of Units (SI) – serum creatinine in μmol/L: 
 
CLcr (mL/min) = 
{× 0.85 for females} 
10.3.2. 
New York Heart Association (NYHA) 
The NYHA classifications are summarized below.33  
Table 10.2: 
New York Heart Association Classifications 
Class 
Functional Capacity 
Objective Assessment 
I 
Subjects with cardiac disease but without resulting limitation of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain. 
A. No objective evidence of 
cardiovascular disease. 
II 
Subjects with cardiac disease resulting in slight limitation of physical 
activity.  They are comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity.  They are comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
IV 
Subjects with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
anginal syndrome may be present even at rest.  If any physical activity 
is undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
Source: American Heart Association. Classification of Functional Capacity and Objective Assessment, Ninth edition 
March 14, 1994. https://professional.heart.org/en/guidelines-and-statements/classification 
10.3.3. 
Eastern Cooperative Oncology Group Performance Status 
The ECOG PS scale scores are summarized below.34  
[140 - age (years)] × weight (kg) 
72 × serum creatinine (mg/dL) 
[140 - age (years)] × weight (kg) 
72 × 0.0113 × serum creatinine (µmol/L)  

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 114 
Table 10.3: 
Eastern Cooperative Oncology Group Performance Status 
Score 
Performance Status 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or 
sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5:649 55. 
10.3.4. 
Highly Effective Contraception 
Methods considered to be highly effective contraception include:35  
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence defined as refraining from heterosexual intercourse when 
it is in line with the preferred and usual lifestyle of the subject.  Study subjects should 
refrain from heterosexual intercourse during and upon completion of the study and for 
at least 7 months for female subjects and 4 months for male subjects after the last 
dose of study drug.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods), declaration of abstinence for the duration of exposure to the 
study drug, and withdrawal are not acceptable methods of contraception. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 115 
10.4. 
Appendix 4: Response Criteria 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
Assessment of tumor responses will be performed according to revised RECIST version 1.1.36 
Some of these definitions and criteria are highlighted below. 
Measurability of Tumor at Baseline Definitions 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (CT scan slice thickness no greater than 5 mm) 
Measurable malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥ 15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm).  At baseline and in follow-up, only the 
short axis will be measured and followed.  See also notes below on “Baseline documentation of 
target and non-target lesions” for information on lymph node measurement. 
Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 116 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously-irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion since the therapy. 
Specifications by Methods of Measurements  
Measurement of Lesions 
All measurements should be recorded in metric notation.  All baseline evaluations should be 
performed as close as possible to the treatment start and NEVER more than 4 weeks (or 28 days) 
before randomization/registration. 
Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical examination. 
CT/MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (eg, for body scans). 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
In this study, only subjects with measurable disease at baseline should be included in the study. 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (representative of all involved organs, with a maximum of 2 per organ).should be 
identified as target lesions and will be recorded and measured at baseline (this means in instances 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 117 
where subjects have only 1 or 2 organ sites involved a maximum of 2 and 4 lesions respectively 
will be recorded).  
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as 2 dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’.  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the SoD of target lesions, taking as reference 
the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the SoD of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. (Note: The appearance of one or more new lesions is also considered 
progression.) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 118 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
Special Notes on the Assessment of Target Lesions 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), 
even if the nodes regress to below 10 mm on study.  This means that when lymph nodes are 
included as target lesions, the ‘sum’ of lesions may not be zero even if CR criteria are met, since 
a normal lymph node is defined as having a short axis of < 10 mm.  For PR, SD, and PD, the 
actual short axis measurement of the nodes is to be included in the sum of target lesions. 
Target lesions that become ‘too small to measure’: While on study, all lesions (nodal and 
non-nodal) recorded at baseline should have their actual measurements recorded at each 
subsequent evaluation, even when very small (eg, 2 mm).  However, sometimes lesions or lymph 
nodes which are recorded as target lesions at baseline become so faint on CT scan that the 
radiologist may not feel comfortable assigning an exact measure and may report them as being 
‘too small to measure’.  When this occurs, it is important that a value be recorded on the eCRF.  
If it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm.  If the lesion is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned.  (Note: It is unlikely that this rule 
will be used for lymph nodes since they usually have a definable size when normal and are 
frequently surrounded by fat such as in the retro-peritoneum.)  This default value is derived from 
the 5 mm CT slice thickness (but should not be changed with varying CT slice thickness.)  The 
measurement of these lesions is potentially non-reproducible; therefore providing this default 
value will prevent false responses or progressions based upon measurement error. 
If the radiologist is able to provide an actual measurement, that should be recorded, even if it is 
below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum.  
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion.  If the lesions have truly 
coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
Evaluation of Non-Target Lesions 
CR: Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph 
nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions.  (Note: The appearance of one or more new lesions is also considered 
progression.) 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 119 
Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows, 
when the subject also has measurable disease.  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the subject’s baseline lesions show PR or CR.  For example, necrosis of a liver 
lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is not. 
A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI of the brain 
which reveals metastases.  The subject’s brain metastases are considered to be evidence of PD 
even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy, and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan 
that indicated its presence. 
Evaluation of Best Overall Response 
The BOR is the best response recorded from the start of the study treatment until the EOT.  
Confirmatory measurement for CR or PR is [not] required in this study.  The subject’s BOR 
assignment will depend on the findings of both target and non-target disease and will also take 
into consideration the appearance of new lesions. 
Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 10.4 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 
All post-baseline scans must be anchored against the baseline scan. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 120 
Table 10.4: 
Time Point Response: Subjects With Target (+/–Non-Target) Disease 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
Stable disease 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; PD = progressive disease; SD = stable disease; and NE = not 
evaluable 
Missing Assessments and In-evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is NE at that 
time point.  If only a subset of lesion measurements is made at an assessment, usually the case is 
also considered NE at that time point, unless a convincing argument can be made that the 
contribution of the individual missing lesion(s) would not change the assigned time point 
response.  This would be most likely to happen in the case of PD.  For example, if a subject had a 
baseline sum of 50 mm with 3 measured lesions and at follow-up only 2 lesions were assessed, 
but those gave a sum of 80 mm, the subject will have achieved PD status, regardless of the 
contribution of the missing lesion. 
Best Overall Response: All Time Points 
The BOR is determined once all the data for the subject are known. 
Best response determination in studies where confirmation of complete or partial response IS 
NOT required: Best response in these studies is defined as the best response across all time 
points (for example, a subject who has SD at first assessment, PR at second assessment, and PD 
on last assessment has a BOR of PR).  When SD is believed to be best response, it must also 
meet the protocol-specified minimum time from baseline (within 4 weeks prior to the first dose 
of study drug), 7 weeks, in the case of scan intervals of 8 weeks (or “5 weeks”, in the case of 
scan intervals of 6 weeks.)  If the minimum time is not met when SD is otherwise the best time 
point response, the subject’s best response depends on the subsequent assessments.  For example, 
a subject who has SD at first assessment, PD at second and does not meet minimum duration for 
SD, will have a best response of PD.  The same subject lost to follow-up after the first SD 
assessment would be considered NE. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 121 
Table 10.5: 
Best Overall Response When Confirmation of CR and PR Required 
Overall response 
 
Overall response 
First time point 
Subsequent time point 
Best 
CR 
CR 
CR 
CR 
PR 
SD, PD or PR
a 
CR 
SD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, 
otherwise, PD 
NE 
NE 
NE 
CR = complete response; PR = partial response; SD = stable disease; NE = not evaluable; PD = progressive disease 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met.  However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not 
CR at the first time point.  Under these circumstances, the original CR should be changed to PR and the best 
response is PR. 
Source: Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1). Table 3. Euro J of Can. 2009:45;228-47 
Special Notes on Response Assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to ‘normal’ 
size (<10 mm), they may still have a measurement reported on scans.  This measurement should 
be recorded even though the nodes are normal in order not to overstate progression should it be 
based on increase in size of the nodes.  As noted earlier, this means that subjects with CR might 
not have a total sum of ‘0’ on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of T-DXd without 
objective evidence of disease progression at that time should be reported as ‘clinical 
progression.’  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study drug.  The objective response status of such subjects is 
to be determined by evaluation of target and non-target disease.  If a radiographic tumor 
assessment has not been performed within 4 weeks of the time of clinical progression, then 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 122 
another radiographic assessment should be performed without waiting for the next regularly 
scheduled scan. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment.  If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted at Screening, and then at the intervals 
specified, or sooner if clinically indicated.  The interval between scans is based on the last scan 
visit.  Tumor measurement will be performed during the EOT visit if it was not done within the 
previous 6 weeks or the previous assessment demonstrated disease progression. 
Baseline tumor assessments must be performed within 4 weeks prior to the first dose of study 
drug. 
All efforts should be made to ensure consistency between the baseline measurements and all 
subsequent measurements in reference to utilization of scanning method, equipment, technique 
(including slice thickness and field of view), and radiographic interpreter. 
The radiographic evaluation must include CT or MRI scanning of the chest, abdomen, and 
pelvis.  Any additional suspected sites of disease should also be imaged.  All evaluations should 
meet the standard of care for imaging of lesions in the respective organ(s) and should conform to 
the image acquisition guidelines according to institutional standards. 
All target and non-target sites are evaluated at each time point of tumor assessment. 
10.5. 
Appendix 6: General Information - Adverse Events 
10.5.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product.37  
It is the responsibility of Investigators, based on their knowledge and experience, to determine 
those circumstances or abnormal laboratory findings which should be considered AEs. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically relevant in the 
medical and scientific judgment of the Investigator (ie, not related to progression of 
underlying disease). 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 123 
 Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.   
Events NOT Meeting the AE Definition 
 Any clinically relevant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
 Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
10.5.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening 
 The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious.  When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline or for administration of anticancer therapy after 
discontinuation of study drug is not considered an AE. 
 Results in persistent or significant disability/incapacity 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 124 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
 Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These events should usually be 
considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Events Exempted from SAE Reporting 
Serious events that are also efficacy endpoints and/or safety endpoints will be exempted from 
SAE processing and expedited reporting.37  Disease progression should not be reported as an 
AE/SAE.  However, when a subject dies from PD with no other immediate causes, “disease 
progression” should be reported as an SAE and captured on designated eCRF.   
10.5.3. 
Grade Assessment 
The severity of AEs will be graded using the latest NCI-CTCAE (version 5.0).  For each episode, 
the highest severity grade attained should be reported. 
The NCI-CTCAE guidelines do not allow certain grades for certain AEs.  For example, pain can 
be Grade 1 to 3 only (ie, cannot be life-threatening or fatal), whereas sepsis can only be Grade 4 
or 5 (ie, can only be life-threatening or fatal).  In addition, alopecia can only be Grade 1 or 2.  
The NCI-CTCAE guidelines should be followed closely. 
 Grade 1: Mild AE 
 Grade 2: Moderate AE 
 Grade 3: Severe AE 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 125 
Difference Between Severity and Seriousness 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe MI); the event itself, however, may be of relatively minor medical 
significance (such as severe headache).  This is not the same as "serious," which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
10.5.4. 
Causality Assessment 
The Investigator should assess causal relationship between an AE and the study drug based on 
his/her clinical judgment and the following definitions.  The causality assessment must be made 
based on the available information and can be updated as new information becomes available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration 
and is a known reaction to the drug under study (or its chemical group) or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration or 
can be reasonably explained by the subject’s clinical state or other factors (eg, 
disease under study, concurrent diseases, and concomitant medications). 
10.5.5. 
Action Taken Regarding Study Drug 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Not Applicable: Subject died, study drug completed/permanently discontinued prior 
to reaction/event, or reaction/event occurred prior to start of treatment 
 Unknown: Subject is lost to follow-up 
10.5.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 126 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
10.5.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no sequelae observed. 
 Recovered/Resolved with Sequelae 
 The subject fully recovered from the AE but with sequelae. 
 Recovering/Resolving 
 The AE is improving but not recovered 
 Not Recovered/Not Resolved 
 The AE continues without improving. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE 
 Unknown 
10.6. 
Appendix 7: Instructions Related to Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2) 
Due to the potential impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 
on subject safety, the Sponsor recommends the following dose modification and management 
plan for subjects with confirmed or suspected SARS-CoV-2 while being treated with T-DXd.  
Dose modifications will be based on the worst CTCAE grade.  Use CTCAE version 5.0 general 
grading criteria to evaluate SARS-CoV-2.  All dose modifications (discontinuation, 
interruptions or reductions) must be recorded on the AE and drug administration eCRFs. 
Dose Modification Criteria for Suspected or Confirmed SARS-CoV-2 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF.  Dose 
modifications will be based on the worst CTCAE grade.  All interruptions or modifications must 
be recorded on the AE and drug administration eCRFs.  Please use CTCAE v5.0 general 
grading criteria to evaluate COVID-19. All dose modifications (discontinuation, interruptions 
or reductions) must be recorded on the AE and drug administration eCRFs. 
Dose Modification Criteria 
If SARS-CoV-2 infection is suspected, interrupt T-DXd and rule out SARS-CoV-2 per local 
guidance. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 127 
 If SARS-CoV-2 is ruled out, follow dose modification and management guidance as 
outlined in Table 6.3. 
 If SARS-CoV-2 is confirmed or diagnosis is still suspected after evaluation follow 
dose modification as outlined in Table 10.6 below and manage SARS-CoV-2 per 
local guidance until recovery of SARS-CoV-2.  SARS-CoV-2 recovery is defined as 
no signs/symptoms of SARS-CoV-2, at least 1 negative real-time reverse 
transcription polymerase chain reaction (RT-PCR) test result, and nearly or 
completely resolved chest CT findings. 
 If PCR testing is not available (locally/at the site), the subject must not have any 
sign/symptoms for at least 2 weeks, in addition to meeting the requirement for 
chest CT imaging to be considered recovered from SARS-CoV-2. 
Table 10.6: 
SARS-CoV-2 Dose Modification Criteria 
SARS-CoV-2 Worst Toxicity NCI-CTCAE Version 
5.0 Grade (unless otherwise specified) 
Schedule Modification for T-DXd 
Grade 1 
Resume study drug at the same dose 
Grade 2 
Resume study drug at the same dose if chest CT 
findings are completely resolved 
Reduce by 1 dose level if chest CT findings are nearly 
resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are 
completely resolved 
Discontinue study drug if chest CT findings are not 
completely resolved 
Grade 4 
Discontinue study drug 
SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; CT = computed tomography 
In addition to the recommendations outlined in Table 10.6, Investigators may consider dose 
modifications of the study drug according to the subject’s condition and after discussion with the 
study Medical Monitor or designee. 
If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline (Table 6.3). 
Prior and Concomitant Medications - Prohibited Therapies/Products 
 Chloroquine or hydroxychloroquine; 
 Concomitant treatment is not allowed during the study treatment (Section 6.6.1). 
 If treatment (with chloroquine or hydroxychloroquine) is absolutely required for 
SARS-CoV-2 T-DXd must be interrupted. 
 If administered, then a washout period of no less than 14 days is required before 
restarting T-DXd. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 128 
PK Assessment(s) if Chloroquine or Hydroxychloroquine is Administered 
Additional PK serum samples should be collected from each subject who provides consent, if 
chloroquine or hydroxychloroquine is administered for SARS-CoV-2 infection, at the time points 
specified in the SoE (Table 1.2 and Table 1.3). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood sample 
collection for PK analysis must be recorded on the eCRF. 
COVID-19 (SARS-CoV-2) Assessment(s) 
All confirmed or suspected SARS-CoV-2 infection events must be recorded in the eCRF.  If a 
subject presents to the clinic with symptoms suggestive of SARS-CoV-2, but the real-time 
RT-PCR test is not available (locally) at the site (the participant must not have any signs or 
symptoms of SARS-CoV-2 infection for at least 2 weeks and nearly or completely resolved chest 
CT findings), a nasopharyngeal swab/saliva sample kit will be provided for sample collection to 
be tested at a central laboratory).  The results will be provided to the site from the central 
laboratory. 
Serum samples will be used for SARS-CoV-2 testing from each subject who provides 
consent.  Samples will be collected prior to the study drug infusion, at the time points specified 
in the SoE (Table 1.3), shipped to a central laboratory, and stored there until the tests become 
available. 
If subjects provide consent, the remaining serum samples will also be stored for future analysis. 
Serum, nasopharyngeal swab/saliva, and PK sample collection, preparation, handling, storage, 
and shipping instructions are provided in the Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of COVID-19 (SARS-CoV-2) 
If deemed appropriate, analyses will be performed to explore the impact of SARS-CoV-2 on the 
safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of SARS-CoV-2 on study conduct, adjustments to the statistical 
analysis and interpretation will be made, if required.  These will be described in the SAP. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 129 
10.7. 
Appendix 8: Patient-Reported Outcomes 
10.7.1. 
EORTC QLQ-CR29 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 130 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 131 
10.7.2. 
EORTC QLQ-C30 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 132 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 133 
10.7.3. 
EQ-5D-5L 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 134 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 135 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 136 
10.7.4. 
PGI-TT 
 
10.7.5. 
PGIS 
 
10.7.6. 
PGIC 
 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 137 
11. 
REFERENCES 
1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN 
estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA 
Cancer J Clin. 2018;68:394–424. 
2. Watanabe T, Muro K, Ajioka Y, et al. Japanese Society for Cancer of the Colon and 
Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol. 
2018;23:1–34.  
3. NCCN Clinical Practice Guidelines in Oncology, Colon Cancer, Rectal Cancer Version 
2. Available from: https://www.nccn.org/professionals/physician_gls/f_guidelines.asp. 
4. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the 
management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386–
422. 
5. Siena S, Sartore-Bianchi A, Marsoni S, et al. Targeting the human epidermal growth 
factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018;29:1108–19. 
6. Nam SK, Yun S, Koh J, et al. BRAF, PIK3CA, and HER2 oncogenic alterations 
according to KRAS mutation status in advanced colorectal cancers with distant 
metastasis. PLoS One. 2016;11:e0151865. 
7. Sawada K, Nakamura Y, Yamanaka T, et al. Prognostic and predictive value of HER2 
amplification in patients with metastatic colorectal cancer. Clin Colorectal Cancer. 
2018;17:198–205. 
8. Bertotti A, Papp E, Jones S et al. The genomic landscape of response to EGFR blockade 
in colorectal cancer. Nature 2015; 526: 263–7. 
9. Leto SM, Trusolino L. Primary and acquired resistance to EGFR-targeted therapies in 
colorectal cancer: impact on future treatment strategies. J Mol Med (Berl). 2014; 92: 
709–22. 
10. Yonesaka K, Zejnullahu K, Okamoto I, et al. Activation of ERBB2 signaling causes 
resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011; 
3: 99ra86.  
11. Wang XY, Zheng ZX, Sun Y, et al. Significance of HER2 protein expression and HER2 
gene amplification in colorectal adenocarcinomas. World J Gastrointest Oncol. 
2019;11:335‐47.  
12. Richman SD, Southward K, Chambers P, et al. HER2 overexpression and amplification 
as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in 
the QUASAR, FOCUS and PICCOLO colorectal cancer trials. J Pathol. 2016;238:562–
70. 
13. Takegawa N, Yonesaka K. HER2 as an Emerging Oncotarget for Colorectal Cancer 
Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. Clin 
Colorectal Cancer. 2017;16:247–51. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 138 
14. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab 
and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive 
metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, 
phase 2 trial. Lancet Oncol. 2016;17(6):738–46. 
15. A Phase 1, Two-part, Multicenter, Non-randomized, Open-label, Multiple-dose, First-in-
human Study of DS-8201a, in Subjects with Advanced Solid Malignant Tumors. Daiichi 
Sankyo. Clinical Study Report. 17 Jul 2019; Study No.: DS8201-A-J101. 
16. A Phase 2 Multicenter, Open-label Study of DS-8201a, an Anti-HER2-Antibody Drug 
Conjugate (ADC) for HER2-positive, Unresectable and/or Metastatic Breast Cancer 
Subjects Previously Treated with T-DM1. Daiichi Sankyo. Clinical Study Report. 18 Jul 
2019; Study No.: DS8201-A-U201. 
17. USPI for Kadcyla (T-DM1). 2019 May [cited on 2019 May 03]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125427s105lbl.pdf 
18. Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients 
with advanced HER2-positive gastric cancer: a dose-expansion, phase 1 study. Lancet 
Oncol 2019;20:827–36. 
19. USPI for ENHERTU® (fam-trastuzumab deruxtecan-nxki), accessed on 20 Dec 2019  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf 
20. Ogitani Y, Hagihara K, Oitate M, et al. Bystander killing effect of DS-8201a, a novel 
anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with 
human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107:1039–46.  
21. Takegawa N, Tsurutani J, Kawakami H, et al. fam- Trastuzumab deruxtecan, antitumor 
activity is dependent on HER2 expression level rather than on HER2 amplification. Int J 
Cancer. 2019;145:3414–24. 
22. Martin V, Landi L, Molinari F, et al. HER2 gene copy number status may influence 
clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer 
patients. Br J Cancer. 2013;108:668–75. 
23. Jeong JH, Kim J, Hong YS, et al. HER2 Amplification and Cetuximab Efficacy in 
Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF. Clin 
Colorectal Cancer. 2017;S1533-0028(17)3003213.  
24. Meric-Bernstam F, Hurwitz H, Raghav KPS, et al. Pertuzumab plus trastuzumab for 
HER2-amplified metastatic colorectal cancer (MyPathway): an updated report from a 
multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2019;20:518–30. 
doi:10.1016/S1470-2045(18)30904-5. 
25. Salvatore S, Di Bartolomeo M, et al. A phase II, multicenter, open-label study of 
trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing 
metastatic colorectal cancer (mCRC): DESTINY-CRC01. Journal of Clinical Oncology. 
2020; 38. 4000-4000. 10.1200/JCO.2020.38.15_suppl.4000. 
26. Trastuzumab deruxtecan (DS-8201a) Investigator’s Brochure. Version 7.0. 31 Aug 2020. 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 139 
27. FDA. Guidance for Industry. Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics. December 2018. 
http://www.fda.gov/downloads/Drugs/.../Guidances/ucm071590.pdf 
28. Bartley, AN, Washington, MK, Ventura, CB, et al. HER2 testing and clinical decision 
making in gastroesophageal adenocarcinoma: guideline from the College of American 
Pathologists, American Society for Clinical Pathology, and American Society of Clinical 
Oncology. Arch Pathol Lab Med. 2016;140(12):1345-63. 
29. Food and Drug Administration. Guidance for industry: drug-induced liver injury: 
premarketing clinical evaluation. July, 2009. 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio 
n/Guidances/UCM072278.pdf 
30. Kluetz PG, O'Connor DJ, Soltys K. Incorporating the patient experience into regulatory 
decision making in the USA, Europe, and Canada. Lancet Oncol. 2018;19:e267–74. 
31. Herdman M, Gudex C, Lloyd A, et al. Development and preliminary testing of the new 
five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–6. 
32. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16:31–41. 
33. American heart Association. Classification of Functional Capacity and Objective 
Assessment, Ninth edition March 14, 1994. Available from: 
https://professional.heart.org/en/guidelines-and-statements/classification 
34. Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55. 
35. Heads of Medicines Agencies. Clinical Trial Facilitation Group (CTFG). 
Recommendations related to contraception and pregnancy testing in clinical trials. 
September 2014. Available from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
36. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Euro J Cancer. 2009:45;228–47. 
37. ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994. Available from: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Effica 
cy/E2A/Step4/E2A_Guideline.pdf 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 140 
12. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AC 
Adjudication Committee 
ADA 
anti-drug antibody 
ADC 
antibody-drug conjugate 
ADCC 
antibody-dependent cellular cytotoxic 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BI 
before infusion 
BICR 
blinded independent central review 
BOR 
best overall response 
BRAF 
v-raf murine sarcoma viral oncogene homologue B1 
CA19-9 
carbohydrate antigen 19-9 
CAP 
College of American Pathologists 
CBC 
complete blood count 
CBR 
clinical benefit rate 
CEA 
carcinoembryonic antigen 
cfDNA 
cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
cfRNA 
cell-free ribonucleic acid 
CHF 
congestive heart failure 
Cmax 
maximum concentration 
CLIA 
Clinical Laboratory Improvement Act 
COPD 
chronic obstructive pulmonary disease 
CQ 
chloroquine 
CR 
complete response  
CRC 
colorectal cancer 
CrCl 
creatinine clearance 
CRF 
case report form 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 141 
Abbreviation 
Definition 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
DAR 
drug-to-antibody ratio 
DCR 
disease control rate 
DoR 
duration of response 
dMMR 
deficient mismatch repair 
EC 
Ethics Committee 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EIU 
exposure in utero 
EOI 
end of infusion 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
End of Study 
EOT 
End of Treatment 
ePRO 
electronic patient-reported outcome 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
FU 
Follow-up 
GCP 
good clinical practice 
GEJ 
gastro-esophageal junction 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCQ 
hydroxychloroquine 
HCV 
hepatitis C virus 
HEOR 
health economic and outcomes research 
HER2 
human epidermal growth factor 2 
HIPAA 
Health Insurance Portability and Accountability Act 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 142 
Abbreviation 
Definition 
HIV 
human immunodeficiency virus 
HOSPAD 
Hospital Admission  
HRQoL 
health-related quality of life 
HRT 
hormone replacement therapy 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ICMJE 
International Council of Medical Journal Editors 
ICR 
independent central review 
ICU 
intensive care unit 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IMP 
investigational medicinal product 
INN 
international non-proprietary name 
INR 
international normalized ratio 
IRB 
institutional review board 
IRT 
interactive response technology 
ISH 
in situ hybridization 
ITT 
intent-to-treat 
IV 
intravenous 
JSCCR 
Japanese Society for Cancer of the Colon and Rectum 
KRAS 
Kirsten rat sarcoma viral oncogene homologue 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCCN 
National Comprehensive Cancer Network 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
not evaluable 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 143 
Abbreviation 
Definition 
NGS 
next-generation sequencing 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
PD 
progressive disease 
PD-(L)-1 
programmed death-ligand 1 
PET 
positron emission tomography 
PFS 
progression-free survival 
PGIC 
Patient Global Impression-Change 
PGIS 
Patient Global Impression-Severity 
PK 
pharmacokinetic 
PR 
partial response 
PS 
performance status 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
Q3M 
every 3 months 
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
QoL 
quality of life 
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RAS 
rat sarcoma viral oncogenes homologue 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors (version 1.1) 
RES 
Response Evaluable Set 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SID 
subject identifier 
SMQ 
Standardized MedDRA Query 

Protocol DS8201-A-U207 (DESTINY-CRC02) 
Version 1.0, 29 Oct 2020 
 
Proprietary and Confidential 
Page 144 
Abbreviation 
Definition 
SOC 
standard of care 
SoD 
sum of diameters 
SoE 
schedule of events 
SOP 
standard operating procedures 
SpO2 
peripheral oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
TBL 
total bilirubin 
T-DM1 
ado-trastuzumab emtansine 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum plasma concentration 
TMB 
tumor mutational burden 
TTD 
time to deterioration 
TTP 
time to progression 
TTR 
time to response 
t1/2 
half life 
ULN 
upper limit of normal 
US 
United States 
VAS 
visual analogue scale 
VEGF 
vascular endothelial growth factor  
WBC 
white blood cell 
WHO 
World Health Organization 
WHODrug 
World Health Organization drug dictionary