HERTHENA-Lung01: A Phase 2 Randomized Open-Label Study of Patritumab Deruxtecan (U3-1402) in Subjects With Previously Treated Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer (NSCLC)
Phase: PHASE2
Conditions: Non-Small Cell Lung Cancer Metastatic, Non-Small Cell Lung Cancer With Mutation in Epidermal Growth Factor Receptor
Sponsor: Daiichi Sankyo

CLINICAL STUDY PROTOCOL 
HERTHENA-Lung01:  A Phase 2 Randomized Open-Label 
Study of Patritumab Deruxtecan (U3-1402) in Subjects with 
Previously Treated Metastatic or Locally Advanced EGFR-
mutated Non-Small Cell Lung Cancer (NSCLC) 
(Patritumab Deruxtecan in Subjects with Metastatic or Locally 
Advanced EGFR-mutated NSCLC) 
 
PROTOCOL NUMBER: U31402-A-U201 
 
IND NUMBER 133343 
EudraCT NUMBER 2020-000730-17  
 
VERSION 3.0, 31 Mar 2021 
 
DAIICHI SANKYO, INC 
211 Mt. Airy Road 
Basking Ridge, NJ 07920 United States 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc.  The information is 
provided to you in confidence, which is requested under an agreed upon and signed 
Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it or reveal 
any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
Daiichi Sankyo, Inc. 

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INVESTIGATOR AGREEMENT 
HERTHENA-Lung01:  A Phase 2 Randomized Open-Label Study of Patritumab 
Deruxtecan (U3-1402) in Subjects with Previously Treated Metastatic or Locally Advanced 
EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) 
Sponsor Approval: 
This clinical study protocol has been reviewed and approved by the Daiichi Sankyo, Inc
representative listed below.
Print Name
Signature
, Global Oncology Research 
and Development 
Title
Date (DD MMM YYYY)
Investigator$
4-B12A88E05?/A??10@41;.61/@5B1?;2@45??@A0E-:0@41/;:@1:@?;2@45?<>;@;/;8C5@4@41'<;:?;>O?
representative.
I understand that information contained in or pertaining to this protocol is confidential and should not 
be disclosed, other than to those directly involved in the execution or the ethical review of the study, 
without written authorization from the Sponsor.  It is, however, permissible to provide information to 
a subject in order to obtain consent. 
I agree to conduct this study according to this protocol and to comply with its requirements, subject 
to ethical and safety considerations and guidelines, and to conduct the study in accordance with 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) Guideline for Good Clinical Practice (ICH E6[R2]), which has its foundations in the 
Declaration of Helsinki, and applicable regional regulatory requirements.
I agree to make available to Sponsor personnel, their representatives and relevant regulatory 
-A@4;>5@51?9E?A.61/@?O?@A0E>1/;>0?5:;>01>@;B1>52E@410-@-@4-@4-B11:@1>105:@;@41/-?1
report forms.  I am aware of my responsibilities as a Principal Investigator as provided by the 
Sponsor.
I understand that the Sponsor may decide to suspend or prematurely terminate the study at any time 
for whatever reason; such a decision will be communicated to me in writing.
Conversely, should I decide to withdraw from execution of the study, I will communicate my 
intention immediately in writing to the Sponsor.
Print Name
Signature
Title
Date (DD MMM YYYY)
ved by the Daiichi Sankyo, Inc
re
D MMM YYYY)
/;:@1:@?;2@45?<>;@;/;8C5@4@41
PPD
PPD
PPD
31 Mar 2021

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DOCUMENT HISTORY 
Version Number 
Version Date 
3.0 
31 Mar 2021 
2.0 
20 Nov 2020 
1.0 
26 Jun 2020 
 

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SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 3.0 (dated 31 Mar 2021) vs. 
protocol Version 2.0 (dated 20 Nov  2020) for actual changes in text.  The summary of changes 
below is a top-line summary of major changes in the current U31402-A-U201 clinical study 
protocol (Version 3.0) by section. 
Amendment Rationale: 
The primary purpose of this amendment is 
 1) to 
ensure that at least 80% of the total randomized/enrolled subjects have received prior osimertinib 
treatment 
 
 for consistency with current standard of care in the US and 2) to ensure that subjects enrolled 
in South Korea known to harbor a clinically actionable genomic alteration in addition to 
epidermal growth factor receptor (EGFR) mutation have received at least 1 approved genotype-
directed therapy per local standard of care 
 
.  
The identified risks for patritumab deruxtecan were updated to include hypokalemia, febrile 
neutropenia, and epistaxis.  The amendment includes revised specifications regarding pregnancy 
assessments and urinalysis. 
Other minor editorial changes were made to enhance clarity. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (Section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in this Summary of Changes document. 
Minor edits, such as update to text that does not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of 
abbreviations, moving verbiage within a section or table, change in style, or change in case, are 
not noted in the table below. 
Section # and Title 
Description of Change 
Brief Rationale 
1.1. Protocol Synopsis 
Figure 1.1 Study Level 
Flow Diagram 
5.1. Inclusion Criteria 
Starting after local approval of this 
amendment, prior osimertinib treatment is 
required for eligibility.  
To address recommendation from 
the US Food and Drug 
Administration and for consistency 
with current standard of care in the 
US. 
1.1. Protocol Summary 
5.1. Inclusion Criteria 
The following text was added to inclusion 
criterion: Subjects known to harbor a 
clinically actionable genomic alteration in 
addition to EGFR mutation (eg, anaplastic 
lymphoma kinase [ALK] or ROS protocol-
oncogene 1 [ROS1] fusion) for which 
treatment is available must have also 
received prior treatment with at least 1 
approved genotype-directed therapy, 
unless unable (ie, if contraindicated).  No 
new testing for these genomic alterations 
To ensure that subjects in South 
Korea known to harbor a clinically 
actionable genomic alteration in 
addition to EGFR mutation have 
received at least 1 approved 
genotype-directed therapy per local 
standard of care.  
CCI
CCI
CCI

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Section # and Title 
Description of Change 
Brief Rationale 
(eg, ALK or ROS1 fusion) is required for 
Screening. 
1.3 Schedule of Events 
Table 1.1 
 
The time frame for the urinalysis 
Screening assessment was changed from 
72 hours prior to Cycle 1 Day 1 to 28 days 
prior to Cycle 1 Day 1. 
To clarify the schedule of urinalysis 
assessment. 
1.3 Schedule of Events, 
Table 1.1 
The following text was deleted: HIV 
antibody test is optional unless required by 
local regulations or IRB/ECs. The 
following text was revised: If required by 
local regulations, perform within 28 days 
prior to Cycle 1 Day 1,  
To clarify the requirement of HIV 
antibody testing. 
1.3. Schedule of Events 
Table 1.1 
8.4.2. Pregnancy 
Specified serum pregnancy testing at 
Screening should be performed within 
28 days prior to Cycle 1 Day 1; a urine or 
serum pregnancy test per institutional 
guidelines should be performed within 
72 hours prior to infusion of each cycle 
(including prior to Cycle 1 Day 1) for all 
female subjects of childbearing potential.  
If a urine pregnancy test result is positive, 
it must immediately be confirmed using a 
serum pregnancy test.  Results are required 
prior to administration of study treatment.  
Cycle 1 Day 1 assessment does not need to 
be repeated if Screening assessment was 
performed within 72 hours prior to Cycle 1 
Day 1 infusion. 
To clarify the schedule of 
pregnancy testing. 
2.3. Benefit and Risk 
Assessment 
Revised text to align with Investigator’s 
Brochure (IB) Version 8.0.  Specifically, 
identified risks were updated to include 
hypokalemia, febrile neutropenia, and 
epistaxis. 
To align with IB Version 8.0. 
10.3.4. Highly Effective 
Contraception 
11. References 
Revised the following text regarding 
abstinence from “Complete sexual 
abstinence” to “True abstinence: when this 
is in line with the preferred and usual 
lifestyle of the subject” and updated 
reference for Clinical Trial Facilitation 
Group (CTFG).  Recommendations related 
to contraception and pregnancy testing in 
clinical studies to the most current version. 
To align with current 
recommendation on true abstinence 
based on CTFG.  Recommendations 
related to contraception and 
pregnancy testing in clinical studies 
to the most current version. 
10.5.2. Serious Adverse 
Event 
Specified that disease progression is also 
an efficacy endpoint and should not be 
reported as an adverse event/serious 
adverse event (SAE).  However, when a 
death occurs due to disease progression 
with no other immediate cause, then 
disease progression should be reported as 
an SAE and should be recorded in the 
To clarify the events that are 
exempt from SAE processing and 
expedited reporting.  

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Section # and Title 
Description of Change 
Brief Rationale 
designated electronic case report form; in 
this circumstance, the SAE will be 
processed and reported as per local 
regulatory requirements and institutions, as 
applicable. 
10.7. Instructions Related to 
Coronavirus Disease 2019 
(COVID-19) 
Revised text pertaining to the management 
of subjects with suspected or confirmed 
COVID-19 infection. 
To clarify the management of 
subjects with suspected or 
confirmed COVID-19 infection. 
 

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TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
1. 
PROTOCOL SUMMARY ............................................................................................13 
1.1. 
Protocol Synopsis ..........................................................................................................13 
1.2. 
Study Schema ................................................................................................................23 
1.3. 
Schedule of Events ........................................................................................................24 
2. 
INTRODUCTION ........................................................................................................39 
2.1. 
Background ...................................................................................................................39 
2.2. 
Study Rationale .............................................................................................................40 
2.3. 
Benefit and Risk Assessment ........................................................................................43 
3. 
OBJECTIVES, OUTCOME MEASURES, AND ENDPOINTS .................................44 
3.1. 
Rationale for Selection of Primary and Key Secondary Endpoints ..............................48 
4. 
STUDY DESIGN ..........................................................................................................49 
4.1. 
Overall Design ..............................................................................................................49 
4.1.1. 
Design Overview ...........................................................................................................49 
4.1.2. 
End of Study ..................................................................................................................51 
4.1.3. 
Dose Regimen(s) ...........................................................................................................52 
4.1.4. 
Duration.........................................................................................................................52 
4.2. 
Rationale for Study Design ...........................................................................................52 
4.3. 
Justification for Dose Regimen(s) .................................................................................53 
5. 
STUDY POPULATION ...............................................................................................56 
5.1. 
Inclusion Criteria ...........................................................................................................56 
5.2. 
Exclusion Criteria..........................................................................................................58 
5.3. 
Screening Failures, Rescreening, and Subject Replacement ........................................60 
6. 
STUDY TREATMENT(S) ...........................................................................................61 
6.1. 
Study Drug(s) Description ............................................................................................61 
6.2. 
Preparation, Handling, Storage, and Accountability for Study Drug(s) .......................61 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ..........................................62 
6.4. 
Treatment Compliance ..................................................................................................63 
6.5. 
Guidelines for Dose Modification .................................................................................63 

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6.6. 
Prior and Concomitant Medications..............................................................................75 
7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION FROM 
THE STUDY .................................................................................................................77 
7.1. 
Discontinuation of Study Drug .....................................................................................77 
7.2. 
Subject Withdrawal/Discontinuation from the Study ...................................................78 
7.3. 
Lost to Follow-up ..........................................................................................................79 
8. 
STUDY PROCEDURES ..............................................................................................80 
8.1. 
Eligibility Assessment ...................................................................................................80 
8.2. 
Randomization/Enrollment ...........................................................................................82 
8.3. 
Efficacy Assessments ....................................................................................................82 
8.4. 
Safety Assessments .......................................................................................................84 
8.4.1. 
Adverse Event ...............................................................................................................84 
8.4.1.1. 
Serious Adverse Events Reporting................................................................................85 
8.4.1.2. 
Adverse Events of Special Interest ...............................................................................87 
8.4.2. 
Pregnancy ......................................................................................................................88 
8.4.3. 
Clinical Laboratory Evaluations ...................................................................................89 
8.4.4. 
Other Safety ..................................................................................................................89 
8.5. 
Pharmacokinetic (PK) Assessment(s) ...........................................................................90 
8.5.1. 
Immunogenicity ............................................................................................................91 
8.6. 
Pharmacodynamic Assessment(s) .................................................................................91 
8.7. 
Biomarker Assessment(s)..............................................................................................91 
8.7.1. 
Biomarker Assessments in Blood Samples ...................................................................91 
8.7.2. 
Biomarker Assessments in Tissue .................................................................................92 
8.8. 
Pharmacogenomic (Inherited Genetic) Analysis ..........................................................93 
8.8.1. 
Banking of Specimens for Inherited Genetic Analysis .................................................93 
9. 
STATISTICAL CONSIDERATIONS ..........................................................................95 
9.1. 
General Statistical Considerations ................................................................................95 
9.2. 
Statistical Hypothesis ....................................................................................................95 
9.3. 
Sample Size Determination ...........................................................................................95 
9.4. 
Population for Analysis Sets .........................................................................................96 
9.5. 
Statistical Analysis ........................................................................................................97 
9.5.1. 
Efficacy Analyses..........................................................................................................97 
9.5.1.1. 
Primary Efficacy Analyses ............................................................................................97 

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9.5.1.2. 
Secondary Efficacy Analyses ........................................................................................97 
9.5.1.3. 
Exploratory Analyses ....................................................................................................98 
9.5.1.4. 
Multiplicity Adjustment ................................................................................................98 
9.5.2. 
Safety Analyses .............................................................................................................98 
9.5.3. 
Other Analyses ............................................................................................................100 
9.6. 
Interim Analyses .........................................................................................................101 
10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS .....................................................................102 
10.1. 
Appendix 1: Regulatory and Ethical Considerations ..................................................102 
10.1.1. 
Regulatory Compliance ...............................................................................................102 
10.1.2. 
Informed Consent ........................................................................................................103 
10.1.3. 
Subject Confidentiality................................................................................................104 
10.1.4. 
Data Integrity and Quality Assurance .........................................................................104 
10.1.5. 
Committees .................................................................................................................106 
10.1.6. 
Study Documentation and Storage ..............................................................................107 
10.1.7. 
Finances.......................................................................................................................108 
10.1.8. 
Publication and Public Disclosure Policy ...................................................................108 
10.1.9. 
Protocol Deviations .....................................................................................................109 
10.1.10. Study and Site Closure ................................................................................................109 
10.1.11. Product Complaints .....................................................................................................110 
10.2. 
Appendix 2: Central and/or Local Laboratory ............................................................110 
10.3. 
Appendix 3: Reference Standards ...............................................................................111 
10.3.1. 
Cockcroft-Gault Equation ...........................................................................................111 
10.3.2. 
New York Heart Association (NYHA) .......................................................................111 
10.3.3. 
Eastern Cooperative Oncology Group (ECOG) Performance Status .........................112 
10.3.4. 
Highly Effective Contraception ..................................................................................112 
10.4. 
Appendix 4: Response Criteria ...................................................................................113 
10.5. 
Appendix 5: General Information - Adverse Events...................................................120 
10.5.1. 
Definition of Adverse Event .......................................................................................120 
10.5.2. 
Serious Adverse Event ................................................................................................122 
10.5.3. 
Grade Assessment .......................................................................................................123 
10.5.4. 
Causality Assessment ..................................................................................................123 
10.5.5. 
Action Taken Regarding Study Drug(s) .....................................................................124 

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10.5.6. 
Other Action Taken for Event .....................................................................................124 
10.5.7. 
Adverse Event Outcome .............................................................................................124 
10.6. 
Appendix 6: Key Data Analysis Requirements ..........................................................125 
10.7. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) ................................125 
11. 
REFERENCES ............................................................................................................129 
12. 
LIST OF ABBREVIATIONS .....................................................................................133 
 

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LIST OF TABLES 
Table 1.1: Schedule of Events for Screening and Cycles 1 through 3 of the Treatment 
Period ..........................................................................................................................24 
Table 1.2: Schedule of Events for Cycle 4 and Subsequent Cycles of the Treatment 
Period, End of Treatment, and Follow-up Period .......................................................33 
Table 2.1: Treatment-emergent Adverse Events Occurring in Greater than 20% of 
Subjects in Ongoing Study U31402-A-U102 .............................................................42 
Table 3.1: Description of Objectives, Outcome Measures, and Endpoints .................................44 
Table 4.1: Subjects Treated and Planned by Dose Regimen .......................................................54 
Table 4.2: Preliminary Data by Dose Regimen in Subjects with HER3-positive Breast 
Cancer in Study U31402-A-J101................................................................................55 
Table 6.1: Study Drug Dosing Information .................................................................................61 
Table 6.2: Dose Reductions for the Fixed Dose 5.6 mg/kg Regimen ..........................................64 
Table 6.3: Dose Reductions for the Up-titration Dose Regimen .................................................64 
Table 6.4: Dose Modifications for Non-Hematologic and Hematologic Toxicity Related 
to Patritumab Deruxtecan ...........................................................................................64 
Table 9.1: Exact 95% Confidence Intervals for Sample Size of 210 Subjects at Various 
Observed ORRs ..........................................................................................................96 
Table 10.1: Clinical Laboratory Tests .........................................................................................110 
Table 10.2: New York Heart Association Classifications ...........................................................112 
Table 10.3: Eastern Cooperative Oncology Group Performance Status ......................................112 
Table 10.4: Time Point Response: Subjects With Target (±Non-Target) Disease ......................118 
Table 10.5: Best Overall Response When Confirmation of CR and PR Required ......................119 
Table 10.6: Key Data Requirements ............................................................................................125 
Table 10.7: COVID-19 Dose Modification Criteria ....................................................................127 
 

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LIST OF FIGURES 
Figure 1.1: Study Level Flow Diagram .........................................................................................23 
Figure 2.1: Patritumab Deruxtecan Inhibits Tumor Growth in HER3-expressing 
EGFR-mutant EGFR TKI-resistant PDX Models ......................................................41 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Protocol Synopsis 
Protocol Title 
HERTHENA-Lung01: A Phase 2 Randomized Open-Label Study of Patritumab Deruxtecan (U3-1402) in 
Subjects with Previously Treated Metastatic or Locally Advanced EGFR-mutated Non-Small Cell Lung Cancer 
(NSCLC) 
Protocol Short Title 
Patritumab Deruxtecan in Subjects with Metastatic or Locally Advanced EGFR-mutated NSCLC 
Protocol Number 
U31402-A-U201 
Sponsor/Collaborators 
Sponsor: Daiichi Sankyo, Inc. 
Registry Identification(s) 
EudraCT Number: 2020-000730-17 
IND Number 
IND Number 133343 
Study Phase 
Phase 2 
Planned Geographical Coverage, Study Sites and Location 
Global study at approximately 135 study sites located in North America, the European Union, and Asia Pacific 
region including Japan 
Study Population 
Subjects with metastatic or locally advanced NSCLC with an activating epidermal growth factor receptor 
[EGFR] mutation (exon 19 deletion or L858R) and who progressed during/after systemic treatment with at least 
1 platinum-based chemotherapy regimen and at least 1 EGFR-tyrosine kinase inhibitor (TKI) 
Study Objectives/Outcome Measures and Endpoints 
The table below lists primary and secondary study objectives and endpoints with outcome measures. 
Objectives 
Outcome Measure 
Endpoints 
Category 
Primary 
 
 
 
To investigate the 
antitumor activity of 
patritumab deruxtecan 
in subjects with 
metastatic or locally 
advanced NSCLC 
with an activating 
EGFR mutation (exon 
19 deletion or L858R) 
Title: ORR  
Description: ORR as 
assessed by BICR per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, 
ORR is defined as the 
proportion of subjects 
with a BOR of 
confirmed CR or 
confirmed PR.   
Efficacy 

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or withdrawal by the 
subject.   
Secondary 
 
 
 
To investigate the 
durability of 
patritumab deruxtecan 
antitumor activity in 
subjects with 
metastatic or locally 
advanced NSCLC 
with an activating 
EGFR mutation (exon 
19 deletion or L858R) 
Title: DoR 
Description: DoR as 
assessed by BICR and 
Investigator per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, 
or withdrawal by the 
subject. 
DoR is defined as the 
time from the first 
documented response 
(confirmed CR or 
confirmed PR) to the 
date of progression or 
death due to any cause. 
Efficacy 
To further investigate 
the antitumor activity 
of patritumab 
deruxtecan in subjects 
with metastatic or 
locally advanced 
NSCLC with an 
activating EGFR 
mutation (exon 19 
deletion or L858R) 
 
 
Title: PFS 
Description: PFS as 
assessed by BICR and 
Investigator per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, 
or withdrawal by the 
subject. 
Death date is collected 
until the subject 
discontinues the study. 
PFS is defined as the 
time from the start of 
study treatment to the 
earlier of the dates of 
the first documentation 
of objective PD or 
death due to any cause.   
Efficacy 
Title: ORR 
Description: ORR as 
assessed by 
Investigator per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression, death, lost 
to follow-up, or 
withdrawal by the 
subject. 
ORR is defined as the 
proportion of subjects 
with a BOR of 
confirmed CR or 
confirmed PR.   
Efficacy 

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Title: DCR 
Description: DCR as 
assessed by BICR and 
Investigator per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, 
or withdrawal by the 
subject. 
DCR is defined as the 
proportion of subjects 
who achieved a BOR 
of confirmed CR, 
confirmed PR, or SD.   
Efficacy 
Title: TTR 
Description: TTR as 
assessed by BICR and 
Investigator per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, 
or withdrawal by the 
subject. 
TTR is defined as the 
time from the start of 
study treatment to the 
date of the first 
documentation of 
response (confirmed 
CR or confirmed PR).   
Efficacy 
 
Title: Best percentage 
change in the SoD of 
measurable tumors 
Description: SoD as 
assessed by BICR and 
by Investigator per 
RECIST V1.1 
Time frame: Data are 
collected at baseline, 
then from the start of 
study treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, 
or withdrawal by the 
subject. 
The best percentage 
change in the SoD of 
measurable tumors is 
defined as the 
percentage change in 
the smallest SoD from 
all post-baseline tumor 
assessments, taking as 
reference the baseline 
SoD. 
Efficacy 
 
Title: OS 
Description: OS  
Time frame: Death 
date is collected until 
the subject discontinues 
the study. 
OS is defined as the 
time from the start of 
study treatment to the 
date of death due to 
any cause. 
Efficacy 

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To assess the safety 
and tolerability of 
patritumab deruxtecan 
in subjects with 
metastatic or locally 
advanced NSCLC 
with an activating 
EGFR mutation (exon 
19 deletion or L858R) 
Title: Safety 
parameters during the 
study* 
Description: 
Descriptive statistics of 
safety endpoints  
Time frame: From the 
time the subject signs 
the main study ICF and 
up to 40 (+ 7) days 
after the last dose of 
study drug (ie, 5 half-
lives of the ADC/the 
follow-up period) 
*Although this is a 
secondary objective, 
this is a primary 
outcome measure. 
Incidence of TEAEs, 
SAEs, AESIs (ILD and 
elevation of 
aminotransferases and 
TBL), ECOG PS, vital 
sign measurements, 
standard clinical 
laboratory parameters 
(hematology, serum 
chemistry, and 
urinalysis), ECG 
parameters, 
ECHO/MUGA scan 
findings, and 
ophthalmologic 
findings.  AEs and 
laboratory test results 
will be coded using the 
most recent version of 
MedDRA and will be 
graded using NCI-
CTCAE v5.0. 
Safety 
To evaluate HER3 
protein expression in 
tumor tissue and its 
relationship with 
efficacy 
Title: Correlation 
between HER3 protein 
expression (as 
determined by HER3 
IHC assay) and 
efficacy 
Description: 
Descriptive summary 
of HER3 status, and a 
correlative analysis 
between HER3 protein 
expression level and 
efficacy 
Time frame: Efficacy 
data are collected at 
baseline, then from the 
start of study treatment 
until documented 
disease progression by 
BICR, death, lost to 
follow-up, or 
withdrawal by the 
subject. 
HER3 data are 
collected at baseline 
(biopsy). 
HER3 protein 
expression in tumor 
tissue (as determined 
by IHC) and 
correlation with ORR, 
DoR, and PFS 
Efficacy/Biomarker 
To assess the 
immunogenicity 
incidence against 
patritumab deruxtecan 
Title: Immunogenicity 
Description: ADA 
prevalence, incidence 
ADA prevalence: the 
proportion of all 
subjects having a 
confirmed positive 
Immunogenicity 

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and titer for patritumab 
deruxtecan. 
Time frame: Data are 
collected from the start 
of study treatment until 
documented disease 
progression.  
Additional time points 
are specified in 
Table 1.1 and 
Table 1.2. 
ADA sample at any 
point in time. 
ADA incidence: the 
proportion of subjects 
having treatment-
emergent ADA. 
ADA titer will be 
determined for 
confirmed ADA 
positive samples. 
Neutralizing 
antibodies: when 
neutralizing assay 
became available 
confirmed ADA 
positive samples may 
be analyzed for 
neutralizing activity. 
ADA = anti-drug antibody; ADC = antibody drug conjugate; AE = adverse event; AESI = adverse event of 
special interest; BICR = blinded independent central review; BOR = best overall response; CR = complete 
response; CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; DoR = 
duration of response; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative 
Oncology Group performance status; EGFR = epidermal growth factor receptor; EOT = End of Treatment; 
HER3 = human epidermal growth factor receptor 3; ICF = informed consent form; IHC = 
immunohistochemistry; ILD = interstitial lung disease; MedDRA = Medical Dictionary for Regulatory 
Activities; mRNA = messenger ribonucleic acid; MUGA = multigated acquisition; NCI = National Cancer 
Institute; NSCLC = non-small cell lung cancer; ORR = objective response rate; OS = overall survival; PFS = 
progression-free survival; PR = partial response; RECIST v1.1 = Response Evaluation Criteria in Solid Tumors 
version 1.1; SAE = serious adverse event; SD = stable disease; SoD = sum of diameters; TBL = total bilirubin; 
TEAE = treatment-emergent adverse event; TTR = time to response; v = version. 
Study Design 
This is a global, multicenter, open-label, Phase 2 study of subjects with metastatic or locally advanced NSCLC 
with an EGFR-activating mutation (exon 19 deletion or L858R) who have received and progressed on or after at 
least 1 EGFR TKI and 1 platinum-based chemotherapy-containing regimen.  This study will initially randomize 
subjects to one of 2 arms in a 1:1 ratio, for dose selection, to receive either a 5.6 mg/kg fixed dose regimen 
(Arm 1) or an up-titration dose regimen (Cycle 1: 3.2 mg/kg; Cycle 2: 4.8 mg/kg; Cycle 3 and subsequent 
cycles: 6.4 mg/kg; Arm 2) of patritumab deruxtecan (HER3-DXd; U3-1402) on Day 1 of each 21-day cycle.   
In the ongoing U31402-A-U102 study, the same population is being studied in multiple expansion cohorts: 
Cohort 3a and 3b (with 45 subjects planned to be randomized to each dose regimen, 5.6 mg/kg every 3 weeks 
[Q3W] or up-titration) and Cohort 1 (45 subjects dosed with 5.6 mg/kg Q3W).  If, during the conduct of the 
current study (U31402-A-U201), analyses from the U31402-A-U102 study indicate that one dose regimen 
provides clear advantages over the other in terms of benefit/risk, further enrollment into one arm may be 
discontinued.   
 
If a single dose regimen (Arm 1 or Arm 2) is selected to continue enrollment, subjects enrolled after the 
decision point will be assigned to the selected dose regimen.  Subjects enrolled before the decision point 
will continue their originally assigned dose regimen without crossover.   
 
If there is no significant difference in efficacy and/or safety from the U31402-A-U102 NSCLC study, both 
dose regimens/arms in this study (U31402-A-U201) will continue to enroll to study completion.  

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The study will be divided into 3 periods: the Screening Period, Treatment Period, and Follow-up Period.   
 
The Screening Period will start on the day of signing the main informed consent form (ICF) and will have a 
maximum duration of 35 days.  The study will allow rescreening once for any subject who failed to meet 
eligibility criteria upon initial Screening or whose Screening window has elapsed. 
 
Eligible subjects will be enrolled and enter the Treatment Period.  The Treatment Period starts on the day of 
enrollment (ie, Cycle 1 Day 1) and continues until a subject permanently discontinues patritumab 
deruxtecan.  To minimize the possibility of developing tumor flare with discontinuation of EGFR TKI, 
subjects who fulfill eligibility criteria and are receiving an EGFR TKI at the time of informed consent 
should be instructed to continue their current EGFR TKI until 5 days prior to Cycle 1 Day 1.  Radiographic 
assessment of tumor response will be performed based on Response Evaluation Criteria in Solid Tumors 
(RECIST) version (v) 1.1 every 6 weeks (± 7 days) from Cycle 1 Day 1 for the first 24 weeks then every 
12 weeks (±7 days) thereafter, independent of treatment cycle, until documented disease progression by 
blinded independent central review (BICR per RECIST v1.1), death, lost to follow-up, or withdrawal of 
consent.   
Subjects will continue to receive patritumab deruxtecan until documented disease progression per RECIST 
v1.1, clinical progression, unacceptable toxicity, withdrawal of consent by the subject, physician’s decision, 
protocol deviation, pregnancy, lost to follow-up, study termination by the Sponsor, death, or other reasons.  
If progressive disease is suspected by Investigator tumor assessment, imaging must be submitted to BICR 
for expedited confirmation of disease progression.  The decision to discontinue patritumab deruxtecan is 
according to Investigator judgement and should consider BICR assessment. 
 
The Follow-up Period will start upon permanent discontinuation of patritumab deruxtecan.  After 
completion of the 40-day (+7 days) safety Follow-up Visit, subjects will be followed every 3 months for 
survival.   
The primary completion date will occur when all subjects have either a minimum of 9 months follow-up or 
have discontinued from the study earlier.  This date is used as the data cut-off (DCO) date for the primary 
analysis of the study.  All subjects still on treatment and continuing to derive benefit from patritumab 
deruxtecan at the primary completion date will continue to follow the study Schedule of Events (SoE) 
(Table 1.2) until the overall End of Study (EOS) is reached.  The overall EOS will occur after the last subject 
last visit has occurred, when all subjects have discontinued treatment and discontinued long-term survival 
follow-up or have died, an alternative study becomes available for subjects continuing to derive benefit from 
treatment with patritumab deruxtecan where the study drug is offered to these subjects, or the study is 
discontinued by the Sponsor for other reasons (administrative, program-level or class-related). 
See Figure 1.1 for the study flow diagram. 
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 portion of the study when the Investigator or designee has obtained written 
informed consent, has confirmed all inclusion and exclusion criteria have been met by the subject, and all 
Screening procedures have been completed.   
Anticipated total duration of the study is expected to be 26 months consisting of approximately 12 months for 
enrollment and 14 months on treatment.  The study will continue until the overall EOS is reached. 
Key Eligibility Criteria 
Key Inclusion Criteria: 
Subjects must meet all of the following criteria to be eligible for inclusion in this study.  Below is a list limited 
to the key inclusion criteria: 
 
Histologically or cytologically documented locally advanced or metastatic NSCLC not 
amenable to curative surgery or radiation. 
 
Documentation of radiological disease progression while on/after receiving most recent 
treatment regimen for locally advanced or metastatic disease.  Subjects must have received 
both of the following: 

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 Prior treatment with osimertinib.  Subjects receiving an EGFR TKI at the time of signing 
informed consent should continue to take the EGFR TKI until 5 days prior to Cycle 1 
Day 1.   
 
       Subjects in South Korea known to harbor a clinically actionable genomic alteration in 
addition to EGFR mutation (eg, anaplastic lymphoma kinase [ALK] or ROS1 protocol 
oncogene 1 [ROS1] fusion) for which treatment is available must have also received 
prior treatment with at least 1 approved genotype-directed therapy, unless unable (eg, if 
contraindicated).  No new testing for these genomic alterations (eg, ALK or ROS1 
fusion) is required for Screening. 
 Systemic therapy with at least 1 platinum-based chemotherapy regimen. 
 
Documentation of an EGFR-activating mutation detected from tumor tissue or blood sample: 
exon 19 deletion or L858R.   
 
At least 1 measurable lesion confirmed by BICR as per RECIST v1.1 (see Section 10.4) 
 
Consented and willing to provide required tumor tissue of sufficient quantity (as defined in the 
Laboratory Manual) and of adequate tumor tissue content (as confirmed by hematoxylin and eosin 
[H&E] staining at the central laboratory).  Required tumor tissue can be provided as either:  
 Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and amenable to 
core biopsy OR 
 Archival tumor tissue collected from a biopsy performed within 3 months prior to signing of 
the tissue consent and since progression while on or after treatment with the most recent 
cancer therapy regimen.   
 
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at Screening (see 
Section 10.3.3). 
 
Has adequate bone marrow reserve and organ function based on local laboratory data within 
14 days prior to Cycle 1 Day 1: 
Laboratory Test 
Laboratory Value 
Platelet count 
≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed 
up to 14 days prior to Cycle 1 Day 1 to meet eligibility) 
Hemoglobin 
≥9.0 g/dL (transfusion and/or growth factor support is allowed) 
Absolute neutrophil count 
≥1500/mm3 or ≥1.5 × 109/L 
Serum creatinine OR 
creatinine clearance 
SCr ≤1.5 × ULN, OR CrCl ≥30 mL/min as calculated using the 
Cockcroft-Gault equation or measured CrCl  
Aspartate aminotransferase/ 
Alanine aminotransferase 
≤3 × ULN (if liver metastases are present, ≤5 × ULN) 
Total bilirubin 
≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of 
documented Gilbert’s syndrome [unconjugated hyperbilirubinemia] or 
liver metastases) 
Serum albumin 
≥2.5 g/dL 
PT or PT-INR and aPTT/PTT 
≤1.5 × ULN, except for subjects on coumarin-derivative 
anticoagulants or other similar anticoagulant therapy, who must have 
PT-INR within therapeutic range as deemed appropriate by the 
Investigator 
aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; INR = international normalized ratio; 
PT = prothrombin time; PTT = partial thromboplastin time; SCr = serum creatinine; ULN = upper limit of 
normal. 

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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: 
 
Any previous histologic or cytologic evidence of small cell OR combined small cell/non-small 
cell disease in the archival tumor tissue or pretreatment tumor biopsy.   
 
Any history of interstitial lung disease (including pulmonary fibrosis or radiation 
pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such disease 
by imaging during Screening. 
 
Clinically severe respiratory compromise (based on Investigator’s assessment) resulting from 
intercurrent pulmonary illnesses including, but not limited to: 
 Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior to the 
study enrollment, severe asthma, severe chronic obstructive pulmonary disease [COPD]), 
restrictive lung disease, pleural effusion); 
 Any autoimmune, connective tissue or inflammatory disorders with pulmonary 
involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); 
OR prior complete pneumonectomy. 
 
Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent 
anti-inflammatory or any form of immunosuppressive therapy prior to enrollment.  Subjects 
who require use of bronchodilators, inhaled or topical steroids, or local steroid injections may 
be included in the study. 
 
Evidence of any leptomeningeal disease. 
 
Evidence of clinically active spinal cord compression or brain metastases, defined as untreated and 
symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated 
symptoms.  Subjects with clinically inactive or treated brain metastases who are asymptomatic (ie, 
without neurologic signs or symptoms and not requiring treatment with corticosteroids or 
anticonvulsants) may be included in the study.  Subjects must have a stable neurologic status for at 
least 2 weeks prior to Cycle 1 Day 1. 
 
Inadequate washout period prior to Cycle 1 Day 1, defined as: 
 Whole brain radiation therapy <14 days or stereotactic brain radiation therapy <7 days; 
 Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a 
previous cancer treatment regimen or clinical study (other than EGFR TKI), <14 days or 
5 half-lives, whichever is longer; 
 Monoclonal antibodies, other than immune checkpoint inhibitors, such as bevacizumab 
(anti-VEGF) and cetuximab (anti-EGFR) <28 days; 
 Immune checkpoint inhibitor therapy <21 days; 
 Major surgery (excluding placement of vascular access) <28 days; 
 Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation <28 days or palliative radiation therapy <14 days; or 
 Chloroquine or hydroxychloroquine <14 days. 
 
Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3) antibody or 
single-agent topoisomerase I inhibitor. 
 
Prior treatment with an antibody drug conjugate (ADC) that consists of any topoisomerase I 
inhibitor. 
 
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than 
alopecia) not yet resolved to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline.  Subjects with chronic Grade 2 

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toxicities may be eligible at the discretion of the Investigator after consultation with the Sponsor 
Medical Monitor or designee. 
 
Has history of other active malignancy within 3 years prior to enrollment, except: 
 Adequately treated non-melanoma skin cancer; 
 Superficial bladder tumors (Ta, Tis, T1); 
 Adequately treated intraepithelial carcinoma of the cervix uteri; 
 Low risk non-metastatic prostate cancer (with Gleason score <7, and following local 
treatment or ongoing active surveillance); 
 Any other curatively treated in situ disease. 
 
Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: 
 QT interval corrected with Fridericia’s formula (QTcF) prolongation interval of >470 ms 
for females and >450 ms for males; 
 Left ventricular ejection fraction (LVEF) <50% by either echocardiogram (ECHO) or 
multigated acquisition (MUGA) scan; 
 Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg; 
 Myocardial infarction within 6 months; 
 New York Heart Association (NYHA) Classes 2 to 4 congestive heart failure (See 
Section 10.3.2); 
 Uncontrolled angina pectoris within 6 months; 
 Cardiac arrhythmia requiring antiarrhythmic treatment. 
 
Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of viral 
infection within 28 days of Cycle 1 Day 1.  
 
Subjects with past or resolved hepatitis B virus (HBV) infection are eligible if:   
▪ 
Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody [anti-
HBc] positive; OR 
▪ 
HBsAg positive and HBV deoxyribonucleic acid (DNA) viral load is documented to 
be ≤2000 IU/mL in the absence of anti-viral therapy and during the previous 12 
weeks prior to the viral load evaluation with normal transaminases values (in the 
absence of liver metastasis); OR 
▪ 
HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL, in the 
absence of anti-viral therapy and during the previous 12 weeks prior to the viral load 
evaluation for subjects with liver metastasis and abnormal transaminases with a result 
of AST/ALT <3 × ULN. 
 
Subjects with a history of hepatitis C infection will be eligible for enrollment only if the viral 
load according to local standards of detection is documented to be below the level of detection 
in the absence of anti-viral therapy during the previous 12 weeks (ie, sustained viral response 
according to the local product label but no less than 12 weeks, whichever is longer). 
 
Subject with any human immunodeficiency virus (HIV) infection. 
 
Any evidence of severe or uncontrolled diseases including active bleeding diatheses, active 
infection, psychiatric illness/social situations, geographical factors, substance abuse, or other 
factors which in the Investigator’s opinion makes it undesirable for the subject to participate 
in the study or which would jeopardize compliance with the protocol.  Screening for chronic 
conditions is not required. 

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Investigational Medicinal Product, Dose and Mode of Administration 
Patritumab deruxtecan drug product will be provided as a sterile lyophilized-drug product (Lyo-DP) consisting 
of 100 mg of lyophilized powder in a single-use amber glass vial to be reconstituted with 5 mL water for 
injection to 20 mg/mL.   
Patritumab deruxtecan will be administered as an intravenous (IV) solution Q3W on Day 1 of each 21-day cycle 
as 1 of 2 dose regimens: 5.6 mg/kg or up-titration (Cycle 1: 3.2 mg/kg; Cycle 2: 4.8 mg/kg; Cycle 3 and 
subsequent cycles: 6.4 mg/kg).   
The dose can be delayed for up to 28 days from the planned date of administration (ie, 49 days from the last 
infusion date).  If a subject is assessed as requiring a dose delay longer than 28 days, the subject should be 
discontinued from the study treatment, unless there is following discussion and agreement between the 
Investigator and the Sponsor to resume study treatment at a later date. 
Active Ingredient(s)/INN 
U3-1402/Patritumab Deruxtecan 
Patritumab deruxtecan is an ADC comprising a recombinant fully human anti-HER3 IgG1 monoclonal antibody 
(patritumab, U3-1287) covalently linked to MAAA-1162a (glycine-glycine-phenylalanine-glycine) tetrapeptide 
linker containing a topoisomerase I inhibitor [MAAA-1181a]).  MAAA-1181a is released after internalization 
and leads to apoptosis of the target tumor cells via the inhibition of topoisomerase I. 
Planned Sample Size 
The primary efficacy endpoint of objective response rate (ORR) is used for sample size determination.  From 
the REVEL trial, ORR of 23% from ramucirumab plus docetaxel arm was observed (upper bound of the exact 
95% confidence interval (CI) = 26.4%.  Clinically meaningful ORR of 37% is expected from patritumab 
deruxtecan.  The one-sample exact binomial test for single proportion with a nominal 2-sided significance level 
of 5% will have approximately 91% power to detect the difference between a null hypothesis (H0) of ORR = 
26.4%and an alternative hypothesis (H1) of ORR = 37% when the sample size is 210.   
Up to approximately 420 subjects will be randomized/enrolled depending on whether one dose arm is dropped 
or not during the study.  The sample size computation is performed using exact test for single proportion in 
nQuery v8.5.2.  No formal comparison between the two arms is planned, and sample size is calculated for each 
arm individually. 
Statistical Analyses 
The primary analysis data cut-off will occur when all enrolled subjects have either a minimum of 9 months of 
follow-up or have discontinued from the study earlier.  The primary analysis will be included in the clinical 
study report (CSR).  
The primary efficacy endpoint is ORR, defined as the proportion of subjects who achieved a best overall 
response (BOR) of confirmed complete response (CR) or partial response (PR) as assessed by BICR per 
RECIST v1.1.  Secondary efficacy endpoints include disease control rate (DCR), duration of response (DoR), 
time to response (TTR), progression-free survival (PFS), and overall survival (OS).  Response endpoints (ORR 
and DCR) will be summarized with the exact 95% CI using the Clopper-Pearson method in the Efficacy 
Analysis Set.  Distribution of time to event endpoints (DoR, PFS, and OS) will be estimated using the Kaplan-
Meier method and results presented graphically.  Median event time with a 2-sided 95% CI will be calculated 
using Brookmeyer and Crowley methods.  TTR will be summarized using descriptive statistics.  Data will be 
summarized by treatment arm.  No formal comparison between the 2 arms is planned. 
Safety analyses in general will be descriptive using the Safety Analysis Set.  Serum concentrations for 
patritumab deruxtecan, total anti-HER3 antibody, and free payload MAAA-1181a will be listed, plotted, and 
summarized at each time point in the Pharmacokinetic (PK) Analysis Set.  PK parameters will be listed and 
summarized by arm using descriptive statistics. 

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1.2. 
Study Schema 
Figure 1.1: 
Study Level Flow Diagram 
 
 
IV = intravenous; NSCLC = non-small cell lung cancer; Q3W = every 3 weeks. 
 
Dose Regimens 
Fixed dose regimen (Arm 1) Q3W:   
 
5.6 mg/kg  
Up-titration dose regimen (Arm 2) IV Q3W:   
 
Cycle 1: 3.2 mg/kg;  
 
Cycle 2: 4.8 mg/kg;  
 
Cycle 3 and subsequent cycles: 6.4 mg/kg 
IV= intravenous; Q3W = every 3 weeks. 
 

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1.3. 
Schedule of Events 
Table 1.1: 
Schedule of Events for Screening and Cycles 1 through 3 of the Treatment Period 
 
Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
Obtain signed tissue ICF and signed main ICF prior to 
performing any study procedures.  See Section 8.1 
and Section 10.1.2. 
Eligibility Assessment 
X 
X 
 
 
 
 
 
 
 
 
 
See Section 5.1, Section 5.2 and Section 8.1. 
Pretreatment Tumor 
Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
Pretreatment or archival tumor tissue is required to be 
of sufficient quantity (as defined in the Laboratory 
Manual) and of adequate tumor tissue content (as 
confirmed by H&E staining at the central laboratory). 
Pretreatment tumor biopsy is required for all subjects.  
Subjects may be exempted from the requirement to 
provide a pretreatment tumor biopsy if the archival 
tumor tissue was collected within 3 months prior to 
signing of the tissue consent and since progression 
while on or after the most recent cancer therapy 
regimen.  See Sections 8.1 and 8.7.2.   
Archived Tumor Biopsy 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Includes: birth date, age at Screening, sex, race, 
ethnicity, country.  See Section 8.1. 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
See Section 8.1. 
Prior Cancer History 
 
X 
 
 
 
 
 
 
 
 
 
See Section 8.1. 
Prior Cancer Medical 
Therapy 
 
X 
 
 
 
 
 
 
 
 
 
See Section 8.1. 
EGFR Mutation History 
 
X 
 
 
 
 
 
 
 
 
 
See Section 8.1. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
HIV Ab Test 
 
X 
 
 
 
 
 
 
 
 
 
If required by local regulations, perform within 
28 days prior to Cycle 1 Day 1.  See Section 8.1. 
HBsAg, HCV Ab, HCV 
RNA 
 
X 
 
 
 
 
 
 
 
 
 
Perform required hepatitis B surface antigen (HBsAg) 
and hepatitis C virus antibody (HCV Ab) test within 
28 days prior to Cycle 1 Day 1.   
Subjects with past or resolved HBV infection are 
eligible if:   
 HBsAg negative and hepatitis B core antibody 
[anti-HBc] positive; OR 
 HBsAg positive and HBV DNA viral load is 
documented to be ≤2000 IU/mL in the absence of 
anti-viral therapy and during the previous 12 
weeks prior to the viral load evaluation with 
normal transaminases values (in the absence of 
liver metastasis); OR 
 HBsAg positive and HBV DNA viral load is 
documented to be ≤2000 IU/mL in the absence of 
anti-viral therapy and during the previous 12 
weeks prior to the viral load evaluation for 
subjects with liver metastasis and abnormal 
transaminases with a result of AST/ALT <3 x 
ULN. 
Subjects with a history of hepatitis C infection will be 
eligible for enrollment only if the viral load according 
to local standards of detection is documented to be 
below the level of detection in the absence of anti-
viral therapy during the previous 12 weeks (ie, 
sustained viral response according to the local product 
label but no less than 12 weeks, whichever is longer).  
See Section 8.1. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
Final Dose of EGFR TKI 
 
 
X 
 
 
 
 
 
 
 
 
Subjects who are currently receiving an EGFR TKI at 
the time of informed consent should be instructed to 
take the final dose of their EGFR TKI 5 days prior to 
the start of Cycle 1, Day 1. 
Randomization a / 
Enrollment 
 
 
 
X 
 
 
 
 
 
 
 
a Dosing must occur within 3 days of randomization.  
Every effort should be made to minimize the time 
between randomization and study drug 
administration.  See Section 8.2. 
Patritumab Deruxtecan 
Administration 
 
 
 
X 
 
X 
X 
 
Subjects must receive study drug within 3 days of 
randomization/enrollment.  The subject’s weight at 
baseline (defined as the last measurement on or prior 
to Cycle 1 Day 1) will be used to calculate the initial 
dose.  The subject’s weight will be determined at the 
beginning of each cycle.  If during Cycle 1 Day 1 or 
throughout the course of treatment, the subject’s 
weight changes ≥10% from the baseline weight, the 
dose will be recalculated using this new weight and 
will be considered the new baseline for all subsequent 
dosing calculations. 
Patritumab deruxtecan will be administered as a 
continuous IV infusion over approximately 90 
minutes on Day 1 of Cycle 1.  If there are no infusion-
related reactions after the initial dose, subsequent 
doses of patritumab deruxtecan will be infused over 
approximately 30 minutes on Day 1 of each 
subsequent cycle Q3W.  Refer to Table 6.4 for 
additional information on drug administration 
following infusion-related reactions.  Refer to 
Pharmacy Manual and Section 6 for information on 
storage and preparation of patritumab deruxtecan.  
Physical 
/Vitals 
Height 
 
X 
 
 
 
 
 
 
 
 
 
Within 28 days prior to Cycle 1 Day 1. 
See Section 8.4.4. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
Weight 
 
X b 
 
X 
 
 
X 
 
X 
 
 
b Within 28 days prior to Cycle 1 Day 1. 
See Sections 8.2 and 8.4.4. 
Physical 
Exam 
including 
ECOG PS 
 
X b 
 
X 
 
 
X 
 
X 
 
 
b Within 28 days prior to Cycle 1 Day 1. 
See Sections 8.4.4 and 10.3.3. 
Vital Signs 
including 
SpO2 
 
X b 
 
X 
X 
X 
X 
X 
X 
X 
 
Includes systolic and diastolic blood pressure, heart 
rate, respiratory rate, temperature, and oxygen 
saturation (SpO2).  Blood pressure and pulse rate 
should be measured after the subject has rested in a 
supine/semi-recumbent position for 5 minutes.   
b Within 28 days prior to Cycle 1 Day 1. 
See Section 8.4.4. 
Safety 
Hematology/ 
Chemistry 
Tests 
 
X c 
 
Xd 
 
X 
Xd 
 
Xd 
 
X 
c Within 14 days prior to Cycle 1 Day 1. 
d Should be performed within 72 hours of scheduled 
visit.  Results are required prior to study treatment.  
See Sections 8.4.3 and 10.2. 
Coagulation 
 
X 
 
 
 
 
 
 
 
 
 
Within 14 days prior to Cycle 1 Day 1.  Subjects 
taking warfarin should be monitored regularly for 
changes in prothrombin time or international 
normalized ratio.  See Sections 8.4.3 and 10.2. 
Urinalysis 
 
X 
 
 
 
 
 
 
 
 
 
 
Screening assessment should be performed within 
28 days  prior to Cycle 1 Day 1.  Assessments may be 
repeated as clinically indicated as part of a scheduled 
or unscheduled visit and should include microscopic 
evaluation as indicated.  See Sections 8.4.3 and 10.2. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
Pregnancy 
Test 
 
Xa 
 
Xb 
 
 
Xb 
 
Xb 
 
 
a For all female subjects of childbearing potential, a serum 
pregnancy test at Screening should be performed within 
28 days prior to Cycle 1 Day 1  
b A pregnancy test (urine or serum test per institutional 
guidelines) should be performed within 72 hours prior to 
infusion of each cycle (including prior to Cycle 1 Day 1) for 
all female subjects of childbearing potential; a positive urine 
pregnancy test result must immediately be confirmed using a 
serum pregnancy test.  Results are required prior to 
administration of study treatment.  Cycle 1 Day 1 assessment 
does not need to be repeated if Screening assessment was 
performed within 72 hours of Cycle 1 Day 1 infusion.  See 
Section 8.4.2 
12-lead ECG 
 
X 
 
 
 
 
 
 
 
 
 
Within 28 days prior to Cycle 1 Day 1.  Subjects 
should rest supine/semi-recumbent for at least 10 
minutes prior to the assessment.  The same test must 
be used for Screening, EOT, and as clinically 
indicated.  See Section 8.4.4. 
 
ECHO/ 
MUGA 
 
X 
 
 
 
 
 
 
 
 
 
Within 28 days prior to Cycle 1 Day 1.  The same test 
must be used for Screening, EOT, and for as clinically 
indicated testing.  See Section 8.4.4. 
COVID-19 
Sample 
 
 
 
X 
 
 
 
 
 
 
 
If subject provides consent, samples should be 
collected prior to study drug infusion. 
For subjects with suspected or confirmed COVID-19 
infections, follow the dose modifications in 
Section 10.7. 
Ophthalmo-
logic 
Assessments 
 
X 
 
 
 
 
 
 
 
 
 
Has to occur within 7 days prior to Cycle 1 Day 1 and 
includes a visual acuity test (ETDRS, Snellens, or 
Landolt), slit lamp examination, fundoscopy, and 
tonometry.  Assessments may be repeated as 
clinically indicated as part of a scheduled or 
unscheduled visit.  See Section 8.4.4. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
BM 
BM Blood 
Sample 
 
 
 
Xe 
 
 
Xf 
 
Xf 
 
 
e For Cycle 1 Day 1, a minimum of 34 mL of blood is 
required to be drawn.  This includes 20 mL for 
cfDNA, 10 mL for cfRNA, and 4 mL for HER3 ECD.   
f A minimum 24 mL of blood is required to be drawn.  
This includes 10 mL for cfDNA, 10 mL for cfRNA, 
and 4 mL for HER3 ECD. 
See Section 8.7.1. 
PGx 
Blood 
Sample 
 
 
 
 
X 
 
 
 
 
 
 
If subject provides consent, a single blood sample for 
PGx analysis should be collected on Cycle 1 Day 1 
post-infusion.  Alternatively, a blood sample may be 
collected at any time after Cycle 1 Day 1.  See 
Section 8.8. 
ADA Blood 
Sample 
 
 
 
X 
 
X 
X 
 
 
 
 
See Section 8.5.1. 
Pharmacokinetics 
Sample 
 
 
 
X 
Xg 
X 
X 
X g 
X 
X g 
X 
g Within 15 minutes of end of infusion then 4 hours 
(±15 minutes) after the end of infusion.   
See Section 8.5. 
PK Sampling for 
CQ/HCQ Administration 
 
 
 
If CQ or HCQ is administered for COVID-19, 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 4h) 
 Last day of the CQ/HCQ treatment, prior to CQ/HCQ dose (within 
4h) 
The day of patritumab deruxtecan resumption, after the CQ/HCQ 
washout period h, (within 8h BI of patritumab deruxtecan). 
If subject provides consent, samples should be 
collected. 
h A washout period of more than 14 days is required 
before restarting patritumab deruxtecan. 
See Section 10.7. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
Tumor Assessmentsi 
 
Xj,k 
 
Xk 
Every 6 weeks (±7 days) from Cycle 1 Day 1 for the first 24 weeks 
then every 12 weeks (±7 days) thereafter, independent of treatment 
cycle, until documented disease progression by BICR per 
RECIST v1.1, death, lost to follow-up, or withdrawal of consent 
i The same methodology (CT or MRI) and scan 
acquisition techniques (including nonuse and use of 
IV contrast unless medically infeasible, ie, newly 
developed AE or allergy to contrast agent) as were 
used for the Screening assessments should be used 
throughout the study for each body region across all 
assessments for each subject unless prior approval is 
obtained from the Sponsor.  Unscheduled tumor 
assessments may be conducted if progression is 
suspected.  Tumor assessments should not be delayed 
by dose interruptions; they are timed relative to 
Cycle 1 Day 1.  Tumor assessments should be 
performed per RECIST v1.1 (Section 10.4) and 
submitted for BICR.  SpO2 should be conducted with 
CT/MRI per Investigator discretion. 
j Within 28 days prior to Cycle 1 Day 1.   
k Perform radiographic tumor assessments (CT/MRI) 
of the chest, abdomen, pelvis, brain, and for all sites 
of disease identified at screening, and for any newly 
suspected disease sites, as per RECIST v1.1 
(Section 10.4).  Objective responses must be 
confirmed at least 4 weeks later (eg, generally at the 
next tumor assessment time point).   
See Section 8.3. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
Bone Scan 
 
Xl 
 
Xm 
Every 24 weeks (±7 days) from Cycle 1 Day 1 
l A bone scan (99mtechnetium polyphosphonate 
scintigraphy, whole body bone MRI, 18F- NaF 
PET/CT or 18F-FDG PET/CT) to assess bone 
metastases should be performed within 6 weeks prior 
to Cycle 1 Day 1 (historical scans are acceptable). 
m A bone scan (99mtechnetium polyphosphonate 
scintigraphy, whole body bone MRI, or 18F-NaF 
PET/CT or 18F-FDG PET/CT) to assess bone 
metastases should be performed every 24 weeks (±7 
days) from Cycle 1 Day 1, or sooner if clinically 
indicated.  In subjects whose body CT/MRI scans 
indicate CR has been achieved, a bone scan is 
required at confirmation of CR to exclude new bone 
metastases.  Lesions detected on bone scans must be 
followed with cross-sectional imaging. 
See Section 8.3. 
Prior/Concomitant 
Medications 
 
X 
See Section 6.6. 

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Tissue 
Requirement 
Screening 
Cycle 1 
Cycle 2 
Cycle 3 
Comments 
Day 
-5 
Day 1 
Day 
8 
Day 1 
Day 1 
Day 8 
 
Pre-I 
Post-I 
 
Pre-I 
Post-I 
Pre-I 
Post-I 
 
 
Visit Window 
 
-35D 
 
 
 
±1D 
±1D 
 
±1D 
 
±1D 
AE 
SAEs 
X 
Any SAEs after signing the appropriate ICF should be 
reported until 40 days (+7 days) after the last dose of 
the study drug.  Any SAEs directly related to a tumor 
biopsy procedure performed after signing the 
appropriate Tissue Screening ICF or Tissue 
Collection ICF should be reported according to the 
Adverse Event Reporting Requirements section.  Any 
serious, untoward event that may occur subsequent to 
the 40-day (+ 7 days) follow-up reporting period that 
the Investigator assesses as related to study drug 
should also be reported and managed as an SAE.  
Record the start date of any medical occurrence that 
started after the ICF was signed and is ongoing at the 
time of the first dose of patritumab deruxtecan on the 
General Medical History and Baseline Conditions 
eCRF.  See Section 8.4.1. 
Non-SAEs 
 
X 
Any AEs from first dose until 40 days (+7 days) after 
the last dose of the study drug should be followed 
until resolution or stabilized.  See Section 8.4.1. 
ADA = anti-drug antibody; AE = adverse event; BICR = blinded independent central review; BM = biomarker; cfDNA = cell-free deoxyribonucleic acid; cfRNA = cell-free RNA; 
COVID-19 = coronavirus disease 2019; CQ = chloroquine; CR = complete response; CT = computed tomography; D = day; DNA = deoxyribonucleic acid; EC = Ethics 
Committee; ECD = extracellular domain; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; 
eCRF = electronic case report form; EGFR = epidermal growth factor receptor; EOT = end of treatment; ETDRS = Early Treatment Diabetic Retinopathy Study; 
FDG = fluorodeoxyglucose; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCQ = hydroxychloroquine; HCV Ab = hepatitis C virus antibody; 
H&E = hematoxylin and eosin; HER3 = human epidermal growth factor receptor 3; HIV Ab = human immunodeficiency virus antibody; ICF = informed consent form; 
IHC = immunohistochemistry; IRB = Institutional Review Board; IV = intravenous; MRI = magnetic resonance imaging; MUGA = multigated acquisition; NGS = next generation 
sequencing; PET = positron emission tomography; PGx = pharmacogenetics; PK = pharmacokinetic(s); Post-I = Post-infusion; Pre-I = Pre-infusion; RECIST v1.1 = Response 
Evaluation Criteria in Solid Tumors version 1.1; RNA = ribonucleic acid; SAE = serious adverse event; SpO2 = peripheral oxygen saturation; TKI = tyrosine kinase inhibitor. 

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Table 1.2: 
Schedule of Events for Cycle 4 and Subsequent Cycles of the Treatment Period, End of Treatment, and 
Follow-up Period 
 
Cycle 4 and Subsequent Cycles Day 
1 
EOTa 
40-Day 
Follow-
upb 
Long-Term 
Follow-up 
(Every 
3 Months) 
Comments 
Pre-I 
Post-I 
 
Visit Window 
±1D 
 
 
+7D 
±14 D 
End-of-Treatment Tumor 
Biopsy 
 
 
X 
 
 
An optional EOT tumor biopsy will also be performed at the 
time of progression or discontinuation from study treatment.  
Consent for this biopsy should be documented in the tissue 
consent portion of the appropriate ICF.  Tumor biopsy should 
be obtained from primary tumor or metastatic site, preferably 
from a site of recent radiographic progression, within 40 days of 
the last dose of patritumab deruxtecan, and prior to starting any 
new anticancer treatment.  See Section 8.7.2. 
Patritumab Deruxtecan 
Administration 
X 
 
 
 
The subject’s weight at baseline (defined as the last 
measurement on or prior to Cycle 1 Day 1) will be used to 
calculate the initial dose.  The subject’s weight will be 
determined at the beginning of each cycle.  If during Cycle 1 
Day 1 or throughout the course of treatment, the subject’s 
weight changes by ≥10% from the baseline weight, the dose 
will be recalculated using this new weight and will be 
considered the new baseline for all subsequent dosing 
calculations. 
Patritumab deruxtecan will be administered as a continuous IV 
infusion over approximately 90 minutes on Day 1 of Cycle 1.  If 
there are no infusion-related reactions after the initial dose, 
subsequent doses of patritumab deruxtecan will be infused over 
approximately 30 minutes on Day 1 of each subsequent cycle 
Q3W.  Refer to Table 6.4 for additional information on drug 
administration following infusion-related reactions.  Refer to 
Pharmacy Manual and Section 6 for information on storage and 
preparation of patritumab deruxtecan.   
Physical 
/Vitals 
Weight 
X 
 
X 
X 
 
See Section 8.2 and Section 8.4.4. 
Physical Exam 
including ECOG 
PS 
X 
 
X 
X 
 
See Section 8.4.4 and Section 10.3.3. 

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Cycle 4 and Subsequent Cycles Day 
1 
EOTa 
40-Day 
Follow-
upb 
Long-Term 
Follow-up 
(Every 
3 Months) 
Comments 
Pre-I 
Post-I 
 
Visit Window 
±1D 
 
 
+7D 
±14 D 
Vital Signs 
including SpO2 
X 
X 
X 
X 
 
Includes systolic and diastolic blood pressure, heart rate, 
respiratory rate, temperature, and oxygen saturation (SpO2).  
Blood pressure and pulse rate should be measured after the 
subject has rested in a supine/semi-recumbent position for 5 
minutes.  See Section 8.4.4. 
Safety 
Hematology/ 
Chemistry Tests 
Xc 
 
X 
X 
 
c Should be performed within 72 hours of scheduled visit.  
Results are required prior to study treatment.  See Sections 8.4.3 
and 10.2. 
Urinalysis 
 
 
X 
 
 
Assessments may be repeated as clinically indicated as part of a 
scheduled or unscheduled visit and should include microscopic 
evaluation as indicated.  See Sections 8.4.3 and 10.2. 
Pregnancy Test 
X 
 
X 
X 
 
Perform pregnancy tests (urine or serum test per institutional 
guidelines) 72 hours before infusion of each cycle and at the 
end of treatment.  See Section 8.4.2. 
12-lead ECG 
 
 
X 
 
 
Subjects should rest supine/semi-recumbent for at least 10 
minutes prior to the assessment.  The same test must be used for 
Screening, EOT, and as clinically indicated.  Assessment for 
EOT Visit may be performed with a window up to 7 days.  See 
Section 8.4.4. 
ECHO/MUGA 
 
 
X 
 
 
The same test must be used for Screening, EOT, and as 
clinically indicated.  Assessment for EOT Visit may be 
performed with a window up to 7 days.  See Section 8.4.4. 
COVID-19 
Sample 
X 
Starting at Cycle 5, Day 1 and every 4 
cycles thereafter 
X 
 
 
If subject provides consent, samples should be collected prior to 
study drug infusion. 
For subjects with suspected or confirmed COVID-19 infections, 
follow the dose modifications in Section 10.7. 

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Cycle 4 and Subsequent Cycles Day 
1 
EOTa 
40-Day 
Follow-
upb 
Long-Term 
Follow-up 
(Every 
3 Months) 
Comments 
Pre-I 
Post-I 
 
Visit Window 
±1D 
 
 
+7D 
±14 D 
Ophthalmologic 
Assessments 
 
 
Xd 
 
 
Includes a visual acuity test (ETDRS, Snellens, or Landolt), slit 
lamp examination, fundoscopy, and tonometry.  Assessments 
may be repeated as clinically indicated as part of a scheduled or 
unscheduled visit.   
d A 40 (+7) Day F/U assessment is required if an on-treatment 
assessment was abnormal at the time of discontinuation of study 
therapy, to confirm reversibility of the abnormality.  See 
Section 8.4.4. 
BM 
BM Blood 
Sample 
X 
 
X 
 
 
A minimum of 24 mL of blood is required to be drawn.  This 
includes 10 mL for cfDNA, 10 mL for cfRNA, and 4 mL for 
HER3 ECD.   
See Section 8.7.1. 
ADA Blood 
Sample 
X e 
Cycle 4, 
Day 1 and 
every 2 
cycles 
thereafter 
 
X e 
 
X e, f 
e PK assay can be performed on the ADA sample collected.   
f For subjects with positive ADA, additional serum ADA 
samples should be collected every 3 months (± 14 days) for up 
to 1 year after the last dose of patritumab deruxtecan, unless one 
or more of the following occurs sooner:  the ADA becomes 
negative; the ADA titer falls below baseline if ADA was 
measurable prior to Cycle 1 Day 1; the subject starts another 
therapy for cancer, or the subject withdraws consent from the 
study, whichever occurs first.   
See Section 8.5.1. 
Pharmacokinetics Sample 
X 
Cycle 4, 6, 8 
 
 
 
Pre-infusion and within 15 minutes of end of infusion.   
See Section 8.5. 

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Cycle 4 and Subsequent Cycles Day 
1 
EOTa 
40-Day 
Follow-
upb 
Long-Term 
Follow-up 
(Every 
3 Months) 
Comments 
Pre-I 
Post-I 
 
Visit Window 
±1D 
 
 
+7D 
±14 D 
PK Sampling for CQ/HCQ 
Administration 
If CQ or HCQ is administered for 
COVID-19, 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 4h) 
 Last day of the CQ/HCQ treatment, 
prior to CQ/HCQ dose (within 4h) 
The day of patritumab deruxtecan 
resumption, after the CQ/HCQ washout 
period g, (within 8h BI of patritumab 
deruxtecan). 
 
 
 
If subject provides consent, samples should be collected. 
g A washout period of more than 14 days is required before 
restarting patritumab deruxtecan. 
See Section 10.7. 
Tumor Assessmentsh 
Xi 
Every 6 weeks (±7 days) from Cycle 1 Day 1 for the first 24 weeks then 
every 12 weeks (±7 days) thereafter, independent of treatment cycle, until 
documented disease progression by BICR per RECIST v1.1, death, lost to 
follow-up, or withdrawal of consent 
h The same methodology (CT or MRI) and scan acquisition 
techniques (including nonuse and use of IV contrast unless 
medically infeasible, ie, newly developed AE or allergy to 
contrast agent) as were used for the Screening assessments 
should be used throughout the study for each body region across 
all assessments for each subject unless prior approval is 
obtained from the Sponsor.  Unscheduled tumor assessments 
may be conducted if progression is suspected.  Tumor 
assessments should not be delayed by dose interruptions; they 
are timed relative to Cycle 1 Day 1.  Tumor assessments should 
be performed per RECIST v1.1 (Section 10.4) and submitted for 
BICR.  SpO2 should be conducted with CT/MRI per 
Investigator discretion.   
i Perform radiographic tumor assessments (CT/MRI) of the 
chest, abdomen, pelvis, brain, and for all sites of disease 
identified at Screening, and for any newly suspected disease 
sites, as per RECIST v1.1 (Section 10.4) .  Objective responses 
must be confirmed at least 4 weeks later (eg, generally at the 
next tumor assessment time point).   
See Section 8.3. 

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Cycle 4 and Subsequent Cycles Day 
1 
EOTa 
40-Day 
Follow-
upb 
Long-Term 
Follow-up 
(Every 
3 Months) 
Comments 
Pre-I 
Post-I 
 
Visit Window 
±1D 
 
 
+7D 
±14 D 
Bone Scan 
X 
Every 24 weeks (±7 days) from Cycle 1 Day 1 
A bone scan (99mtechnetium polyphosphonate scintigraphy, 
whole body bone MRI, 18F-NaF PET/CT or 18F- FDG PET/CT) 
to assess bone metastases should be performed every 24 weeks 
(±7 days) from Cycle 1 Day 1, or sooner if clinically indicated.  
In subjects whose body CT/MRI scans indicate CR has been 
achieved, a bone scan is required at confirmation of CR to 
exclude new bone metastases.  Lesions detected on bone scans 
must be followed with cross-sectional imaging.  See 
Section 8.3. 
Prior/Concomitant 
Medications 
X 
See Section 6.6. 
AE 
SAEs 
X 
Any SAEs after signing the appropriate ICF should be reported 
until 40 days (+7 days) after the last dose of the study drug.  
Any SAEs directly related to a tumor biopsy procedure 
performed after signing the appropriate the Tissue Screening 
ICF or Tissue Collection ICF should be reported according to 
the Adverse Event Reporting Requirements section.  Any 
serious, untoward event that may occur subsequent to the 40-
day (+ 7 days) follow-up reporting period that the Investigator 
assesses as related to study drug should also be reported and 
managed as an SAE.  See Section 8.4.1. 
Non-SAEs 
X 
 
Any AEs from first dose until 40 days (+7 days) after the last 
dose of the study drug should be followed until resolution or 
stabilized.  Record the start date of any medical occurrence that 
started after the ICF was signed and is ongoing at the time of 
the first dose of patritumab deruxtecan on the General Medical 
History and Baseline Conditions eCRF.  See Section 8.4.1. 
OS 
New Cancer Tx 
 
 
 
 
X 
 
Survival F/U 
 
 
 
 
X 
See Section 7.1.  
ADA = anti-drug antibody; AE = adverse event; BICR = blinded independent central review; BM = biomarker; cfDNA – cell-free deoxyribonucleic acid; cfRNA = cell-free 
ribonucleic acid; COVID-19 = coronavirus disease 2019; CQ = chloroquine; CR = complete response; CT = computed tomography; D = day; EC = Ethics Committee; 
ECD = extracellular domain; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; eCRF = electronic case 
report form; EGFR = epidermal growth factor receptor; EOT = end of treatment; ETDRS = Early Treatment Diabetic Retinopathy Study; FDG = fluorodeoxyglucose; 
F/U = follow-up; HCQ = hydroxychloroquine; ICF = informed consent form; IRB = Institutional Review Board; IV = intravenous; MRI = magnetic resonance imaging; 

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MUGA = multigated acquisition; OS = overall survival; PET = positron emission tomography; PK = pharmacokinetic(s); Post-I = Post-infusion; Pre-I = Pre-infusion; RECIST 
v1.1 = Response Evaluation Criteria in Solid Tumors version 1.1; SAE = serious adverse event; SpO2 = peripheral oxygen saturation; TKI = tyrosine kinase inhibitor; TR= tumor 
requirement; Tx = treatment. 
a This visit occurs within 7 days after the final dose of study treatment, or before starting new anticancer treatment, whichever comes first.  If the decision to discontinue 
patritumab deruxtecan occurs >7 days after the final dose of patritumab deruxtecan, then this visit will occur within 7 days after the decision to discontinue patritumab 
deruxtecan or before the start of new anticancer treatment; whichever comes first  If the EOT Visit occurs ≥40 days after the final dose of patritumab deruxtecan, the 40-Day F/U 
Visit does not need to be conducted. 
b 40 days (+ 7 days) after the last study drug administration or before starting new anticancer treatment, whichever comes first. 

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2. 
INTRODUCTION 
2.1. 
Background 
Non-small Cell Lung Cancer Background 
Lung cancer is the most common cancer and the leading cause of cancer-related mortality 
worldwide, with an estimated 2.1 million new cases in 2018 (11.6% of all new cases) and 
1.8 million deaths (18.4% of all cancer deaths) globally based on GLOBOCAN data.1  In the 
United States alone, 228,820 newly diagnosed cases (12.7% of all new cases) and 135,720 deaths 
(22.4% of all cancer deaths) associated with cancers of the lung and bronchus are estimated to 
occur in 2020.2  In Japan, lung cancer is the leading cause of cancer related deaths in males 
(52,505 deaths) and the second leading cause of cancer-related death in females (20,891 deaths).3  
Advances in early detection of lung cancer have been slow, and more than half of lung cancers 
are still diagnosed at an advanced stage.4  Only 19.4% of all patients with lung cancer are alive 
5 years or more after diagnosis.5  Non-small cell lung cancer (NSCLC) accounts for 
approximately 85% of all lung cancers.6  
In epidermal growth factor receptor (EGFR)-mutated NSCLC, it has been well established 
through multiple large Phase 3 studies that EGFR tyrosine kinase inhibitors (TKIs) represent the 
first-line treatment of choice.7,8,9,10,11,12,13  Among EGFR TKIs, the greatest clinical benefit as 
measured by progression-free survival (PFS) and overall survival (OS) has been demonstrated 
with osimertinib in the Phase 3 FLAURA study, which compared osimertinib versus erlotinib or 
gefitinib in patients with untreated advanced EGFR-mutated (EGFRm) NSCLC.  In this study, 
first-line osimertinib demonstrated superiority to erlotinib or gefitinib as measured by PFS 
(18.9  months vs. 10.2 months; hazard ratio: 0.46; 95% confidence interval [CI]: 0.37 to 0.57; 
P <0.001).14  At the final OS analysis, the median OS was 38.6 months (95% CI: 34.5, 41.8) in 
the osimertinib arm vs. 31.8 months (95% CI: 26.6, 36.0) in the comparator arm with a hazard 
ratio of 0.80 (95% CI: 0.64, 1.00); P=0.046.15  Despite a higher duration of exposure of 
20.7 months in the osimertinib arm and 11.5 months in the comparator arm; the incidence of 
Grade 3 or higher adverse events was 42% and 47%, respectively.15 Osimertinib has also 
demonstrated benefit in the second-line setting in patients who develop resistance to first- or 
second- generation TKIs and harbor the T790M mutation.16,17  
Although osimertinib confers benefit (median PFS of 18.9 months and median OS of 
38.6 months) in previously untreated patients, development of resistance with disease 
progression is typical.  In order to further investigate osimertinib resistance mechanisms, 
circulating tumor deoxyribonucleic acid (DNA) from patient plasma samples who had 
progressed and/or discontinued from the Phase 3 FLAURA and AURA3 studies were analyzed 
utilizing next generation sequencing (NGS).  In the first-line setting, 91/113 evaluable plasma 
samples were analyzed in patients with untreated EGFRm (exon 19 deletion or L858R) NSCLC 
and as part of the FLAURA study.  The most common acquired resistance mechanisms identified 
were MET amplification and C797S detected in 14/91 (15%) and 6/91 (7%) patients, 
respectively.  Other mechanisms included PIK3CA 6/91 (7%), human epidermal growth factor 
receptor 2 (HER2) amplification 2/91 (2%), and RAS mutation 3/91 (3%).18  In the second-line 
setting, plasma samples were analyzed in EGFRm T790M advanced NSCLC patients as part of 

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the AURA3 study.  Of the 73/83 evaluable plasma samples, 11/73 (15%) acquired secondary 
mutation in C797 (C797S n=1; C797G n=1) and amplification of MET, HER2, and PIK3CA in 
14/73 (19%), 4/73 (5%), and 3/73 (4%) respectively.19   
Following progression on EGFR TKIs, platinum-based chemotherapy remains the standard 
treatment; however, these responses are generally not durable.20  In patients with EGFRm 
NSCLC, immune checkpoint inhibitors have also yet to demonstrate clear benefit compared to 
platinum-based chemotherapy.21  For patients who develop resistance to platinum-based 
chemotherapy in the NSCLC setting, standard of care options have limited efficacy and are 
associated with a high toxicity profile.22  One such option, ramucirumab plus docetaxel, has 
demonstrated modest benefit in OS over docetaxel in patients with squamous or non-squamous 
NSCLC who had progressed during or after a first-line platinum-based chemotherapy regimen.  
In that study, median OS was 10.5 months for the ramucirumab plus docetaxel group and 
9.1 months for the placebo plus docetaxel group (hazard ratio: 0.86; 95% CI: 0.75 to 0.98; 
P=0.023).  Therefore, NSCLC patients who have experienced progression on platinum-based 
chemotherapy and who require subsequent systemic treatment because of symptoms or tumor 
growth represent an important unmet medical need. 
Patritumab Deruxtecan 
Patritumab deruxtecan (U3-1402) is an antibody drug conjugate (ADC) comprising a 
recombinant fully human anti- human epidermal growth factor receptor 3 (HER3) 
immunoglobulin G1 (IgG1) monoclonal antibody (patritumab, U3-1287) covalently linked to 
MAAA-1162a (glycine-glycine-phenylalanine-glycine [GGFG]) tetrapeptide linker containing a 
topoisomerase I inhibitor [MAAA-1181a]).  MAAA-1181a, a derivative of exatecan 
(DX-8951f),23,24,25 is released after internalization and leads to apoptosis of the target tumor cells 
via the inhibition of topoisomerase I.   
2.2. 
Study Rationale 
In NSCLC, HER3 overexpression has been demonstrated to be one of the mechanisms of 
acquired resistance to gefitinib treatment of EGFRm tumors and is an important mechanism of 
resistance in tumors such as those with amplification of c-MET.26  The Erb-B2 receptor tyrosine 
kinase 3 (ERBB3)/HER3 is overexpressed in many cancers including breast,27 ovarian,28 
prostate,29 head and neck,30 gastric,31 and lung.32  In addition, higher expression of HER3 
correlates with poorer outcomes.33  Published retrospective prevalence studies show that HER3 
is expressed in a substantial number of NSCLC patient tumors.  A large series (n = 443) of 
NSCLC patient tumors were analyzed for HER3 expression using immunohistochemistry (IHC), 
and 68% of these patient tumors demonstrated the presence of HER3 expression.34  In a study of 
192 NSCLC patients, ERBB3 messenger ribonucleic acid (mRNA) expression was measured by 
quantitative polymerase chain reaction.  Comparison of EGFRm-positive patients to 
EGFRm-negative patients demonstrated that the ERBB3 level was significantly higher in 
patients with an EGFR mutation (24.610 ± 34.626) than in those without EGFR mutation 
(13.868 ± 24.034; P=0.0124).35  Furthermore, HER3 expression is increased in human tumor cell 
lines after treatment with gefitinib in vitro.36,37 

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Exatecan (DX-8951f), the parent component of the topoisomerase I inhibitor payload component 
(MAAA-1181a) of patritumab deruxtecan, has activity in NSCLC subjects and a wide range of 
advanced solid tumors.24,25,38,39 
Patritumab deruxtecan at 5 mg/kg showed significant antitumor activity in an 
osimertinib-resistant xenograft model of human EGFRm NSCLC using the PC9AZDR7 cell line.  
In vivo studies indicate that patritumab deruxtecan exhibits HER3 expression-dependent cell 
growth inhibition activity.   
Antitumor activity of patritumab deruxtecan was also evaluated in vivo using four 
patient-derived xenograft (PDX) models derived from EGFR-mutant NSCLC.40  These models 
were obtained from two patients who developed resistance to osimertinib (Dana-Farber Cancer 
Institute [DFCI] 306 and DFCI 284) and two patients who developed resistance to erlotinib 
(DFCI 161 and DFCI 259).  As shown in Figure 2.1, a subset of patients from whom the 
xenograft tumors were derived had known specific resistance mechanisms identified and 
immunohistochemical evaluation of membrane HER3 (using H-score) demonstrated moderate to 
high expression in three models (DFCI 161, DFCI 259, DFCI 284) and low/negative expression 
in one model (DFCI 306).  NSG mice with subcutaneous tumors (150-200 mm3) were treated 
with either immunoglobulin G1 (IgG1) control or a single dose of patritumab deruxtecan, 
administered at 10 mg/kg, and tumor growth was assessed twice weekly with digital calipers.  
Tumor growth inhibition by patritumab deruxtecan compared to control was observed in the 
3 models with moderate to high expression of HER3. 
Figure 2.1: 
Patritumab Deruxtecan Inhibits Tumor Growth in HER3-expressing 
EGFR-mutant EGFR TKI-resistant PDX Models 
 
EGFR = epidermal growth factor receptor; HER3 = human epidermal growth factor receptor 3; IgG = immunoglobulin G; PDX = 
patient-derived xenograft; TKI = tyrosine kinase inhibitor. 
Source:  Jänne PA, Yu HA, Johnson ML, et al.  Safety and preliminary antitumor activity of U3-1402, a HER3-targeted antibody 
drug conjugate in EGFR TKI-resistant, EGFRm NSCLC.  J Clin Oncol.  2019;37 (15 suppl):9010. 
In addition to the evidence for the activity of patritumab deruxtecan in non-clinical models, early 
clinical evidence, specifically in the U31402-A-U102 study, suggests that patritumab deruxtecan 
is adequately tolerated in patients with NSCLC and has evidence of clinical activity, particularly 
in patients with NSCLC harboring an EGFR-activation mutation.  

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The U31402-A-U102 study is an ongoing multicenter, open-label, Phase 1 study of patritumab 
deruxtecan in subjects with metastatic or unresectable NSCLC.  This study includes Dose 
Escalation in which subjects receive intravenous (IV) patritumab deruxtecan in 21-day cycles 
with a starting dose of 3.2 mg/kg, and Dose Expansion in which subjects receive patritumab 
deruxtecan at the recommended dose for expansion (RDE) determined in Dose Escalation or an 
up-titration dose regimen.   
As of the 03 May 2019 data cut off, 30 EGFRm TKI-resistant NSCLC subjects were evaluated 
for safety and efficacy.  Of the 30 subjects enrolled, the most frequent treatment-emergent 
adverse events (TEAEs) reported in >20% of subjects, all grades, regardless of causality and in 
decreasing order of frequency were nausea, fatigue, vomiting, thrombocytopenia, alopecia, 
decreased appetite, constipation, and diarrhea.  Dose-limiting toxicities observed included one 
(1) grade 3 febrile neutropenia and one (1) grade 4 platelet count decreased in the 5.6 mg/kg 
cohort, three (3) grade 4 platelet count decreased in the 6.4 mg/kg cohort and no dose limiting 
toxicities in the 3.2 mg/kg and 4.8 mg/kg cohorts.41  Of 26 efficacy-evaluable subjects, 23 
subjects had at least 1 post-baseline tumor assessment and confirmed responses were observed in 
6 subjects (2 partial responses each at 4.8, 5.6, and 6.4 mg/kg), including 3 subjects with an 
EGFR C797S resistance mutation and 1 subject with a MET amplification.41  This preliminary 
safety and efficacy data indicates that patritumab deruxtecan administered as a single agent may 
provide clinical benefit in subjects with metastatic or locally advanced NSCLC, particularly in 
patients with NSCLC harboring an EGFR-activating mutation with diverse mechanisms of TKI 
resistance and previously treated with osimertinib. 
As of the data cut-off date of 05 Aug 2019, all (100.0%) of the 36 enrolled subjects in the 
U31402-A-U102 study had received at least one dose of patritumab deruxtecan.  Subjects had a 
median duration of treatment of 4.5 months (range 0.7 to13.8 months).  All (100%) subjects had 
at least one TEAE.  The most frequent TEAEs reported in >20% of subjects, all grades, 
regardless of causality and in decreasing order of frequency are presented in Table 2.1. 
Table 2.1: 
Treatment-emergent Adverse Events Occurring in Greater than 20% of 
Subjects in Ongoing Study U31402-A-U102 
Preferred Term 
Number of Subjects (N = 36): n (%) 
All Grades 
Grade ≥3a 
Subjects with any TEAE 
36 (100) 
16 (44.4) 
Nausea 
23 (63.9) 
1 (2.8) 
Vomiting 
15 (41.7) 
0 
Fatigue 
14 (38.9) 
1 (2.8) 
Platelet count decreased 
11 (30.6) 
7 (19.4) 
Constipation 
10 (27.8) 
0 
Alopecia 
9 (25.0) 
NA 
Decreased appetite  
9 (25.0) 
0 
MedDRA = Medical Dictionary for Regulatory Activities; NA = not applicable; TEAE = treatment-emergent 
adverse event. 
a None of the reported TEAEs with preferred terms listed in this table were Grade 5. 
Note: Coded with MedDRA version 21.0. 
Source: Data cutoff of 05 Aug 2019. 

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TEAEs of Grade 3 or higher were reported in 16 (44.4%) subjects as of 05 Aug 2019.  The most 
common Grade ≥3 TEAEs in more than 5% of subjects included platelet count decreased 
(7 [19.4%] subjects), troponin increased (3 [8.3%] subjects), and anaemia and hypoxia (2 [5.6%] 
subjects each). 
Seven (19.4%) subjects experienced TEAEs that were associated with a dose interruption; the 
Investigator considered these TEAEs as related to study drug in 5 (13.9%) subjects.  There were 
8 (22.2%) subjects who underwent a dose reduction and 3 (8.3%) subjects who discontinued 
study drug due to TEAEs (all considered drug-related by the Investigator) as of the data cut-off 
date.  One (2.8%) subject experienced an adverse event of special interest (AESI) of pneumonitis 
(Grade 2) considered by the Investigator as related to patritumab deruxtecan.  No subject met the 
potential Hy’s Law criteria as of the data cut-off date.  No subject had a TEAE that was 
associated with a fatal outcome.  This clinical experience indicates that patritumab deruxtecan 
can be administered safely to subjects with previously treated NSCLC. 
With consideration to this clinical experience, a dose of 5.6 mg/kg was identified for further 
clinical investigation in subjects with NSCLC with an EGFR-activating mutation.  Moreover, 
preliminary evidence for the tolerability of an “up-titration” regimen with initial dose escalation 
of patritumab deruxtecan was identified, and this regimen was selected also for further clinical 
evaluation. 
See Section 4.3 for dose justification. 
2.3. 
Benefit and Risk Assessment 
In subjects with EGFRm NSCLC who have progressed after TKI and platinum doublet therapy, 
standard therapy (eg, with ramucirumab plus docetaxel) is associated with a median OS of 
approximately 10 months.  Thus, there is a considerable unmet medical need for such subjects. 
Based on the preliminary clinical safety data from the ongoing patritumab deruxtecan studies, 
nausea, decreased appetite, vomiting, diarrhea, platelet count decreased/thrombocytopenia, white 
blood cell count decreased/leukopenia, neutrophil count decreased/neutropenia, febrile 
neutropenia, anemia, fatigue, malaise, stomatitis, constipation, hypokalemia, alanine 
aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, epistaxis, and 
alopecia are identified risks.42 The dose regimens comprising a fixed dose of 5.6 mg/kg or the 
up-titration regimen have each demonstrated tolerability in study subjects (see Section 4.3).  
Preliminary data as of 03 May 2019 from the ongoing study U31402-A-U102 are as follows: of 
the 23 efficacy-evaluable patients, 6 had confirmed partial responses (2 each at 4.8, 5.6, and 
6.4 mg/kg).  Thus, preliminary evidence of efficacy has been demonstrated in patients with 
EGFR mutated NSCLC (see Section 2.2).41  Therefore, the collective information from both 
clinical as well as preclinical evaluations indicates that the benefit/risk ratio of patritumab 
deruxtecan investigation therapy is favorable in subjects with EGFRm NSCLC.   
Please refer to the most recent version of the Investigator’s Brochure (IB) for more information.  

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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, and Section 9.5.3. 
Table 3.1: 
Description of Objectives, Outcome Measures, and Endpoints 
Objectives 
Outcome Measure 
Endpoints 
Category 
Primary 
 
 
 
To investigate the 
antitumor activity of 
patritumab deruxtecan in 
subjects with metastatic 
or locally advanced 
NSCLC with an 
activating EGFR 
mutation (exon 19 
deletion or L858R) 
Title: ORR 
Description: ORR as 
assessed by BICR per 
RECIST v1.1 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
ORR is defined as the 
proportion of subjects 
with a BOR of confirmed 
CR or confirmed PR.   
Efficacy 
Secondary 
 
 
 
To investigate the 
durability of patritumab 
deruxtecan antitumor 
activity in subjects with 
metastatic or locally 
advanced NSCLC with 
an activating EGFR 
mutation (exon 19 
deletion or L858R) 
Title: DoR 
Description: DoR as 
assessed by BICR and 
Investigator per RECIST 
v1.1 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
DoR is defined as the time 
from the first documented 
response (confirmed CR 
or PR) to the date of 
progression or death due 
to any cause. 
Efficacy 
To further investigate the 
antitumor activity of 
patritumab deruxtecan in 
subjects with metastatic 
or locally advanced 
NSCLC with an 
activating EGFR 
Title: PFS 
Description: PFS as 
assessed by BICR and 
Investigator per RECIST 
v1.1  
PFS is defined as the time 
from the start of study 
treatment to the earlier of 
the dates of the first 
documentation of 
objective PD or death due 
to any cause. 
 

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Objectives 
Outcome Measure 
Endpoints 
Category 
mutation (exon 19 
deletion or L858R) 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
Death date is collected 
until the subject 
discontinues the study. 
Title: ORR 
Description: ORR as 
assessed by Investigator 
per RECIST v1.1 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression, death, lost to 
follow-up, or withdrawal 
by the subject. 
ORR is defined as the 
proportion of subjects 
with a BOR of confirmed 
CR or confirmed PR. 
Efficacy 
Title: DCR 
Description: DCR as 
assessed by BICR and 
Investigator per RECIST 
v1.1 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
DCR is defined as the 
proportion of subjects 
who achieved a BOR of 
confirmed CR, confirmed 
PR, or SD.   
Efficacy 
 
Title: TTR 
Description: TTR as 
assessed by BICR and 
Investigator per RECIST 
v1.1 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
TTR is defined as the time 
from the start of study 
treatment to the date of 
the first documentation of 
response (confirmed CR 
or PR). 
Efficacy 

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Objectives 
Outcome Measure 
Endpoints 
Category 
 
Title: Best percentage 
change in the SoD of 
measurable tumors 
Description: SoD as 
assessed by BICR and by 
Investigator per RECIST 
V1.1 
Time frame: Data are 
collected at baseline, then 
from the start of study 
treatment until 
documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
The best percentage 
change in the SoD of 
measurable tumors is 
defined as the percentage 
change in the smallest 
SoD from all post-
baseline tumor 
assessments, taking as 
reference the baseline 
SoD. 
Efficacy 
 
Title: OS 
Description: OS  
Time frame: Death date is 
collected until the subject 
discontinues the study. 
OS is defined as the time 
from the start of study 
treatment to the date of 
death due to any cause. 
Efficacy 
To assess the safety and 
tolerability of patritumab 
deruxtecan in subjects 
with metastatic or locally 
advanced NSCLC with 
an activating EGFR 
mutation (exon 19 
deletion or L858R) 
Title: Safety during the 
study* 
Description: Descriptive 
statistics of safety 
endpoints  
Time frame: From the 
time the subject signs the 
main study ICF and up to 
40 (+ 7) days after the last 
dose of study drug (ie, 5 
half-lives of the ADC/the 
follow-up period). 
*Although this is a 
secondary objective, this is 
a primary outcome 
measure. 
Incidence of TEAEs, 
SAEs, AESIs (ILD and 
elevation of 
aminotransferases and 
TBL), ECOG PS, vital 
sign measurements, 
standard clinical 
laboratory parameters 
(hematology, serum 
chemistry, and urinalysis), 
ECG parameters, 
ECHO/MUGA scan 
findings, and 
ophthalmologic findings.  
AEs and laboratory test 
results will be coded using 
the most recent version of 
MedDRA and will be 
graded using NCI-
CTCAE v5.0. 
Safety 
To evaluate HER3 
protein expression in 
tumor tissue and its 
relationship with efficacy 
Title: Correlation between 
HER3 protein expression 
(as determined by HER3 
IHC assay) and efficacy 
Description: Descriptive 
summary of HER3 status, 
and a correlative analysis 
between HER3 protein 
expression level (as 
HER3 protein expression 
in tumor tissue (as 
determined by IHC) and 
correlation with ORR, 
DoR, and PFS 
Efficacy/Biomarker 

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Objectives 
Outcome Measure 
Endpoints 
Category 
determined by HER3 IHC 
assay) and efficacy 
Time frame: Efficacy 
data are collected at 
baseline, then from the 
start of study treatment 
until documented disease 
progression by BICR, 
death, lost to follow-up, or 
withdrawal by the subject. 
HER3 data are collected at 
baseline (biopsy). 
To assess the 
immunogenicity 
incidence against 
patritumab deruxtecan 
Title: Immunogenicity 
Description: ADA 
prevalence, incidence and 
titer for patritumab 
deruxtecan. 
Time frame: Data are 
collected from the start of 
study treatment until EOT.  
Additional time points are 
specified in Table 1.1 and 
Table 1.2. 
ADA prevalence: the 
proportion of all subjects 
having a confirmed 
positive ADA sample at 
any point in time. 
ADA incidence: the 
proportion of subjects 
having treatment-
emergent ADA. 
ADA titer will be 
determined for confirmed 
ADA positive samples. 
Neutralizing antibodies: 
when neutralizing assay 
became available 
confirmed ADA positive 
samples may be analyzed 
for neutralizing activity. 
Immunogenicity 
Exploratory 
 
 
 
To explore changes in 
HER3 expression levels 
(mRNA in tissue and 
blood-based 
measurement) and HER3 
dynamics 
Not applicable 
HER3 expression level 
(mRNA in tissue and 
blood-based 
measurement) and HER3 
dynamics (mRNA and 
protein level) will be 
assessed in correlation 
with ORR, DoR, and PFS 
(confirmed by BICR). 
Biomarker 
To explore biomarkers 
that may identify subjects 
that will derive optimal 
therapeutic benefit from 
patritumab deruxtecan 
Not applicable  
Potential biomarkers 
(gene expression, genomic 
alteration, gene 
signatures) will be 
assessed in association 
with patritumab 
deruxtecan 
sensitivity/resistance 
Biomarker 

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Objectives 
Outcome Measure 
Endpoints 
Category 
To characterize the 
pharmacokinetics (PK) of 
patritumab deruxtecan in 
subjects with metastatic 
or locally advanced 
NSCLC with an 
activating EGFR 
mutation (exon 19 
deletion or L858R) 
Not applicable  
Serum concentration of 
patritumab deruxtecan 
(ADC, total anti-HER3 
antibody, and MAAA-
1181a) 
Population PK (PopPK) 
analysis 
Pharmacokinetic 
To evaluate the 
Exposure-Response for 
efficacy and safety 
endpoints 
Not applicable  
Exposure-Response for 
efficacy and safety 
parameters 
Efficacy/Safety 
ADA = anti-drug antibody; ADC = antibody drug conjugate; AE = adverse event; AESI = adverse event of special 
interest; BICR = blinded independent central review; BOR = best overall response; CR = complete response; 
CTCAE = Common Terminology Criteria for Adverse Events; DCR = disease control rate; DoR = duration of 
response; ECG = electrocardiogram; ECHO = echocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; EGFR = epidermal growth factor receptor; EOT = end of treatment; HER3 = human epidermal 
growth factor receptor 3; ICF = informed consent form; IHC = immunohistochemistry; ILD = interstitial lung 
disease; MedDRA = Medical Dictionary for Regulatory Activities; mRNA = messenger ribonucleic acid; MUGA = 
multigated acquisition; NCI = National Cancer Institute; NSCLC = non-small cell lung cancer; ORR = objective 
response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; RECIST v1.1 = 
Response Evaluation Criteria in Solid Tumors version 1.1; SAE = serious adverse event; SD = stable disease; SoD = 
sum of diameters; TBL = total bilirubin; TEAE = treatment-emergent adverse event; TTR = time to response; v = 
version. 
3.1. 
Rationale for Selection of Primary and Key Secondary Endpoints 
The primary and key efficacy endpoints selected will evaluate evidence of drug activity.  ORR is 
defined as the proportion of subjects with complete or partial response as defined by Response 
Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 in this study.  ORR is a direct 
measure of drug antitumor activity, which can be evaluated in a single-arm study.  Because ORR 
is directly attributable to drug effect, it is an appropriate measure of efficacy in single-arm 
studies.43  
Duration of response in subjects with confirmed response of complete response (CR) or partial 
response (PR) is an important secondary endpoint of the study.  A durable response is clinically 
meaningful in subjects with locally advanced or metastatic NSCLC who have received at least 
1 regimen of platinum-based chemotherapy with or without immunotherapy in which there 
remains an unmet medical need. 

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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a global, multicenter, open-label, Phase 2 study of subjects with metastatic or locally 
advanced NSCLC with an EGFR-activating mutation (exon 19 deletion or L858R) who have 
received and progressed on or after at least 1 EGFR TKI and 1 platinum-based 
chemotherapy-containing regimen.  This study will initially randomize subjects to one of 2 arms 
in a 1:1 ratio, for dose selection, to receive either a 5.6 mg/kg fixed dose regimen (Arm 1) or an 
up-titration dose regimen (Cycle 1: 3.2 mg/kg; Cycle 2: 4.8 mg/kg; Cycle 3 and subsequent 
cycles: 6.4 mg/kg every 3 weeks [Q3W]; Arm 2) of patritumab deruxtecan on Day 1 of each 
21-day cycle.  
In the ongoing U31402-A-U102 study the same population is being studied in multiple 
expansion cohorts: Cohorts 3a and 3b (with 45 subjects planned to be randomized to each dose 
regimen, 5.6 mg/kg Q3W or up-titration) and Cohort 1 (45 subjects dosed with 5.6 mg/kg Q3W).  
If, during the conduct of the current study (U31402-A-U201), analyses from the U31402-A-
U102 study indicate that one dose regimen provides clear advantages over the other in terms of 
benefit/risk, further enrollment into one arm may be discontinued:   
 If a single dose regimen (Arm 1 or Arm 2) is selected to continue enrollment, subjects 
enrolled after the decision point will be assigned to the selected dose regimen.  
Subjects enrolled before the decision point will continue their originally assigned 
dose regimen without crossover.   
 If there is no significant difference in efficacy and/or safety from the 
U31402-A--U102 NSCLC study, both dose regimens/arms in this study 
(U31402-A-U201) will continue to enroll to study completion.  
The subject population is described in Section 5. 
The study will be conducted at approximately 135 study sites located in North America, the 
European Union (EU), and the Asia Pacific region including Japan. 
The study start date is the date when the first subject has signed the main informed consent.  A 
subject is eligible to be enrolled into the interventional phase of the study when the Investigator 
or designee has obtained written consent, has confirmed all eligibility criteria have been met by 
the subject, and all Screening procedures have been completed. 
4.1.1. 
Design Overview 
This study will initially randomize subjects to one of 2 arms in a 1:1 ratio, for dose selection, to 
receive either a 5.6 mg/kg fixed dose regimen (Arm 1) or an up-titration dose regimen (Arm 2) 
of patritumab deruxtecan on Day 1 of each 21-day cycle.   
Based on the accumulated data collected in the ongoing Phase 1 U31402-A-U102 study, a 
decision to continue enrollment in Arm 1, Arm 2, or both arms of this study (U31402-A-U201) 
will be made.  The total number of subjects will be dependent on the following scenarios: 
 Scenario 1 (continue enrollment in the 5.6 mg/kg fixed dose regimen arm only) - 
will enroll approximately 210 subjects in the 5.6 mg/kg fixed dose regimen arm only 

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and enrollment in the up-titration dose regimen arm will be halted at the time of the 
decision point.  Subjects enrolled in the up-titration dose regimen arm will continue 
with their assigned treatment and will NOT cross over to the 5.6 mg/kg fixed dose 
regimen arm.  Sample size in the up-titration dose regimen arm cannot be determined 
a priori, since it depends on enrollment speed and the timing of the decision from the 
Phase 1 (U31402-A-U102) data. 
 Scenario 2 (continue enrollment in the up-titration dose regimen arm only) - 
analogous considerations to scenario 1. 
 Scenario 3 (continue enrollment in both arms) - The 5.6 mg/kg fixed dose regimen 
arm and the up-titration dose regimen arm will enroll approximately 210 subjects in 
each arm for a total of up to approximately 420 subjects. 
The Schedule of Events (SoE) is presented in Table 1.1 (Screening and Cycles 1 through 3 of 
Treatment Period) and Table 1.2 (Cycle 4 onwards, End of Treatment [EOT], and Follow-up).   
The study will be divided into 3 periods: a Screening Period, Treatment Period, and Follow-up 
Period.   
 The Screening Period will start on the day of signing the main informed consent form 
(ICF) and will have a maximum duration of 35 days.  During the 35-day Screening 
Period, the subject’s eligibility will be determined.  The subject will undergo a 
medical history evaluation, hepatitis B and C testing, a physical examination, 
measurement of vital signs, standard clinical laboratory tests, an electrocardiogram 
(ECG) recording, an echocardiogram (ECHO) or multigated acquisition (MUGA) 
scan, and an ophthalmologic assessment.  Baseline tumor imaging must be performed 
within 28 days prior to Cycle 1 Day 1.  A pretreatment tumor biopsy can be 
performed or archival tumor tissue can be provided prior to enrollment during the 
Screening Period.  Pretreatment or archival tumor tissue must be of sufficient quantity 
(as defined in the Laboratory Manual) and of adequate tumor tissue content (as 
confirmed by hematoxylin and eosin [H&E] staining at the central laboratory).  
Archival tumor tissue must have been collected from a biopsy within 3 months prior 
to signing of the tissue consent and since progression on the most recent cancer 
therapy.  Subjects must have documentation of an EGFR-activating mutation detected 
from tumor tissue: exon 19 deletion or L858R.  If test results for an EGFR-activating 
mutation are not available, subjects are required to undergo testing for these genomic 
alterations using assays approved in their country of testing (see Section 8.1).   
 Eligible subjects will be enrolled and enter the Treatment Period.  The Treatment 
Period starts on the day of enrollment (ie, Cycle 1 Day 1) and continues until a 
subject permanently discontinues patritumab deruxtecan.  To minimize the possibility 
of developing tumor flare with discontinuation of EGFR TKI, subjects who fulfill 
eligibility criteria and are receiving an EGFR TKI at the time of informed consent 
should be advised to continue their current EGFR TKI until 5 days prior to Cycle 1 
Day 1.  See the washout period for prior treatments in Sections 5.2 and 6.6.  Subjects 
will undergo radiographic assessment of tumor response based on RECIST v1.1 every 
6 weeks (±7 days) from Cycle 1 Day 1 for the first 24 weeks then every 12 weeks 
(±7 days), independent of treatment cycle, until documented disease progression by 

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blinded independent central review (BICR), death, lost to follow-up, or withdrawal of 
consent.   
Subjects will continue to receive patritumab deruxtecan until documented disease 
progression per RECIST v1.1, clinical progression, unacceptable toxicity, withdrawal 
of consent by the subject, physician’s decision, protocol deviation, pregnancy, lost to 
follow-up, study termination by the Sponsor, death, or other reasons.  If progressive 
disease is suspected by Investigator tumor assessment, imaging must be submitted to 
BICR for expedited confirmation of disease progression.  The decision to discontinue 
patritumab deruxtecan is according to Investigator judgement and should consider 
BICR assessment. 
 The Follow-up Period will start upon permanent discontinuation of patritumab 
deruxtecan.  After completion of the 40-day (+7 days) safety follow-up visit, subjects 
will be followed every 3 months for survival.  Subjects who discontinue study 
treatment for any reason other than documented disease progression by BICR, death, 
lost to follow-up, or withdrawal of consent by the subject will continue to undergo 
tumor assessments at the same frequency of every 6 weeks (±7 days) from Cycle 1, 
Day 1 for the first 24 weeks then every 12 weeks (±7 days) during the Follow-up 
Period.   
The primary analysis of ORR as assessed by BICR will be conducted after all enrolled subjects 
have either a minimum of 9 months of follow-up or have discontinued from the study earlier.  
The final analysis will occur after all subjects have discontinued from the study (see definition of 
overall End of Study [EOS] in Section 4.1.2).   
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 all enrolled subjects have either a minimum of 
9 months of follow up or have discontinued from the study earlier.  This date will be used as the 
data cut-off (DCO) date for the primary analysis of the study.  All subjects still on treatment and 
continuing to derive benefit from patritumab deruxtecan at the primary completion date will 
continue to follow the study SoE (Table 1.2) until the overall End of Study (EOS) is reached.   
The subject’s EOS is the date of their last study visit/contact. 
Overall EOS will occur when: 
 after the last subject last visit; 
 all subjects have discontinued treatment and discontinued long-term survival follow-
up or have died; 
 an alternative study becomes available, for subjects continuing to derive benefit from 
treatment with patritumab deruxtecan, where the study drug is offered to these 
subjects; 
 the study is discontinued by the Sponsor for other reasons (administrative, 
program-level or class-related).  In the event the end of study is reached prior to last 

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subject last dose, the Sponsor will provide notification and rationale according to 
local regulatory requirements. 
At the time of study closure, any subjects who are continuing treatment with patritumab 
deruxtecan and who are judged by the Investigator to have ongoing benefit may continue to 
receive treatment with patritumab deruxtecan through a rollover protocol or another 
mechanism consistent with local requirements. 
4.1.3. 
Dose Regimen(s) 
Patritumab deruxtecan will be administered as an IV infusion Q3W on Day 1 of each 21-day 
cycle as a fixed dose regimen of 5.6 mg/kg Q3W or an up-titration dose regimen at a dose of 
3.2 mg/kg at Cycle 1, 4.8 mg/kg at Cycle 2, and 6.4 mg/kg at Cycle 3 Q3W and subsequent 
cycles (depending on the assigned dose group) on Day 1 of each 21-day cycle.  The study will 
use the intended patritumab deruxtecan lyophilized-drug product (Lyo-DP).   
See Table 6.1 for complete details on dose regimen. 
4.1.4. 
Duration 
Study duration is inclusive of 3 periods: the Screening Period, Treatment Period, and Follow-up 
Period (which includes the long-term survival follow-up) as shown in Figure 1.1. 
Duration of Treatment and Subject Participation 
The duration of study treatment will continue until progressive disease, clinical progression, 
unacceptable toxicity, withdrawal of consent by the subject, physician’s decision, protocol 
deviation, pregnancy, lost to follow-up, study termination by the Sponsor, death, or other 
reasons, whichever occurs first.  The total duration of subject participation will include a 
40 (+7) day safety follow-up and every 3-month survival follow-up, or until withdrawal of 
consent by the subject, lost to follow-up, study termination by the Sponsor, death, or other 
reasons.   
Overall Study Duration 
Anticipated total duration of the study is expected to be 26 months consisting of approximately 
12 months for enrollment and 14 months on treatment.  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 is designed to investigate the antitumor activity of patritumab deruxtecan 
using the primary endpoint of ORR (as assessed by BICR per RECIST v1.1) and key secondary 
endpoint of duration of response (DoR) (as assessed by BICR per RECIST v1.1).  Two dose 
regimens will be investigated in this study: a 5.6 mg/kg fixed dose regimen and an up-titration 
dose regimen.  Each dose regimen has demonstrated preliminary efficacy and acceptable safety 
based on a program-wide analysis conducted in the U31402-A-U102 and U31402-A-J101 

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studies (see Section 4.3).  Both regimens are also being further explored in the U31402-A-U102 
Phase 1 study (Section 4.1). 
This study will be based on the assumption that treatment with patritumab deruxtecan will result 
in a clinically meaningful confirmed ORR of 37% (alternative hypothesis) that is durable 
compared to an ORR of 26.4% (null hypothesis) that is based on the upper bound of the 95% CI 
of a historic ORR of 23% of the ramucirumab plus docetaxel arm from the REVEL trial.22  These 
assumptions will be utilized to help determine the potential clinical benefit of patritumab 
deruxtecan. 
To enroll subjects into each arm with similar subject demographic and baseline, randomization is 
being implemented but there will be no direct comparison between the study arms.  However, 
accumulated efficacy, safety, and pharmacokinetic (PK)/pharmacodynamic (PD) data from 
U31402-A-U102 will support the Sponsor’s decision to continue enrollment in Arm 1, Arm 2, or 
both arms of this study (U31402-A-U201).  This decision will be made in order to select the 
most optimal dose regimen with the most favorable benefit/risk profile in subjects with NSCLC 
harboring activating EGFR mutations (exon 19 deletion or L858R). 
Until this decision is made, both the 5.6 mg/kg fixed dose regimen (Arm 1) and the up-titration 
dose regimen (Arm 2) will continue to be explored in this study (U31402-A-U201). 
The rationale for selection of the primary and key secondary efficacy endpoints is presented in 
Section 3.1.   
4.3. 
Justification for Dose Regimen(s) 
Two dose regimens are being evaluated for safety and efficacy in this study (U31402-A-U201): 
 Fixed dose regimen (Arm 1): 5.6 mg/kg IV Q3W  
 Up-titration dose regimen (Arm 2): Cycle 1: 3.2 mg/kg; Cycle 2: 4.8 mg/kg; Cycle 3 
and subsequent cycles: 6.4 mg/kg IV Q3W 
The 2 dose regimens are currently being evaluated in studies U31402-A-U102 and 
U31402-A-J101.  See Table 4.1 for details. 

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Table 4.1: 
Subjects Treated and Planned by Dose Regimen 
 
Fixed Dose Regimen 
Up-titration Dose Regimen 
Dosing 
5.6 mg/kg IV Q3W 
Cycle 1: 3.2 mg/kg;  
Cycle 2: 4.8 mg/kg;  
Cycle 3 and subsequent 
cycles: 6.4 mg/kg  
IV Q3W cycles 
Study 
Cohort 
Treated 
Planned 
Treated 
Planned 
U31402-A-
U102 
Dose Escalation (NSCLC with 
EGFR-activating mutations) 
12 
12 
-- 
-- 
Dose Expansion Cohort 1 (NSCLC 
with EGFR-activating mutations) 
45 
45 
-- 
-- 
Dose Expansion Cohort 2 (NSCLC 
without EGFR-activating mutations) 
19 
45 
-- 
-- 
Dose Expansion Cohort 3a 
(NSCLC with EGFR-activating 
mutations) 
1 
45 
-- 
-- 
Dose Expansion Cohort 3b 
(NSCLC with EGFR-activating 
mutations) 
-- 
-- 
1 
45 
U31402-A-
J101 
Dose Finding (HER3-positive 
metastatic breast cancer) 
-- 
-- 
12 
12 
EGFR= epidermal growth factor receptor; HER3 = human epidermal growth factor receptor 3; IV = intravenous; 
NSCLC= Non-small cell lung cancer; Q3W = every 3 weeks. 
Source: Preliminary data as of 30 Apr 2020 for study U31402-A-U102 and as of 11 Mar 2020 for study 
U31402-A-J101 
The 5.6 mg/kg fixed dose regimen was selected based on preliminary analysis of PK, safety, 
and efficacy from 30 subjects in U31402-A-U102 (DCO 03 May 2019)41 and 130 subjects in 
U31402-A-J101 (DCO 29 Mar 2019) studies.  Together with exposure-response modeling of 
efficacy and safety parameters, these analyses supported 5.6 mg/kg as the RDE.  For further 
details, see Section 2.2. 
The up-titration dose regimen was additionally chosen for study based on data collected in the 
U31402-A-J101 study that demonstrated preliminary evidence of a favorable safety profile at 
this dose regimen.  During the U31402-A-J101 dose escalation, Grade 3 or 4 thrombocytopenia 
was observed most often in Cycle 1 followed by a reactive thrombocytosis over Cycle 2 and 
Cycle 3 resulting in a pre-infusion Cycle 3 platelet count equal to or greater than baseline 
(Screening).  The incidences of both ≥Grade 3 thrombocytopenia and (≥Grade 3 neutropenia 
increased with respect to administered dose, and exposure-response analyses showed that 
probability of either of these events correlated with the Cmax of the drug payload 
(MAAA-1181a).  Furthermore, the payload Cmax was noted to be higher in Cycle 1 versus 
Cycle 3.  Based on these preliminary observations, an up-titration dose regimen was chosen for 
study in the U31402-A-J101 study, whereby 3.2 mg/kg is administered in Cycle 1, 4.8 mg/kg in 
Cycle 2, and 6.4 mg/kg in Cycle 3 and beyond, in 3-week cycles.  This is based on the 
hypothesis that starting with a lower dose in Cycle 1 would be associated with a lower payload 

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Cmax and hence a lower risk of ≥Grade 3 thrombocytopenia or neutropenia during Cycle 1, and 
that reactive thrombocytosis and decreases in payload Cmax over Cycles 2 and 3 might present a 
lower risk of ≥Grade 3 thrombocytopenia or neutropenia in later cycles. 
As of 05 Aug 2019, the up-titration dose regimen in the U31402-A-J101 study has shown an 
incidence of ≥Grade 3 thrombocytopenia in 16.7% of subjects; whereas, the 4.8 mg/kg or 
6.4 mg/kg fixed dose regimens was 24.4% and 53.5%, respectively (Table 4.2).  In addition, 
≥Grade 3 neutropenia was observed in 50.0% of subjects treated with the up-titration dose 
regimen compared to 22.2% and 48.8%, respectively, in the 4.8 mg/kg or 6.4 mg/kg fixed dose 
regimens.   
Based on this preliminary evidence, both a fixed dose regimen and an up-titration dose regimen 
are being evaluated in the present study to provide a deeper understanding of the safety and 
efficacy of both regimens. 
Table 4.2: 
Preliminary Data by Dose Regimen in Subjects with HER3-positive Breast 
Cancer in Study U31402-A-J101 
 
Fixed Dose Regimen 
Up-Titration Regimen 
 Dosing 
4.8 mg/kg 
IV Q3W 
6.4 mg/kg 
IV Q3W 
Cycle 1: 3.2 mg/kg; Cycle 2: 
4.8 mg/kg; Cycle 3 and subsequent 
cycles: 6.4 mg/kg IV Q3W cycles 
Efficacy Analysis Set (n) 
37 
36 
12 
 
Confirmed ORR (by Investigator 
Assessments), n (%) 
8 (21.6) 
11 (30.6) 
5 (41.7) 
Safety Analysis Set (n) 
45 
43 
12 
 
Serious TEAEs 
12 (26.7) 
18 (41.9) 
3 (25.0) 
 
Grade ≥3 Thrombocytopenia (%) 
11 (24.4) 
23 (53.5) 
2 (16.7) 
 
Grade ≥3 Neutropenia (%) 
10 (22.2) 
21 (48.8) 
6 (50.0) 
 
Grade ≥3 Anemia (%) 
9 (20.0) 
11 (25.6) 
1 (8.3) 
HER3 = human epidermal growth factor receptor 3; IV = intravenous; ORR = objective response rate; Q3W = every 
3 weeks; TEAE = treatment-emergent adverse event. 
As of the 05 Aug 2019 data cut-off date 

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5. 
STUDY POPULATION 
Adult subjects (aged ≥18 years in the United States [US]; ≥20 years old in Japan and South 
Korea; for other countries, guidelines on the legal age to consent44 should be followed) with a 
diagnosis of metastatic or locally advanced NSCLC with an EGFR-activating mutation (exon 19 
deletion or L858R) after progression with systemic therapy who have received at least one prior 
line of TKI and 1 platinum-based chemotherapy containing regimen in the metastatic or locally 
advanced setting. 
5.1. 
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for enrollment into the study: 
1. Sign and date the tissue ICF and the main ICF, prior to the start of any study-specific 
qualification procedures. 
2. Male or female subjects aged ≥18 years (follow local regulatory requirements if the legal 
age of consent44 for study participation is >18 years old). 
3. Histologically or cytologically documented locally advanced or metastatic NSCLC not 
amenable to curative surgery or radiation. 
4. Documentation of radiological disease progression while on/after receiving most recent 
treatment regimen for locally advanced or metastatic disease.  Subjects must have 
received both of the following: 
a. Prior treatment with osimertinib.  Subjects receiving an EGFR TKI at the time of 
signing informed consent should continue to take the EGFR TKI until 5 days 
prior to Cycle 1 Day 1.   
 
Subjects in South Korea known to harbor a clinically actionable genomic alteration in 
addition to EGFR mutation (eg, anaplastic lymphoma kinase [ALK] or ROS1 
protocol oncogene 1 [ROS1] fusion) for which treatment is available must have also 
received prior treatment with at least 1 approved genotype-directed therapy, unless 
unable (ie, if contraindicated).  No new testing for these genomic alterations (eg, 
ALK or ROS1 fusion) is required for Screening. 
 
b. Systemic therapy with at least 1 platinum-based chemotherapy regimen. 
5. Documentation of an EGFR-activating mutation detected from tumor tissue or blood 
sample: exon 19 deletion or L858R.  
6. At least 1 measurable lesion confirmed by BICR as per RECIST v1.1 (see Section 10.4) 
7. Consented and willing to provide required tumor tissue of sufficient quantity (as defined 
in the Laboratory Manual) and of adequate tumor tissue content (as confirmed by H&E 
staining at the central laboratory).  Required tumor tissue can be provided as either:  
a. Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and 
amenable to core biopsy  

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OR 
b. Archival tumor tissue collected from a biopsy performed within 3 months prior to 
signing of the tissue consent and since progression while on or after treatment with 
the most recent cancer therapy regimen.   
8. Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at 
Screening (see Section 10.3.3). 
9. Has adequate bone marrow reserve and organ function, based on local laboratory data 
within 14 days prior to Cycle 1 Day 1: 
Laboratory Test 
Laboratory Value 
Platelet count 
≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not 
allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility) 
Hemoglobin 
≥9.0 g/dL (transfusion and/or growth factor support is allowed) 
Absolute neutrophil count 
≥1500/mm3 or ≥1.5 × 109/L  
Serum creatinine OR creatinine 
clearance 
SCr ≤1.5 × ULN, OR CrCl ≥30 mL/min as calculated using the 
Cockcroft-Gault equation or measured CrCl 
Aspartate aminotransferase/ 
Alanine aminotransferase 
≤3 × ULN (if liver metastases are present, ≤5 × ULN) 
Total bilirubin 
≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of 
documented Gilbert’s syndrome [unconjugated 
hyperbilirubinemia] or liver metastases) 
Serum albumin 
≥2.5 g/dL 
PT or PT-INR and aPTT/PTT 
≤1.5 × ULN, except for subjects on coumarin-derivative 
anticoagulants or other similar anticoagulant therapy, who must 
have PT-INR within therapeutic range as deemed appropriate by 
the Investigator 
aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; INR = international normalized 
ratio; PT = prothrombin time; PTT = partial thromboplastin time; SCr = serum creatinine; ULN = upper 
limit of normal. 
10. If the subject is a female of childbearing potential, she must have a negative serum 
pregnancy test at Screening and must be willing to use highly effective birth control, as 
detailed in Section 10.3.4, upon enrollment, during the Treatment Period, and for 
7 months following the last dose of study drug.  A female 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) with surgery at least 1 month before 
the first dose or confirmed by follicle stimulating hormone (FSH) test.  See Section 8.4.2 
Pregnancy Test for further details regarding confirmation of post-menopausal status. 
11. 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. 

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12. If male, the subject must be surgically sterile or willing to use highly effective birth 
control (Section 10.3.4) upon enrollment, during the treatment period, and for at least 
4 months following the last dose of study drug. 
13. 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. 
14. Is willing and able to comply with scheduled visits, drug administration plan, laboratory 
tests, other study procedures, and study restrictions. 
5.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Any previous or current histologic or cytologic evidence of small cell OR combined 
small cell/non-small cell disease in the archival tumor tissue or pretreatment tumor 
biopsy. 
2. Any history of interstitial lung disease (including pulmonary fibrosis or radiation 
pneumonitis), has current interstitial lung disease (ILD), or is suspected to have such 
disease by imaging during Screening. 
3. Clinically severe respiratory compromise (based on Investigator’s assessment) resulting 
from intercurrent pulmonary illnesses including, but not limited to:  
a. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior to 
the study enrollment, severe asthma, severe chronic obstructive pulmonary disease 
[COPD], restrictive lung disease, pleural effusion); 
b. Any autoimmune, connective tissue or inflammatory disorders with pulmonary 
involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); 
OR prior complete pneumonectomy. 
4. Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or equivalent 
anti-inflammatory or any form of immunosuppressive therapy prior to enrollment.  
Subjects who require use of bronchodilators, inhaled or topical steroids, or local steroid 
injections may be included in the study.   
5. Evidence of any leptomeningeal disease  
6. Evidence of clinically active spinal cord compression or brain metastases, defined as 
untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants 
to control associated symptoms.  Subjects with clinically inactive or treated brain 
metastases who are asymptomatic (ie, without neurologic signs or symptoms and not 
requiring treatment with corticosteroids or anticonvulsants) may be included in the study.  
Subjects must have a stable neurologic status for at least 2 weeks prior to Cycle 1 Day 1. 
7. Inadequate washout period prior to Cycle 1 Day 1, defined as: 
a. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy 
<7 days; 

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b. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a 
previous cancer treatment regimen or clinical study (other than EGFR TKI), <14 days 
or 5 half-lives, whichever is longer; 
c. Monoclonal antibodies, other than immune checkpoint inhibitors, such as 
bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) <28 days; 
d. Immune checkpoint inhibitor therapy <21 days; 
e. Major surgery (excluding placement of vascular access) <28 days; 
f. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation <28 days or palliative radiation therapy <14 days; or 
g. Chloroquine/hydroxychloroquine ≤14 days. 
8. Prior treatment with an anti-HER3 antibody or single-agent topoisomerase I 
inhibitor. 
9. Prior treatment with an ADC that consists of any topoisomerase I inhibitor. 
10. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline.  Subjects with 
chronic Grade 2 toxicities may be eligible at the discretion of the Investigator after 
consultation with the Sponsor Medical Monitor or designee. 
11. Has history of other active malignancy within 3 years prior to enrollment, except: 
a. Adequately treated non-melanoma skin cancer; 
b. Superficial bladder tumors (Ta, Tis, T1); 
c. Adequately treated intraepithelial carcinoma of the cervix uteri; 
d. Low risk non-metastatic prostate cancer (with Gleason score <7, and following local 
treatment or ongoing active surveillance); 
e. Any other curatively treated in situ disease. 
12. Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1, including: 
a. QT interval corrected with Fridericia’s formula (QTcF) prolongation interval of 
>470 ms for females and >450 ms for males; 
b. Left ventricular ejection fraction (LVEF) <50% by either ECHO or MUGA scan; 
c. Resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg; 
d. Myocardial infarction within 6 months; 
e. New York Heart Association (NYHA) Classes 2 to 4 congestive heart failure 
(See Section 10.3.2) within 28 days; 
f. Uncontrolled angina pectoris within 6 months; 
g. Cardiac arrhythmia requiring antiarrhythmic treatment. 
13. Active hepatitis B and/or hepatitis C infection, such as those with serologic evidence of 
viral infection within 28 days of Cycle 1 Day 1.  
a. Subjects with past or resolved HBV infection are eligible if:   
i. 
Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody 
(anti-HBc) positive; OR  
ii. 
HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL 
in the absence of anti-viral therapy and during the previous 12 weeks prior to 

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the viral load evaluation with normal transaminases values (in the absence of 
liver metastasis); OR 
iii. 
HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL 
in the absence of anti-viral therapy and during the previous 12 weeks prior to 
the viral load evaluation for subjects with liver metastasis and abnormal 
transaminases with a result of AST/ALT <3 × ULN. 
b. Subjects with a history of hepatitis C infection will be eligible for enrollment only if 
the viral load according to local standards of detection is documented to be below the 
level of detection in the absence of anti-viral therapy during the previous 12 weeks 
(ie, sustained viral response according to the local product label but no less than 
12 weeks, whichever is longer). 
14. Subject with any human immunodeficiency virus (HIV) infection. 
15. Any evidence of severe or uncontrolled diseases including active bleeding diatheses, 
active infection, psychiatric illness/social situations, geographical factors, substance 
abuse, or other factors which in the Investigator’s opinion makes it undesirable for the 
subject to participate in the study or which would jeopardize compliance with the 
protocol.  Screening for chronic conditions is not required. 
16. History of hypersensitivity to either the drug substance or any excipients in patritumab 
deruxtecan. 
17. Female who is pregnant or breast-feeding or intends to become pregnant during the study. 
18. Prior or ongoing clinically relevant illness, medical condition, surgical history, physical 
finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the 
safety of the subject; alter the absorption, distribution, metabolism or excretion of the 
study drug; or confound the assessment of study results. 
19. Has clinically significant corneal disease. 
5.3. 
Screening Failures, Rescreening, and Subject Replacement 
The study will allow rescreening once for any subject who failed to meet eligibility criteria upon 
initial Screening or whose Screening window has elapsed.  The Investigator will consult with the 
Sponsor prior to making the decision to rescreen a subject.  A unique subject identification 
number will be assigned at the time of rescreening.  The initial reason why the subject is 
ineligible for the initial evaluation will be recorded on the Screening Log at the site and will be 
entered into the clinical database.  If a subject undergoes rescreening, the subject must repeat all 
out of window assessments (ie, procedures performed beyond the specified window prior to 
Cycle 1 Day 1). 

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6. 
STUDY TREATMENT(S) 
See Figure 1.1 for treatment sequence. 
6.1. 
Study Drug(s) Description 
Table 6.1 describes the formulation, dose, regimen, duration, packaging, and labeling of 
patritumab deruxtecan (U3-1402). 
Table 6.1: 
Study Drug Dosing Information 
Study Drug Name 
Patritumab Deruxtecan (U3-1402) for Injection 100 mg 
Dosage Formulation 
Patritumab deruxtecan (U3-1402) drug product will be provided as 100 mg of lyophilized-
drug powder (Lyo-DP) in single-use amber glass vials of sterile drug product to be 
reconstituted with 5 mL water for injection to 20 mg/mL prior to use. 
Dosage Level(s) 
Fixed dose regimen:  5.6 mg/kg 
Up-titration dose regimen:  Cycle 1: 3.2 mg/kg; Cycle 2: 4.8 mg/kg;  
Cycle 3 and subsequent cycles: 6.4 mg/kg 
Route of Administration 
Intravenous (IV) 
Dosing 
One IV infusion every 3 weeks on Day 1 of each 21-day cycle 
Duration 
Patritumab deruxtecan (U3-1402) will be infused as a continuous IV infusion over 
approximately 90 minutes on Day 1 of Cycle 1.  In the absence of infusion-related reaction 
(IRR), the subsequent doses will be infused over approximately 30 minutes.  In case of 
IRR at any time during treatment, subsequent doses will be infused over 90 minutes. 
Packaging 
Patritumab deruxtecan (U3-1402) will be supplied by the Sponsor.  Study drug will be 
packaged in cartons containing 1 vial of patritumab deruxtecan for Injection 100 mg 
(lyophilized powder).  Each vial is single use only.   
Labeling 
Patritumab deruxtecan (U3-1402) packaging will be labeled as required per local 
regulatory requirement.   
6.2. 
Preparation, Handling, Storage, and Accountability for Study 
Drug(s) 
Preparation, Handling, and Disposal 
The preparation of study drug will be conducted in accordance with the Dose Preparation 
Instructions in the Pharmacy Manual provided by the Sponsor.   
Prepared medicinal solutions should be used immediately.  Refer to the Dose Preparation 
Instructions for detailed information about preparation and administration of patritumab 
deruxtecan. 
Procedures for proper handling and disposal of anticancer drugs should be followed in 
compliance with the standard operating procedures (SOPs) of the site. 
Administration 
The selected dose of patritumab deruxtecan will be reconstituted with 5 mL water for injection to 
20 mg/mL prior to use.  Following the reconstitution in 5 mL water for injection the product will 
be diluted in 5% dextrose solution for infusion.  Patritumab deruxtecan will be administered as a 
continuous IV infusion over approximately 90 minutes on Day 1 of Cycle 1.  If there are no 

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infusion-related reactions after the initial dose, subsequent doses of patritumab deruxtecan will 
be infused over approximately 30 minutes on Day 1 of each subsequent cycle Q3W.  Refer to 
Table 6.4 for additional information on drug administration following infusion-related reactions.   
Subjects should receive the study drug within 3 days of randomization/enrollment.  The subject’s 
weight at baseline (defined as the last measurement on or prior to Cycle 1 Day 1) will be used to 
calculate the initial dose.  The subject’s weight will be determined at the beginning of each cycle.  
If during Cycle 1 Day 1 or throughout the course of treatment, the subject’s weight changes by 
≥10% from the baseline weight, the dose will be recalculated using this new weight and will be 
considered the new baseline for all subsequent dosing calculations. 
The drug formulation used in this study will be Lyo-DP. 
Storage 
Patritumab deruxtecan vials must be stored in a secure, limited access storage area under the 
recommended storage conditions noted on the label and protected from light: Lyo-DP should be 
stored at 5°C±3°C (between 2°C and 8°C).   
If storage conditions are not maintained per specified requirements, then the Sponsor or contract 
research organization (CRO) should be contacted. 
See the Pharmacy Manual for additional information on storage conditions of the study drug. 
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. 
The Receipt of Shipment Form should be faxed as instructed on the form unless receipt is 
controlled by interactive response technology (IRT).  The original will be retained at the study 
site. 
In addition, the Investigator or designee shall contact the Sponsor as soon as possible if there is a 
problem with the shipment. 
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). 
At the end of the study or as directed, all unused, used and/or partially used patritumab 
deruxtecan will be destroyed at the site as per site policy or local laws (and documented).  As 
applicable, the study site must file a copy of the appropriate institution policy (and certificate of 
destruction) within their Investigator site file and provide a copy to the Sponsor.  Please see the 
Pharmacy Manual for details.   
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
Method of Treatment Allocation 
This will be an open-label study.  Initially, subjects will be randomized to one of the 2 arms 
(5.6 mg/kg fixed dose regimen [Arm 1] or up-titration dose regimen [Arm 2]) in a 1:1 ratio until 

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a decision is made based on data from the U31402-A-U102 study to continue enrollment in 
Arm 1, Arm 2, or in both arms.  A maximum of 3 days is allowed between randomization and 
Cycle 1 Day 1 of the treatment in the study.   
An independent biostatistician from the CRO, not otherwise part of the Sponsor study team, will 
generate the randomization list.  Based on this information, the system will assign a unique 
randomization number and dose group for that subject.   
Overall enrollment will be managed through the IRT for subjects meeting all eligibility criteria.  
The instructions on how to use the system will be provided in the IRT Manual.   
Blinding 
This is an open-label study; therefore, no blinding will be used. 
6.4. 
Treatment Compliance 
Patritumab deruxtecan will be administered as an IV infusion to subjects under the supervision of 
study site personnel.  Therefore, treatment compliance will be guaranteed as long as the subject 
attends each visit for administration of study drug.  Start and stop date/time of injection and 
amount of drug administered must be recorded in the electronic case report form (eCRF).   
6.5. 
Guidelines for Dose Modification 
All dose modifications (ie, dose interruption, dose reduction, and/or treatment discontinuation) 
should be based on the worst preceding toxicity (NCI-CTCAE v5.0).  Possible exceptions to the 
dose modification criteria may be allowed on a case-by-case basis after discussion and 
agreement between the Investigator and Sponsor.  The agreement must be documented.  Dose 
modification decisions may be based on local laboratory results. 
All dose modifications must be recorded on the adverse event (AE) and drug administration 
eCRF pages.  If study drug is interrupted, missed doses will not be made up.   
Dose modifications are applicable only to TEAEs that are assessed as related to use of 
patritumab deruxtecan by the Investigator(s).  For non-drug related TEAEs, follow standard 
clinical practice.  Appropriate clinical experts should be consulted as deemed necessary.   
Dose Delay Guidelines 
The dose can be delayed for up to 28 days from the planned date of administration (ie, 49 days 
from the last infusion date).  If a subject is assessed as requiring a dose delay longer than 
28 days, the subject should be discontinued from the study treatment.   
Dose Reduction Guidelines 
If dose reduction is required, patritumab deruxtecan dosing should be reduced by 1 dose level at 
a time (Table 6.2).  Once the dose of patritumab deruxtecan has been reduced due to an AE, all 
subsequent cycles should be administered at that lower dose level unless further dose reduction is 
required.   
Dose reductions for the fixed dose 5.6 mg/kg regimen are described in Table 6.2. 

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Table 6.2: 
Dose Reductions for the Fixed Dose 5.6 mg/kg Regimen 
Starting Dose (0) 
5.6 mg/kg IV infusion Q3W 
Dose Level (− 1) 
4.8 mg/kg IV infusion Q3W 
Dose Level (− 2) 
3.2 mg/kg IV infusion Q3W 
IV = intravenous; Q3W = every 3 weeks. 
In the up-titration regimen, subjects will undergo up-titration as follows: Cycle 1 at 3.2 mg/kg, 
Cycle 2 at 4.8 mg/kg, Cycle 3 and subsequent cycles at 6.4 mg/kg Q3W.  The recommended 
dose reduction is described in Table 6.3.  If a TEAE requiring dose reduction occurs during 
up-titration (ie, Cycles 1 or 2), a further increase in dose is prohibited. 
Table 6.3: 
Dose Reductions for the Up-titration Dose Regimen 
Starting Dose (0) 
6.4 mg/kg IV Q3W 
4.8 mg/kg Q3W 
3.2 mg/kg Q3W 
Dose Level (− 1) 
4.8 mg/kg IV Q3W 
3.2 mg/kg Q3W 
Discontinue 
Dose Level (− 2) 
3.2 mg/kg IV Q3W 
Discontinue 
Discontinue 
IV = intravenous; Q3W = every 3 weeks. 
Subjects will be withdrawn from the study treatment if further toxicity meeting the requirement 
for dose reduction occurs. 
Dose Modification Guidelines 
Table 6.4 provides schedule modifications for specific toxicities.   
Table 6.4: 
Dose Modifications for Non-Hematologic and Hematologic Toxicity Related 
to Patritumab Deruxtecan 
 
Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
General disorders and administration site conditions 
Infusion-related 
reaction (eg, same 
reduced rate as 
previous infusion) 
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 must be reduced by 50% and subject must be 
closely monitored. 
If no other reactions appear, the subsequent infusion rate can 
be resumed at the initial planned rate. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Grade 2 
Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
nonsteroidal anti-
inflammatory drugs 
[NSAIDs], narcotics, 
intravenous [IV] injection 
fluids); prophylactic 
medications indicated for 
≤24 hours 
Patritumab deruxtecan infusion must be interrupted. 
Symptomatic treatment (eg, antihistamines, NSAIDs, 
narcotics, IV fluids) must be started. 
If the event resolves or improves to Grade 1, infusion can be 
re-started at a 50% reduced infusion rate. 
Upon restart, if Grade 2 symptoms recur, no further 
patritumab deruxtecan must be administered at that visit.  
The amount of patritumab deruxtecan infused must be 
recorded in the eCRF. 
Subsequent infusions must be conducted at the 50% reduced 
infusion rate (ie, same reduced rate as previous infusion). 
Grade 3 
Prolonged (eg, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for clinical sequelae 
 
Grade 4 
Life-threatening 
consequences, urgent 
intervention indicated 
Administration of patritumab deruxtecan must be 
discontinued immediately and permanently. 
Urgent intervention is indicated.  Antihistamines, steroids, 
epinephrine, bronchodilators, vasopressors, IV fluid therapy, 
oxygen inhalation, etc., must be administered as clinically 
indicated. 
Fatigue/Asthenia/ 
Malaise 
Grade 3 
Delay dose until resolved to ≤Grade 1, then: 
 If resolved to ≤Grade 1 or baseline values in ≤14 days, 
resume patritumab deruxtecan; 
 If resolved to ≤Grade 1 or baseline values in 14 days, 
reduce patritumab deruxtecan by 1 dose level and 
resume. 
Blood and lymphatic system disorders 
Neutrophil count 
decreased 
Grade 3 
(500 to 1000/mm3;  
0.5-1 × 109/L) 
Delay dose until resolved to ≤Grade 2, then resume 
patritumab deruxtecan. 
Grade 4 
(500/mm3; <0.5 × 109/L) 
Delay dose until resolved to ≤Grade 2; then reduce 
patritumab deruxtecan by 1 dose level. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Febrile 
neutropenia 
(ANC <1000/mm3; 
1 × 109/L, fever 
38.3°C or a 
sustained 
temperature of 
≥38°C for more 
than 1 hour) 
Grade 3 
Delay dose until resolved; then resume patritumab 
deruxtecan.  Consider reducing patritumab deruxtecan by 1 
dose level.   
Consider administration of G-CSF as prophylaxis for all 
subsequent cycles and according to local guidelines. 
Febrile 
neutropenia (ANC 
<1000/mm3; <1 × 
109/L, fever 
>38.3°C or a 
sustained 
temperature of 
≥38°C for more 
than 1 hour) 
Grade 4 
Delay dose until resolved, then reduce patritumab 
deruxtecan by 1 dose level and resume. 
Administer G-CSF as prophylaxis for all subsequent cycles 
and according to local guidelines. 
Lymphocyte count 
decreaseda 
Grade 4 
(<0.2 × 109/L) 
Delay dose until resolved to ≤Grade 2, then:  
 If resolved in ≤14 days, resume patritumab deruxtecan. 
 If resolved in 14 days; reduce patritumab deruxtecan 
by 1 dose level and resume. 
Anemia 
Grade 3 
(Hemoglobin 8.0 g/dL) 
Delay dose until resolved to ≤Grade 2 or baseline; then 
resume patritumab deruxtecan.   
For recurrent anemia, delay dose until resolved ≤Grade 2 or 
baseline, then reduce patritumab deruxtecan by 1 dose level 
and resume. 
Consider transfusion per institutional guidelines. 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention indicated) 
Delay dose until resolved to ≤Grade 2 or baseline, then 
reduce patritumab deruxtecan by 1 dose level and resume. 
Consider transfusion per institutional guidelines. 
Platelet count 
decreased 
Grade 3 
(Platelet 50 – 25 × 
109/L) 
Delay dose until resolved to ≤Grade 1, then: 
 If resolved in ≤14 days, resume patritumab deruxtecan; 
 If resolved in 14 days, patritumab deruxtecan may be 
resumed.  Consider reducing patritumab deruxtecan by 
1 dose level. 
Consider transfusion per institutional guidelines. 
Grade 4 
(Platelet 25 × 109/L) 
Delay dose until resolved to ≤Grade 1, then reduce 
patritumab deruxtecan by 1 dose level and resume. 
Consider transfusion per institutional guidelines. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Cardiac disorders 
Heart failure 
Grade ≥2 
(Symptoms with moderate 
activity or exertion) 
Cardiologist consultation as necessary. 
Delay dose until resolved to ≤Grade 1, then reduce 
patritumab deruxtecan by 1 dose level. 
 
Ejection fraction 
decreased 
Decrease in LVEF 10% to 
20% (absolute value), but 
LVEF 45% 
Continue patritumab deruxtecan. 
LVEF 40% to ≤45% and 
decrease is 10% 
(absolute value) from 
baseline 
Continue patritumab deruxtecan. 
Repeat LVEF assessment within 3 weeks. 
LVEF 40% to ≤45% and 
decrease is ≥10% to 20% 
(absolute value) from 
baseline 
Delay patritumab deruxtecan. 
Repeat LVEF assessment within 3 weeks. 
If LVEF has not recovered to within 10% (absolute value) 
from baseline, discontinue subject from study treatment. 
LVEF 40% or 20% 
(absolute value) drop 
from baseline 
Delay patritumab deruxtecan. 
Repeat LVEF assessment within 3 weeks. 
If LVEF 40% or 20% (absolute value) drop from baseline 
is confirmed, discontinue patritumab deruxtecan. 
Cardiologist consultation as necessary. 
Electrocardiogram 
QT corrected 
interval prolonged 
Grade 3 
(Average QTcF ≥501 ms; 
60 ms change from 
baseline) 
Delay patritumab deruxtecan until resolved to ≤Grade 1 
(QTcF ≤ 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. 
If QTcF prolongation is attributed to patritumab deruxtecan, 
then reduce patritumab deruxtecan by 1 dose level. 
Cardiologist consultation as necessary. 
Grade 4 (Torsades de 
pointes; polymorphic 
ventricular tachycardia; 
signs/symptoms of serious 
arrhythmia) 
Discontinue subject from patritumab deruxtecan. 
Cardiologist consult as necessary. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Respiratory, thoracic and mediastinal disorders 
Pulmonary toxicity 
See next column 
If a subject develops radiographic changes potentially 
consistent with ILD or develops an acute onset of new or 
worsening pulmonary or other related signs/symptoms such 
as dyspnea, cough or fever, rule out ILD. 
If ILD is suspected, delay patritumab deruxtecan dosing 
pending further evaluation and start corticosteroid treatment 
promptly unless clinically contraindicated.45 
Evaluations must include CT (preferably high-resolution 
CT), and pulmonologist consultation (when the Investigator 
is not a pulmonologist).  The following evaluations must 
also be obtained, as indicated: 
 
Infectious disease consultation as clinically indicated 
 
Blood culture and CBC (other blood tests could be 
considered as needed) 
 
Bronchoscopy and bronchoalveolar lavage if clinically 
indicated and feasible 
 
Pulmonary function tests 
 
Pulse oximetry (SpO2) 
 
Arterial blood gases, as clinically indicated 
 
Diffusing capacity of the lungs for carbon monoxide 
(DLCO), as clinically indicated 
 
One blood sample collection for PK analysis as soon 
as ILD is suspected, if feasible 
 
Other tests, as clinically indicated 
If a non-inflammatory/infectious etiology is confirmed by 
the Investigator, treat accordingly and resumption of 
patritumab deruxtecan may occur after discussion between 
the Investigator and Sponsor. 
All events of ILD regardless of severity or seriousness will 
be followed until resolution including after drug 
discontinuation. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Grade 1 
The administration of patritumab deruxtecan must be 
delayed.  Patritumab deruxtecan can be restarted only if the 
event is fully resolved to Grade 0: 
 If resolved in ≤28 days from day of onset, maintain 
dose. 
 If resolved in >28 days from day of onset, reduce dose 
1 level. 
Toxicity Management: 
 Monitor and closely follow-up in 2 to 7 days for onset 
of clinical symptoms and pulse oximetry. 
 Consider follow-up imaging in 1-2 weeks (or as 
clinically indicated). 
 Consider starting systemic steroids (eg, at least 
0.5 mg/kg/day prednisone or equivalent) until 
improvement, followed by gradual taper over at least 4 
weeks. 
 If worsening of diagnostic observations despite 
initiation of corticosteroids, then follow Grade 2 
guidelines (if subject is asymptomatic, then subject 
must still be considered as Grade 1 even if steroid 
treatment is given). 
Grade 2 
Permanently discontinue subject from study treatment. 
Toxicity Management: 
 Promptly start systemic steroids (eg, at least 1 
mg/kg/day prednisone or equivalent) for a minimum of 
14 days or until complete resolution of clinical 
symptoms and chest CT findings, followed by gradual 
taper over at least 4 weeks. 
 Monitor symptoms closely. 
 Re-image as clinically indicated. 
 If worsening or no improvement in clinical or 
diagnostic observations in 5 days,  
 
Consider increasing dose of steroids (eg, 2 
mg/kg/day prednisone or equivalent) and 
administration may be switched IV (eg, 
methylprednisolone). 
 
Re-consider additional work-up for alternative 
etiologies as described above. 
 
Escalate care as clinically indicated. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Grade 3 or 4 
Permanently discontinue subject from study treatment. 
Toxicity Management: 
 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 a minimum of 14 days 
or until complete resolution of clinical symptoms and 
chest CT findings, followed by gradual taper over at 
least 4 weeks. 
 Re-image as clinically indicated. 
 If still no improvement within 3 to 5 days,  
 
Re-consider additional work-up for alternative 
etiologies as described above. 
Consider other immuno-suppressants and/or treat per local 
practice. 
Eye disorders 
Ocular 
Grade 3 
Delay dose until resolved to ≤Grade 2, then: 
 If resolved in ≤7 days, resume patritumab deruxtecan; 
 If resolved in 7 days, then reduce patritumab 
deruxtecan by 1 dose level. 
Ophthalmologist consultation as necessary. 
Grade 4 
Discontinue subject from patritumab deruxtecan. 
Ophthalmologist consultation as necessary. 
Renal and urinary disorders 
Creatinine 
increased 
Grade 3 (3.0 × baseline; 
3.0 – 6.0 × ULN) 
Delay dose until resolved to ≤Grade 1 or baseline, then 
reduce patritumab deruxtecan by 1 dose level. 
Grade 4 (6.0 × ULN) 
Discontinue subject from patritumab deruxtecan. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Hepatobiliary disorders 
AST or ALT 
increased without 
total bilirubin 
(TBL) increased 
Grade 2 (>3.0 - 5.0 × 
ULN if baseline was 
normal; >3.0 - 5.0 × 
baseline if baseline was 
abnormal) 
Continue patritumab deruxtecan. 
In subjects without liver metastasis, monitor AST/ALT 24 
to 72 hours later, and continue regular monitoring until 
resolution. 
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 x ULN. 
Delay patritumab deruxtecan dose until resolved to ≤Grade 
1, then: 
 If resolved in ≤7 days, resume patritumab deruxtecan; 
 If resolved in 7 days, then reduce patritumab 
deruxtecan by 1 dose level. 
>8.0 - 20.0 x ULN if 
baseline was normal; >8.0 
- 20.0 x baseline if 
baseline was abnormal 
In subjects with liver 
metastases, if the baseline 
level was > 3 x ULN. 
Delay patritumab deruxtecan dose until resolved to ≤baseline 
level, then: 
 If resolved in ≤7 days, resume patritumab deruxtecan; 
 If resolved in 7 days, then reduce patritumab 
deruxtecan by 1 dose level. 
Grade 4 (>20.0 × ULN if 
baseline was normal; 
>20.0 × baseline if 
baseline was abnormal) 
Discontinue subject from patritumab deruxtecan. 
Gastroenterologist or hepatologist consultation as necessary. 
TBL increased 
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 patritumab deruxtecan until resolved to 
≤Grade 1, then: 
 If resolved in ≤7 days, resume patritumab deruxtecan; 
 If resolved in >7 days, reduce patritumab deruxtecan by 
1 dose level. 
If documented Gilbert’s syndrome or liver metastases at 
baseline, continue patritumab deruxtecan. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Grade 3 (>3.0 – 10.0 × 
ULN if baseline was 
normal; >3.0 - 10.0 × 
baseline if baseline was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at 
baseline, delay patritumab deruxtecan dose until resolved to 
≤Grade 1, then: 
 If resolved in ≤7 days, reduce patritumab deruxtecan by 
1 dose level; 
 If resolved in >7 days, discontinue subject from 
patritumab deruxtecan. 
If documented Gilbert’s syndrome or liver metastases at 
baseline, delay patritumab deruxtecan dose until resolved to 
≤Grade 2, then: 
 If resolved in ≤7 days, reduce patritumab deruxtecan by 
1 dose level; 
 If resolved in >7 days, discontinue subject from 
patritumab deruxtecan. 
Grade 4 
(>10.0 × ULN if baseline 
was normal; >10.0 × 
baseline if baseline was 
abnormal) 
Discontinue subject from patritumab deruxtecan. 
AST or ALT 
increased and TBL 
increased 
AST or ALT ≥3 × ULN 
with simultaneous TBL 
2 × ULN 
Delay patritumab deruxtecan until drug-induced liver injury 
can be ruled out.  The Investigator must consult with a 
gastroenterologist or hepatologist as needed, and the subject 
must be treated accordingly. 
Monitor AST/ALT and TBL twice weekly until resolution or 
return to baseline. 
It is strongly recommended to perform a full diagnostic 
workup to exclude alternative causes, such as viral or 
autoimmune hepatitis, alcoholic liver injury, biliary tract 
disorders, or hemodynamic abnormalities.  Results from 
diagnostic workup (including, for example:  INR, direct 
bilirubin, serologic tests for hepatitis A, B, and C; alcohol 
use, ultrasound, MRI, CT scan, concomitant medication use, 
immunoglobulin levels, ECHO) must be recorded within the 
eCRF. 
If drug-induced liver injury is ruled out, the subject must be 
treated accordingly, and resumption of patritumab 
deruxtecan may occur after discussion between the 
Investigator and Sponsor. 
Patritumab deruxtecan will be permanently discontinued if 
drug-induced liver injury cannot be ruled out from 
diagnostic workup. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
AST or ALT> 3.0 x 
ULN (if liver 
metastases are 
present, >5 ×ULN) 
with known 
Hepatitis B and/or 
Hepatitis C 
infection at baseline 
-- 
Delay patritumab deruxtecan until reactivation of Hepatitis B 
and/or Hepatitis C can be ruled out.   
Perform HBV DNA and/or HCV RNA to rule out 
reactivation of Hepatitis B and/or Hepatitis C, respectively. 
Hepatologist and infectious disease consultations are 
recommended.   
If reactivation of Hepatitis B and/or Hepatitis C is 
confirmed, permanently discontinue patritumab deruxtecan. 
Gastrointestinal disorders 
Nausea 
Grade 3 
(inadequate oral caloric or 
fluid intake; tube feeding, 
total parenteral nutrition 
[TPN], or hospitalization 
indicated) 
Delay patritumab deruxtecan until resolved to ≤ Grade 1, 
and consider treatment with anti-emetics and/or 
corticosteroids as per Investigators judgement and local 
practice/guidelines, then: 
 If resolved to ≤Grade 1 in ≤14 days, resume patritumab 
deruxtecan. 
 If does not resolve to ≤Grade 1 in >14 days, reduce 
patritumab deruxtecan by 1 dose level. 
Vomiting 
Grade 3 
(tube feeding, TPN, or 
hospitalization indicated) 
Delay patritumab deruxtecan until resolved to ≤Grade 1, and 
consider treatment with anti-emetics and/or corticosteroids 
as per Investigators judgement and local practice/guidelines, 
then: 
 If resolved to ≤Grade 1 in ≤7 days, resume patritumab 
deruxtecan; 
 If does not resolve to ≤Grade 1 in >7 days, reduce 
patritumab deruxtecan by 1 dose level. 
Grade ≥4 
Discontinue subject from patritumab deruxtecan 
Based on currently available clinical safety data for patritumab deruxtecan, it is recommended that subjects 
receive premedication with antiemetic agents.  Suggested agents include a 5-HT3 blocker in combination with 
another antiemetic or corticosteroid approximately 30 minutes prior to patritumab deruxtecan infusion.  Choice of 
agents is based on Investigator’s discretion as per local/institutional guidelines.  Investigators must also consider 
providing subjects with an antiemetic regimen for subsequent use as needed. 
Diarrhea/Colitis 
Grade 3 
Delay patritumab deruxtecan until resolved to ≤Grade 1, and 
consider treatment per local practice/guidelines, then: 
 If resolved to ≤Grade 1 in ≤7 days, resume patritumab 
deruxtecan; 
 If resolved to ≤Grade 1 in >7 days, then reduce 
patritumab deruxtecan by 1 dose level. 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention indicated) 
Discontinue subject from patritumab deruxtecan. 

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Worst Toxicity NCI-
CTCAE v5.0 Grade 
(unless otherwise 
specified) 
Schedule Modification for Patritumab Deruxtecan 
Mucositis oral 
Grade 3 
Delay patritumab deruxtecan until resolved to ≤Grade 1, and 
consider treatment per local practice/guidelines, then: 
 If resolved to ≤Grade 1 in ≤14 days, resume patritumab 
deruxtecan; 
 If resolved to ≤Grade 1 in >14 days, then reduce 
patritumab deruxtecan by 1 dose level. 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention indicated) 
Discontinue subject from patritumab deruxtecan. 
Other Adverse 
Events (Non-
laboratory or 
Laboratory) 
Grade 3 
Delay patritumab deruxtecan until resolved to ≤Grade 1, or 
baseline level, then: 
 If resolved in ≤7 days, resume patritumab deruxtecan; 
 If resolved >7 days, then reduce patritumab deruxtecan 
by 1 dose level. 
Grade 4 
(Life-threatening 
consequences; urgent 
intervention indicated) 
Discontinue subject from patritumab deruxtecan. 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; CBC = 
complete blood count; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECHO = echocardiogram; eCRF = electronic case report 
form; G-CSF = granulocyte colony stimulating factor; HBV = hepatitis B virus; HCV = hepatitis C virus; ILD = 
interstitial lung disease; INR = international normalized ratio; IV = intravenous; LVEF = left ventricular ejection 
fraction; MRI = magnetic resonance imaging; NCI = National Cancer Institute; NSAIDs = non-steroidal anti-
inflammatory drugs; PK = pharmacokinetic; QTcF = corrected QT using Fridericia’s formula; RNA = ribonucleic 
acid; SpO2 = peripheral oxygen saturation; TBL = total bilirubin; ULN = upper limit of normal. 
a There will be no dose interruptions for Grade 1 to Grade 3 lymphocyte count decreases.  All dose interruptions 
must be based on the worst preceding toxicity. 
During study treatment, subjects who develop systolic and/or diastolic hypertension that is 
deemed by the Investigator to be clinically significant should receive treatment with anti-
hypertensive therapy according to the Investigator’s judgement and local institutional guidelines. 
In addition, Investigators may consider dose reductions or discontinuations of the study drug 
according to the subject’s condition and after discussion with the study Medical Monitor or 
designee. 

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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 patritumab deruxtecan will be recorded 
in the eCRF.  Prophylactic therapies (including any required premedication), prior therapies and 
all concomitant therapies will be recorded in the eCRF.  Based on currently available clinical 
safety data for patritumab deruxtecan, it is recommended that subjects receive premedication 
with antiemetic agents.  Refer to Table 6.4. 
All therapies received by the subjects within 35 days prior to enrollment will be recorded as prior 
therapies.  Concomitant therapies include all prescription, over-the-counter, and herbal remedies. 
Therapies Requiring a Washout Period Before Enrollment 
The following medications/therapies and products require a washout period before enrollment: 
 Whole brain radiation therapy ≥14 days or stereotactic brain radiation therapy 
≥7 days; 
 Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s) from a 
previous cancer treatment regimen or clinical study (other than EGFR TKI), ≥14 days 
or 5 half-lives, whichever is longer; 
 Monoclonal antibodies, other than immune checkpoint inhibitors, such as 
bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) ≥28 days; 
 Immune checkpoint inhibitor therapy ≥21 days; 
 Major surgery (excluding placement of vascular access) ≥28 days; 
 Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of 
radiation ≥28 days or palliative radiation therapy ≥14 days. 
 Chloroquine or hydroxychloroquine >14 days. 
Prohibited Therapies/Products 
The following medications/therapies and products will be prohibited during the Treatment Period 
through 40 days after the last dose of patritumab deruxtecan: 
 Other anticancer therapy, including cytotoxic, immune checkpoint inhibitors, or 
targeted agents; 
 Chloroquine and hydroxychloroquine; 
 Live virus vaccination (beginning from 28 days prior to Cycle 1 Day 1); 
 Other investigational therapeutic agents; 
 Radiotherapy, except palliative radiation (as long as the radiation field does not 
include a measurable lesion or does not interrupt treatment for more than 28 days 
from the planned date of administration [ie, 49 days from the last infusion date]).   
 Radiotherapy to the thorax is also prohibited.  See “Permitted Therapies/Products” 
section below for exceptions on palliative radiation;   
 Concomitant use of chronic systemic (IV or oral) corticosteroids (ie, >10 mg 
prednisone or equivalent anti-inflammatory) or other immunosuppressive medications 
except for managing AEs.   

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Restricted Therapies/Products 
Subjects are permitted to receive the following only when absolutely necessary: 
 Investigators’ discretion/clinical judgement is recommended in accordance with the 
institutional guidelines for the following: 
 Prophylactic or supportive treatment for expected toxicities, including 
management of study drug;  
 Hematopoietic growth factors used for prophylaxis or treatment;  
 Bisphosphonates (eg, pamidronate or zoledronate) or denosumab for pain 
management and palliation of bony metastases, or treatment of osteoporosis. 
 Subjects who wear contact lenses must discontinue wearing their lenses if they have 
any mild to moderate eye symptoms (CTCAE Grade ≤2) while receiving treatment 
until at least 1 week after symptoms have resolved.  If a subject has a recurrence of 
eye symptoms or experiences any severe (CTCAE Grade ≥3) ocular events they must 
discontinue wearing their contact lenses until at least 1 week after treatment is 
permanently discontinued.  Subjects must not use any eye drops or ointment for 
treatment of eye symptoms, unless agreed to by a study doctor, at any time during the 
study and for ≥1 week after permanent discontinuation of study treatment. 
Permitted Therapies/Products 
Subjects are permitted to receive prophylactic or supportive treatment as standard of care during 
the Treatment Period, per Investigator’s discretion and institutional guidelines. 
 Palliative radiation to known metastatic sites as long as the radiation field does not 
include a measurable lesion or interrupt treatment for more than 28 days from the 
planned date of administration (ie, 49 days from the last infusion date).  Palliative 
radiotherapy to the thorax is permitted one week after infusion; however, the next 
infusion should start at least two weeks after the radiotherapy.  Whenever possible, 
subjects should have a tumor assessment of the lesion(s) prior to receiving 
radiotherapy in order to rule out progression of disease.  In cases of progression of 
disease, subjects should be discontinued from patritumab deruxtecan. 
 Inhaled or topical steroids or intra-articular steroid injections 
 Inactive/killed virus vaccinations  
 Menstruating females may receive Depo-Provera or another suppressant of menses 
during the entire course of study treatment.  In addition, after completion of study 
treatment, suppression of menses should be continued until the platelet count is 
≥50,000/mm3 without transfusion support 
 Subjects taking warfarin should be monitored regularly for changes in PT or INR. 

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7. 
STUDY DRUG DISCONTINUATION AND DISCONTINUATION 
FROM THE STUDY 
7.1. 
Discontinuation of Study Drug 
The primary reason for the permanent discontinuation of patritumab deruxtecan treatment 
administration must be recorded.  Reasons for treatment discontinuation include: 
 Death 
 Adverse Event 
 Progressive Disease per RECIST v1.1 
 Clinical Progression: provide date (ie, definitive clinical signs of disease progression, 
but a recent radiographic assessment did not meet the criteria for PD according to 
RECIST v1.1) 
 Withdrawal by the subject (to discontinue study drug) NOTE: In this section this is 
only withdrawal for treatment with study drug and is NOT the same thing as a 
complete withdrawal from the study.  Discuss with the subject that they will remain 
in the study (ie, continue with study visits and assessments, including survival 
follow-up). 
 Physician Decision 
 Lost to Follow-up (see Section 7.3 for details on when a subject is considered Lost to 
Follow-up) 
 Pregnancy 
 Protocol Deviation 
 Study Termination by Sponsor 
 Other 
After study drug is permanently discontinued for any reason other than death or lost to 
follow-up, the subject will be treated as clinically indicated by the Investigator or referring 
physician. 
The Investigator must discuss with the subject that their decision to permanently discontinue the 
study drug means the subject still agrees to continue into the Follow-up Period for onsite or 
modified follow-up visits.  Subjects will be followed for disease progression, if applicable, and 
survival at regularly scheduled intervals (see Table 1.2). 
Procedures for Discontinuation from Study Drug 
The subject should be instructed to contact the Investigator or study site staff before or at the 
time study drug is discontinued.   
If a subject is discontinued from the study drug: 
 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; 

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 An EOT evaluation should be performed as described in the SoE (Table 1.2); 
 A safety follow-up evaluation should be performed approximately 40 days (+7 days) 
after the last dose of study drug as described in the SoE (Table 1.2); 
 If subject has discontinued study drug for any reason other than progressive disease 
or criteria specified below in Section 7.2, tumor assessments and survival follow-up 
should be continued as described in the SoE (Table 1.2);  
 Long-term follow-up evaluations will be performed to assess survival as described in 
the SoE (Table 1.2). 
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. 
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.  If a subject does not come back to the study site, every effort 
should be made to contact the subject to gain required information, such as the approaches listed 
below. 
 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 in the eCRF.  See Section 7.2 for 
definition of withdrawal by the subject from the study (ie, withdrawal of consent). 
7.2. 
Subject Withdrawal/Discontinuation from the Study 
Subjects may discontinue from the study for any of the following reasons: 
 Death 
 Withdrawal by the 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 

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If the reason for study discontinuation is the death of the subject, the options for categorizing the 
primary cause of death are progressive disease or adverse event.  If reason of death is unknown 
every effort should be made to obtain the primary cause of death.  Only one AE will be 
recognized as the primary cause of death. 
Only subjects who refuse all of the following methods of follow-up will be considered to have 
withdrawn consent from study participation (ie, from the interventional portion and follow-up): 
 Attendance at study visits per protocol 
 Study personnel contacting the subject by telephone 
 Study personnel contacting an alternative person 
 Study personnel accessing and reviewing the subject’s medical information from 
alternative sources 
If the subject refuses all of the above methods of follow-up, the Investigator should personally 
speak to the subject to ensure the subject understands all of the potential methods of follow-up.  
If the subject continues to refuse all potential methods of follow up, the Investigator will 
document this as a withdrawal of consent (from the interventional portion and follow-up). 
Withdrawal Procedures 
If a subject is withdrawn from both the interventional and follow-up portions of the study: 
 The Investigator will complete and report the observations as thoroughly as possible 
up to the date of withdrawal including the date of last dose, date of last contact, and 
the reason for withdrawal; 
 And disclosure of future information is also withdrawn, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent; 
 The subject may request destruction of any samples taken and not tested, and the 
Investigator must document this in the site study records; 
 Study site personnel may use local, regional, and national public records (in 
accordance with local law) to monitor vital status. 
See SoE (Table 1.2) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 
7.3. 
Lost to Follow-up 
A subject will be considered lost to follow-up if he/she fails to return for 2 consecutive scheduled 
visits and is unable to be contacted by the study site staff.  Before a subject is deemed lost to 
follow-up, the Investigator or designee will make every effort to regain contact with the subject 
(where possible, 3 telephone calls, text messages, 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. 

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8. 
STUDY PROCEDURES 
See the SoE in Table 1.1 for study procedures during the Screening Period and the first 3 cycles 
of Treatment Period, and Table 1.2 for study procedures during Cycle 4 and the subsequent 
cycles of the Treatment Period, EOT, and the Follow-up Period. 
8.1. 
Eligibility Assessment 
Review the subject’s demographics, medical and NSCLC history, prior medications, non-drug 
therapies and radiotherapy, vital signs, and results of tests (physical examination, height, weight, 
peripheral oxygen saturation (SpO2), ECOG PS, ophthalmologic assessment, 12-lead ECG, 
ECHO/MUGA scan, and clinical laboratory assessments) and compare against the eligibility 
criteria (Section 5.1 and Section 5.2).  See Section 5.3 for (re-screening/subject replacement). 
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. 
Qualifying Tumor Tissue Specimen 
A pretreatment tumor biopsy or archival tumor tissue is required to be collected from all subjects 
after signing tumor tissue ICF and prior to enrollment of sufficient quantity (as defined in the 
Laboratory Manual) and of adequate tumor tissue content (as confirmed by H&E staining at 
central laboratory).   
 A baseline pretreatment tumor biopsy must be of the primary (if intact) and/or 
metastatic lesion(s) not previously irradiated and amenable to core biopsy.  Any 
serious adverse event (SAE) directly related to the new biopsy should be reported as 
outlined in Section 8.4.1.1.   
 Archival tumor tissue must be collected from a biopsy performed within 3 months 
prior to signing of the tissue consent and since progression while on or after treatment 
with the most recent cancer therapy regimen.   
Biomarker analysis details are provided in Section 8.7 and the Laboratory Manual. 
Non-small Cell Lung Cancer History 
Subject’s NSCLC history will be obtained by the Investigator or a qualified designee. 
Actionable Mutation Status 
Subjects must have documented test results indicating presence of an EGFR-activating mutation 
(exon 19 deletion or L858R), as detected from tumor tissue or blood sample, in order to be 
enrolled into the study.  If tests result(s) for EGFR-activating mutations are not available, 

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subjects are required to undergo testing for these genomic alterations using assays approved in 
their country of testing.   
HER3 Expression Status 
HER3 protein expression level will be retrospectively assessed as an exploratory marker and the 
result will not be required for eligibility.   
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 NSCLC/vital signs that are out of range) that were diagnosed or known to exist 
prior to signing the ICF will be recorded on the General Medical History and Baseline 
Conditions eCRF, not the Adverse Event eCRF.  Record the start date of any medical occurrence 
that started after the ICF was signed and is ongoing at the time of the first dose of patritumab 
deruxtecan on the General Medical History and Baseline Conditions eCRF. 
Demographics 
Review the subject’s demographics against the eligibility criteria. 
Human Immunodeficiency Virus (HIV) Antibody Test 
HIV antibody test should be performed, prior to enrollment, as required by local regulations or 
independent Institutional Review Boards (IRBs)/Ethics Committees (ECs).   
Hepatitis Screening 
Hepatitis B surface antigen (HBsAg) and hepatitis C virus antibody (HCV Ab) must be 
performed prior to enrollment. 
 Subjects with past or resolved HBV infection are eligible if:   
 Hepatitis surface antigen (HBsAg) negative and hepatitis B core antibody 
(anti-HBc) positive; OR  
 HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL in 
the absence of anti-viral therapy and during the previous 12 weeks prior to the 
viral load evaluation with normal transaminases values (in the absence of liver 
metastasis); OR 
 HBsAg positive and HBV DNA viral load is documented to be ≤2000 IU/mL in 
the absence of anti-viral therapy and during the previous 12 weeks prior to the 
viral load evaluation for subjects with liver metastasis and abnormal 
transaminases with a result of AST/ALT <3 x ULN. 
 Subjects with a history of hepatitis C infection will be eligible for enrollment only if 
the viral load according to local standards of detection is documented to be below the 
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(ie, sustained viral response according to the local product label but no less than 
12 weeks, whichever is longer). 
8.2. 
Randomization/Enrollment 
After all Screening procedures are performed, results of Screening tests are available (ie, 
between the Screening visit and the Cycle 1 Day 1 visit), and subjects are confirmed to have met 
all eligibility criteria, eligible subjects will be randomized to 1 of the 2 following dose regimens:  
 Fixed dose regimen:  5.6 mg/kg (Arm 1) 
 Up-titration dose regimen (Arm 2):  Cycle 1: 3.2 mg/kg; Cycle 2: 4.8 mg/kg; Cycle 3 
and subsequent cycles: 6.4 mg/kg 
Following a decision based on the benefit/risk from the U31402-A-U102 study, subsequent 
subjects will be enrolled into the selected optimal dose regimen (Arm 1 or Arm 2). 
Randomization/enrollment is defined as the time point at which the Investigator has determined 
the subject has met all eligibility criteria and has registered the transaction through the IRT.   
If subjects do not meet eligibility criteria on the day of randomization/enrollment, they will not 
be randomized/enrolled into the study.   
Subjects should receive the study drug on the same day as randomization/enrollment.  The 
subject’s weight at baseline (defined as the last measurement on or prior to Cycle 1 Day 1) will 
be used to calculate the initial dose.  The subject’s weight will be determined at the beginning of 
each cycle.  If during Cycle 1 Day 1 or throughout the course of treatment, the subject’s weight 
changes by ≥10% from the baseline weight, the dose will be recalculated using this new weight 
and will be considered the new baseline for all subsequent dosing calculations.   
8.3. 
Efficacy Assessments 
Radiographic Tumor Assessments 
Radiographic tumor assessments (computed tomography [CT]/magnetic resonance imaging 
[MRI]) will include all sites of disease identified at Screening, and any newly suspected disease 
sites, as per RECIST v1.1 (Section 10.4).  Imaging must include chest, abdomen, pelvis, and 
brain for all subjects.   
The CT scans should be performed with contrast agents unless contraindicated for medical 
reasons; follow the local label/package insert/summary of product characteristics (SmPC) or 
institutional guidelines for allergic reactions to contrast agents.   
Baseline tumor assessment must be performed within 28 days of enrollment and confirmed for 
measurable disease by BICR.  A tumor assessment performed to assess for disease progression 
on the prior therapy will be acceptable as baseline if performed within 28 days of enrollment and 
after signing the main ICF.   
A complete set of scans is required in this study.  Perform radiographic tumor assessments using 
spiral CT or MRI with ≤5 mm cuts unless another modality of disease assessment is necessary 
for the lesions.  SpO2 should be conducted with CT/MRI per Investigator discretion. 

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Antitumor activity will be assessed at baseline (Screening), and every 6 weeks (±7 days) from 
Cycle 1 Day 1 for the first 24 weeks then every 12 weeks (±7 days), independent of treatment 
cycle, until documented disease progression by BICR per RECIST v1.1, death, lost to follow-up, 
or withdrawal of consent (Table 1.1 and Table 1.2).  Subjects who discontinue study treatment 
for any reasons other than documented disease progression by BICR or are withdrawn from 
study for criteria specified in Section 7.2 will continue to undergo tumor assessments at the same 
frequency of every 6 weeks (± 7 days) from Cycle 1 Day 1 for the first 24 weeks then every 
12 weeks (±7 days) during the Follow-up Period.  Imaging timing should follow calendar days 
relative to Cycle 1 Day 1.  Imaging time points will be projected from Cycle 1 Day 1 and should 
not be adjusted for delays in cycle start.  In addition, radiological tumor assessments will also be 
conducted whenever disease progression is suspected (eg, symptomatic deterioration).  Tumor 
assessments will be performed as per RECIST v1.1 (see Section 10.4).  Objective responses 
(CR or PR) must be confirmed at least 4 weeks later (eg, generally at the next tumor assessment 
time point). 
The same imaging technique (with or without contrast) used to characterize each identified and 
reported lesion at baseline will be employed in the subsequent tumor assessments, unless 
medically infeasible (ie, newly developed AE or allergy to contrast agent).   
Bone scan (using 99mtechnetium polyphosphonate scintigraphy, whole body bone MRI, 18F-NaF 
positron emission tomography [PET]/CT or 18F-fluorodeoxyglucose [FDG] PET/CT) should be 
performed within 6 weeks prior to Cycle 1 Day 1 (historical scans are acceptable).  Thereafter, a 
bone scan should be performed every 24 weeks (±7 days) from Cycle 1 Day 1, or sooner if 
clinically indicated.  In subjects whose body CT/MRI scans indicate CR has been achieved, a 
bone scan should be required at confirmation of CR to exclude new bone metastases.  Lesions 
detected on bone scans must be followed with cross-sectional imaging.   
When tumor assessments at a visit are performed over multiple days, the date of response for that 
assessment (CR, PR, stable disease [SD], Non-CR/Non-PD [subjects with non-target lesions 
(NTL) only] or not evaluable [NE]) should be recorded as the date of the last radiographic 
evaluation included in the series for that assessment, and the date of progression (PD) should be 
recorded as the date of the earliest radiographic evaluation included in the series for that 
assessment.   
Measurable or evaluable lesions that have been previously irradiated will not be considered 
target lesions (TLs) unless increase in size has been observed following completion of radiation 
therapy.   
Response Assessment 
Assessment of response will be made by BICR and Investigator based on RECIST v1.1 
(Section 10.4).  However, tumor assessments will continue until disease progression is confirmed 
by BICR.   
Subsequent Anticancer Treatments 
Subsequent anticancer treatments taken since the EOT must be monitored and recorded in the 
eCRF until the end of the study. 

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Survival Follow-up 
All subjects should be followed for survival at least every 3 months after discontinuing study 
drug (see Table 1.2).  Survival monitoring will continue until the overall end of the study. 
8.4. 
Safety Assessments 
8.4.1. 
Adverse Event 
Method to Detect Adverse Events 
The definitions of an AE or SAE can be found in Section 10.5.  Adverse events may be directly 
observed, reported spontaneously by the subject or by questioning the subject (or, when 
appropriate, by a caregiver, surrogate, or the subject's legally authorized representative) at each 
study visit.  Subjects should be questioned in a general way, without asking about the occurrence 
of any specific symptoms.  The Investigator must assess all AEs to determine seriousness, 
severity, and causality.  The Investigator and any qualified designees are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE and 
remain responsible for following AEs that are serious, considered related to the study drug or 
study procedures, or that caused the subject to discontinue patritumab deruxtecan. 
All clinical laboratory results, vital signs, and ECG results or findings should be appraised by the 
Investigator to determine their clinical significance.  Isolated abnormal laboratory results, vital 
sign findings, or ECG findings (ie, not part of a reported diagnosis) should be reported as AEs if 
they are symptomatic, lead to study drug discontinuation, lead to dose reduction, require 
corrective treatment, or constitute an AE in the Investigator’s clinical judgment. 
Time Period for Collecting Adverse Events, including AESIs and Serious Adverse Events 
All SAEs occurring after the subject signs the main ICF and up to 47 days after the last dose of 
study medication (ie, from the beginning of the Screening Period to the end of the Follow-up 
Period), whether observed by the Investigator or reported by the subject, will be recorded on the 
Adverse Event eCRF.  Any serious, adverse event that may occur subsequent to the 40-day 
(+7 days) follow-up reporting period that the Investigator assesses as related to study drug should 
also be reported as an SAE.  All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up. 
When an AE of potential ILD (Section 8.4.1.2) is observed after 47 days since the last dose of 
patritumab deruxtecan, the AE (serious or non-serious) should be reported and recorded in AE 
eCRF if it is considered related to patritumab deruxtecan. 
All non-serious AEs occurring after the subject has taken the first dose of patritumab deruxtecan 
until 47 days after the last dose of study medication will be recorded on the Adverse Event 
eCRF. 
Exacerbation of a pre-existing medical condition and symptom after the first dose of patritumab 
deruxtecan including increase in severity of the symptom will be recorded as an AE on the 
Adverse Event eCRF, unless it is a condition of NSCLC. 

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Reporting Procedure for Investigators 
All AEs (including adverse events of special interest [AESIs] and SAEs) and medication errors 
including overdose will be reported in the Adverse Event eCRF.  All AEs (serious and 
non-serious) must be reported with the Investigator’s assessment of seriousness, severity, and 
causality to the study drug patritumab deruxtecan. 
Always report the diagnosis as the AE or SAE term.  When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available.  If the signs and symptoms are distinct and do not suggest 
a common diagnosis, report them as individual entries of AE or SAE. 
Additional relevant information regarding the AESIs, ILD, and all hepatic events which meet an 
elevated ALT or AST ≥ 3 × upper limit of normal (ULN) and an elevated total bilirubin > 2 × 
ULN that may occur simultaneously or at different time points during the study for the 
patritumab deruxtecan clinical program regardless of seriousness, is to be collected through the 
targeted questionnaires within the clinical study database. 
Disease-Specific AEs and SAEs 
Disease progression/worsening of NSCLC will not be recorded as an AE on the Adverse Event 
eCRF.  However, events associated with disease progression may be recorded as AEs. 
Death due to disease progression should be recorded on the Death eCRF. 
8.4.1.1. 
Serious Adverse Events Reporting 
The following types of events should be reported by the Investigator in the electronic data 
capture (EDC) within 24 hours of awareness: 
 SAEs (Section 10.5.2) 
 All potential ILD cases should be reported within 24 hours, including both serious 
and non-serious potential ILD cases (potential ILD is defined by the Event 
Adjudication Site Manual List of Preferred Terms]) (as defined in Section 8.4.1.2). 
 Hepatic events (both serious and non-serious) meeting the laboratory criteria of a 
potential Hy’s Law criteria (as defined in Section 8.4.1.2 for details).   
 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. 
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. 

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In the event that the eCRF is unavailable, report SAEs by faxing or emailing the serious adverse 
event report (SAVER) Form to the CRO using the provided fax transmittal form and the 
appropriate fax number provided for your country or email address.  Once EDC becomes 
available, please enter SAEs reported on the SAVER Form into the eCRF as soon as possible.  
Please refer to the eCRF Completion Guide for additional instructions. 
Call the local SAE Hotline (see Study Site Manual) or your study monitor for any questions on 
SAE reporting. 
See Section 8.4.1 for details on the time period for collecting SAEs. 
Reporting Requirement to Sites and Regulatory Authorities 
The Sponsor and CRO will inform Investigators and regulatory authorities of any suspected 
unexpected serious adverse reactions (SUSARs) occurring in study sites or other studies of 
patritumab deruxtecan, as appropriate per institutional and/or local reporting requirements. 
The Sponsor and 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.42 
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 health care 
professionals. 
Urgent safety queries and follow-up information such as events upgraded to fatal/life threatening 
must be followed up and addressed promptly.  The Investigator will submit any updated SAE 
data to the CRO within 24 hours of receipt of the information.  Other follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up report. 
8.4.1.1.1. 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 
reported to the CRO within 24 hours of awareness.  Overdose 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.   

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8.4.1.2. 
Adverse Events of Special Interest 
Interstitial Lung Disease 
Interstitial lung disease 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 cases reviewed by the independent ILD Adjudication Committee 
(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.42 
If a subject develops an acute onset of new or worsening pulmonary or other related 
signs/symptoms such as dyspnea, cough, or fever, rule out ILD.  If ILD is suspected, delay 
patritumab deruxtecan dosing pending further evaluation and start corticosteroid treatment 
promptly per consensus statement45  unless clinically contraindicated.  Refer to Table 6.4 for 
guidance on further evaluation and management of ILD. 
If a non-inflammatory/infectious etiology is confirmed by the Investigator, treat accordingly; 
resumption of patritumab deruxtecan may occur after discussion between the Investigator and 
Sponsor. 
All events of ILD regardless of severity or seriousness should be followed until resolution 
including after drug discontinuation. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD AC for patritumab deruxtecan is responsible for reviewing all cases of 
potential ILD.  To ensure adequate and relevant independent evaluation, systematic additional 
data collection will be conducted for all cases that will be brought for adjudication.  This data 
collection will be triggered for AEs reported using Medical Dictionary for Regulatory Activities 
(MedDRA) preferred terms (PTs) from the current ILD Standard MedDRA Query (SMQ) and 
the PTs of acute respiratory failure and respiratory failure. 
Combined Elevations of Aminotransferases and Bilirubin 
Elevations of aminotransferase(s) and bilirubin in association with patritumab deruxtecan are 
considered to be an important potential risk based on a comprehensive cumulative review of the 
available safety data from the clinical development program, the available pre-clinical data, 
review of the cumulative literature and review of available information for products of the same 
class.  Refer to the current IB for a summary of preliminary clinical study data.42 
Hepatic events (both serious and non-serious) which meet the potential Hy’s Law criteria defined 
as an elevated ALT and/or AST ≥3 × ULN and an elevated TBL >2 × ULN, regardless if it is 
due to disease progression per Investigator assessment, that may occur at different time points 
during the study conduct, should always be reported to the Sponsor.46  These events must be 
reported via eCRF, with the Investigator’s assessment of seriousness, severity, causality, and a 
detailed narrative for SAEs and AESIs.  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. 

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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. 
Follow the management guidance outlined in the designated “Hepatobiliary disorders” dose 
modification section of the study protocol (Table 6.4). 
8.4.2. 
Pregnancy 
The Sponsor must be notified of any female subject who becomes pregnant while receiving or 
within 7 months of last dose of patritumab deruxtecan.  The Sponsor must be notified of any 
male subject whose female partner becomes pregnant while the subject is receiving, or within 
4 months of discontinuing patritumab deruxtecan. 
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  If a pregnancy is reported, the Investigator should inform the Sponsor 
within 24 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. 
Pregnancy Test 
For women of childbearing potential (as defined in Section 5.1): document the results of a 
negative serum pregnancy test within 28 days of Cycle 1 Day 1.  Within 72 hours prior to 
infusion of each cycle (including prior to Cycle 1 Day 1) and at the EOT Visit, a urine or serum 
pregnancy test per institutional guidelines must be performed for all female subjects of 
childbearing potential (Table 1.1).  A positive urine pregnancy test result must immediately be 
confirmed using a serum test.  Results are required prior to administration of study treatment.  
Cycle 1 Day 1 assessment does not need to be repeated if Screening assessment was performed 
within 72 hours of Cycle 1 Day 1 infusion.  
A female 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) with surgery at 
least 1 month before the first dose or confirmed by FSH test (FSH >40 mIU/mL and estradiol 
<40 pg/mL [<147pmol/L] is confirmatory).  Females on hormone replacement therapy (HRT) 
and whose menopausal status is in doubt will be required to use 1 of the contraception methods 
outlined for women of childbearing potential if they wish to continue their HRT during the study.  

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Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to 
first dose of patritumab deruxtecan treatment.  For most forms of HRT, at least 2 to 4 weeks 
must elapse between the cessation of therapy and the blood draw; this interval depends on the 
type and dosage of HRT.  Following confirmation of their post-menopausal status, they can 
resume use of HRT during the study without use of a contraceptive method. 
8.4.3. 
Clinical Laboratory Evaluations 
The clinical laboratory tests including hematology, coagulation, blood chemistry, and urinalysis 
will be performed as per the SoE by the local laboratory (Table 1.1 and Table 1.2).  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, an SAE should be reported in the eCRF and other 
relevant procedures must be followed (see Section 8.4.1.1). 
Abnormal laboratory values (NCI-CTCAE Grade 3 or 4) occurring during the clinical study will 
be followed until repeat test results return to normal (or baseline), stabilize, or are no longer 
clinically relevant.  New or worsened clinically relevant abnormalities should be recorded as 
AEs on the Adverse Event eCRF. 
8.4.4. 
Other Safety 
Physical Examinations 
Physical examinations should be performed as per the SoE (Table 1.1 and Table 1.2).  A 
complete physical examination should include a weight measurement and an evaluation of the 
head, eyes, ears, nose, and throat and the cardiovascular, dermatological, musculoskeletal, 
respiratory, gastrointestinal, genitourinary, and neurological systems.  Any abnormality 
identified at baseline should be recorded on the General Medical History and Baseline 
Conditions eCRF.  At subsequent visits (or as clinically indicated), limited, symptom-directed 
physical examinations should be performed.  Changes from baseline abnormalities should be 
collected in the subject’s study record.  New or worsened clinically relevant abnormalities should 
be recorded as AEs on the Adverse Event eCRF. 
Vital Signs 
Vital signs will be measured and recorded as per the SoE (Table 1.1 and Table 1.2).  Vital signs 
will include the measurements of respiratory rate, heart rate, systolic and diastolic blood 
pressures, temperature, SpO2, height (obtained once, prior to dosing), body weight.  Blood 
pressure and pulse rate will be measured after the subject has rested in a supine/semi-recumbent 
position for 5 minutes or more and prior to laboratory draws.  SpO2 should be conducted with 
CT/MRI per Investigator discretion. 
Electrocardiograms 
12 lead-ECGs will be performed and recorded for every subject as per the SoE (Table 1.1 and 
Table 1.2).  Subjects should rest supine/semi-recumbent for at least 10 minutes prior to the ECG.  

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The same test must be used for Screening, EOT, and as clinically indicated.  Assessment for the 
EOT Visit may be performed with a window up to 7 days.  At any visit during which a subject 
exhibits a heart rate ≤ 50 bpm or other clinical indications for ECG, the ECG will be repeated.  
Abnormal, clinically relevant findings occurring post-baseline will be reported as AEs.   
Multi-gated Acquisition Scan or Echocardiogram 
MUGA/ECHO must be performed as per the SoE and must be performed within 28 days of 
enrollment (Table 1.1 and Table 1.2).  Subjects must have a LVEF ≥50% to be eligible for the 
study.  The same test must be used for screening, EOT, and as clinically indicated.  Assessment 
for the EOT Visit may be performed with a window of up to 7 days. 
ECOG PS 
Assess and record the subject’s ECOG PS as per the SoE (Table 1.1 and Table 1.2).  See 
Section 10.3.3 for the ECOG PS scale. 
Ophthalmologic Assessments 
The ophthalmologic assessment must be performed as per the SoE (Table 1.1 and Table 1.2) and 
must include a visual acuity test (Early Treatment Diabetic Retinopathy Study [ETDRS], 
Snellens, or Landolt), slit lamp examination, fundoscopy, and tonometry.  Assessment may be 
repeated as clinically indicated as part of a scheduled or unscheduled visit. 
8.5. 
Pharmacokinetic (PK) Assessment(s) 
Blood samples for patritumab deruxtecan PK analyses will be obtained at the time points 
specified in the SoE (Table 1.1 and Table 1.2).  Additionally, samples may be obtained at any 
time during the study if deemed clinically necessary.  At each time point, blood will be collected 
for patritumab deruxtecan PK analysis.  Instructions for the collection and handling of blood 
samples and shipping of serum samples for patritumab deruxtecan PK analysis are included in 
the Laboratory Manual.  The actual time of patritumab deruxtecan administration (Pre-Infusion 
and Post-Infusion) and the exact time of blood sampling for patritumab deruxtecan PK analysis 
must be recorded on the eCRF. 
If time points coincide for different blood samplings, the PK samples should be taken at the 
exact nominal time point, followed by serum chemistry, hematology, and then biomarker 
samples.  If time points of procedures coincide with blood sampling, vital signs should be taken 
immediately prior to PK sampling time. 
The patritumab deruxtecan PK samples will be shipped to a central laboratory for forwarding to 
a Sponsor-designated bioanalytical laboratory.  Serum concentrations of patritumab deruxtecan 
(intact ADC) and total anti-HER3 antibody (naked antibody plus intact ADC) will be measured 
with validated analyte-specific ligand binding assays.  Serum concentrations of released payload 
MAAA-1181a will be measured with validated liquid chromatography/mass spectrometry assay. 
Blood samples for PK analyses will be obtained at the time points shown in Table 1.1 and 
Table 1.2.   

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8.5.1. 
Immunogenicity 
Blood samples for serum anti-drug antibody (ADA) analyses will be collected in all subjects as 
per the SoE (Table 1.1 and Table 1.2) at the following time points: 
 Within 8 hours before infusion of patritumab deruxtecan at Cycle 1 Day 1, Cycle 2 
Day 1, Cycle 4 Day 1, then every 2 cycles on Day 1 from Cycle 6 to EOT 
(ie, Cycle 6, Cycle 8, Cycle 10, etc.) 
 At Cycle 1 Day 8 (± 1 day) 
 At the EOT Visit 
 For subjects with a positive anti-drug antibody (ADA) on-study, an additional plasma 
ADA sample must be collected every 3 months (± 14 days) up to 1 year from the last 
dose of patritumab deruxtecan, or until the ADA becomes negative, or the ADA titer 
becomes less than baseline, or the subject starts another anticancer therapy, or the 
subject withdraws consent from the study, whichever occurs first.   
Details for ADA plasma sampling, processing, and storage will be provided in the Laboratory 
Manual.   
The ADA testing will be performed using a validated ADA assay following tiered assay steps 
including Screening, confirmatory as well as titer determination.  If ADA is confirmed, the 
sample will be banked for neutralizing antidrug-antibody (NAB) when the NAB assay is 
available.  Serum concentrations of patritumab deruxtecan (intact ADC, total anti-HER3 
antibody, and released payload MAAA-1181a) may also be measured using the same ADA 
samples for the purpose of ADA assessment.   
8.6. 
Pharmacodynamic Assessment(s) 
Not applicable. 
8.7. 
Biomarker Assessment(s) 
8.7.1. 
Biomarker Assessments in Blood Samples 
Biomarkers (such as HER3 extracellular domain [ECD], cell-free deoxyribonucleic acid 
[cfDNA] and cell-free ribonucleic acid [cfRNA]) will be analyzed with the intent of monitoring 
the biological or antitumor impact of treatment with patritumab deruxtecan.   
Other biomarkers in addition to or in place of these may be considered as suggested by updated 
literature.   
At Cycle 1 Day 1 pre-infusion, a minimum of 34 mL of blood is required to be drawn.  This 
includes 20 mL for cfDNA, 10 mL for cfRNA, and 4 mL for HER3 ECD.  At all other time 
points, a minimum 24 mL of blood is required to be drawn.  This includes 10 mL for cfDNA, 
10 mL for cfRNA, and 4 mL for HER3 ECD.  These biomarkers will be assessed in blood 
collected at the following time points (see the SoE in Table 1.1 and Table 1.2), using validated 
assays: 
 Pre-infusion Cycle 1 Day 1 

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 Pre-infusion Cycle 2 Day 1 
 Pre-infusion Cycle 3 Day 1, Cycle 4 Day 1, and subsequent cycles 
 EOT 
One or more of the aforementioned biomarkers may also be explored for predictive value.   
Biomarker samples will be shipped to a central laboratory.  Sample collection, preparation, 
handling, storage, and shipping instructions are provided in the Laboratory Manual. 
8.7.2. 
Biomarker Assessments in Tissue 
Biomarker analyses will be used to investigate the effect of patritumab deruxtecan at the 
molecular and cellular level as well as to determine how changes in the biomarkers may relate to 
exposure and clinical outcomes.  The tumor biopsy will be performed if medically feasible.  The 
exploratory biomarker analyses may be performed using methods such as protein, ribonucleic 
acid (RNA), or DNA analysis in tissue.  The following samples for biomarker research are 
required and will be collected from all subjects in this study as specified in Table 1.1 and 
Table 1.2: 
 Pretreatment tumor biopsy or archival tumor tissue of sufficient quantity (as defined 
in the Laboratory Manual) and of adequate tumor tissue content (as confirmed by 
H&E staining at the central laboratory) collected prior to study entry.  Pretreatment 
tumor biopsy is required but subjects may be exempted from the requirement to 
provide a pretreatment tumor biopsy if the archival tumor tissue was collected within 
3 months prior to signing of tissue consent and since progression while on or after the 
most recent cancer therapy.  The pretreatment tumor tissue biopsy or archival tumor 
tissue sample(s) will be stained for HER3 expression using IHC.  HER3 expression 
will be assessed as an exploratory biomarker at a later date.   
 Other potential exploratory biomarkers will be analyzed as well.  Archival samples 
can be formalin-fixed, paraffin-embedded (FFPE) tissue block(s), prepared by the 
standard procedure at the study site.  Additional information on tumor tissue 
collection, processing and immediate shipping procedures is included in the 
Laboratory Manual. 
In addition to the biomarkers specified above, additional exploratory biomarker may be 
evaluated on any of the collected samples.  The following samples for biomarker research should 
be collected from study subjects where possible:  
 Optional EOT tumor biopsy will be performed at the time of progression or 
discontinuation from study treatment.  Consent for this biopsy should be documented 
in the tissue consent portion of the appropriate ICF.  The tumor biopsy should be 
obtained from the primary tumor or metastatic site, preferably from a site of recent 
radiographic progression, within 40 days of the last dose of patritumab deruxtecan, 
and prior to starting any new anticancer treatment. 
These studies would extend the search for other potential biomarkers relevant to the effects of 
patritumab deruxtecan and/or the resistance to the treatment.  This may include the development 
of ways to detect, monitor, or treat malignancies.  These additional investigations would be 

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dependent upon clinical outcome, reagent, and sample availability.  If the subject agrees, samples 
may be stored for a maximum of 15 years (or according to local regulations) following the last 
subject’s last visit for the study at a facility selected by the Sponsor to enable further analysis and 
address scientific questions.   
The sample collection information as required should be recorded on the eCRF pages and central 
laboratory requisition forms.  Detailed instructions for the collection, handling, and shipping of 
biomarker samples are outlined in the Laboratory Manual. 
8.8. 
Pharmacogenomic (Inherited Genetic) Analysis 
If a subject provides consent, a single blood sample (3 mL) for pharmacogenetic analysis will be 
collected from each subject.  The pharmacogenomic blood sample will be scheduled for Cycle 1 
Day 1 post-dose (see Table 1.1) but may be collected at any time after the first dose of 
patritumab deruxtecan.  Detailed instructions for the collection, handling, and shipping of 
samples are outlined in the Laboratory Manual.   
Genetic analyses will not be performed on blood samples collected for PK or safety assessments.  
Subject confidentiality will be maintained.   
If subjects agree, the remaining DNA will be stored, as outlined in Section 8.8.1 for performing 
future pharmacogenetic analysis.  Otherwise, all remaining DNA samples will be destroyed.   
8.8.1. 
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 who 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 patritumab deruxtecan.  Additionally, samples may be 
analyzed for genes involved in patritumab deruxtecan-related signaling pathways, or to examine 
diseases or physiologic processes or safety related to patritumab deruxtecan.  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. 
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 patritumab deruxtecan, 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. 

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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. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
General Statistical Considerations 
The DCO date for the primary analysis will occur when all enrolled subjects have either a 
minimum of 9 months of follow-up or have discontinued from the study earlier.  All data 
collected up to the DCO date will be included in the primary analyses.  The primary analysis will 
be included in the CSR.   
The final analysis of the study will occur after all subjects have discontinued from the study.  
Data collected beyond the primary analysis DCO will be presented as appropriate in a CSR 
addendum if deemed necessary.   
Descriptive statistics on continuous data will include mean, median, standard deviation, and 
range (as well as geometric mean and geometric coefficient of variation for PK data).  
Categorical data will be summarized using frequency counts and percentages.  Graphical 
summaries of the data may be presented.  Time-to-event endpoints except for time to response 
(TTR) will be reported using Kaplan-Meier estimates. 
Assessments of change from baseline to post-treatment or the ratio of post-treatment to baseline 
will include only those subjects with both baseline and post-treatment measurements.  The last 
non-missing value of a variable taken prior to Cycle 1 Day 1 will be used as the baseline value, 
unless otherwise specified.  In general, missing data will not be imputed for the purpose of data 
analysis, unless otherwise specified.   
Efficacy endpoints will be analyzed based on Efficacy Analysis Set.  Safety analyses will be 
performed based on the Safety Analysis Set.  Analysis of PK data will use the PK Analysis Set.  
Data from all sites will be pooled for the analyses.  The analyses will be performed by treatment 
arm. 
9.2. 
Statistical Hypothesis 
The primary objective of this study is to investigate the antitumor activity of patritumab 
deruxtecan in subjects with metastatic or locally advanced NSCLC with an activating EGFR 
mutation (exon 19 deletion or L858R).  The primary efficacy endpoint is ORR as assessed by 
BICR per RECIST v1.1.  ORR is defined as the proportion of subjects with a best overall 
response (BOR) of confirmed CR or confirmed PR according to RECIST v1.1.   
The following statistical hypothesis will be tested at 2-sided significance level of 5%: 
H0: ORR = 26.4% vs.  H1: ORR ≠ 26.4% 
The null hypothesis of 26.4% is the upper bound of the exact 95% CI of the ORR (23%) 
observed in the ramucirumab plus docetaxel arm from the REVEL trial.22   
9.3. 
Sample Size Determination 
The primary efficacy endpoint of ORR is used for sample size determination.  From the REVEL 
trial, the ORR of 23% from the ramucirumab plus docetaxel arm was observed (upper bound of 
exact 95% CI = 26.4%).22  A clinically meaningful ORR of 37% is expected from patritumab 
deruxtecan.  The one-sample exact binomial test for single proportion with a nominal 2-sided 

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significance level of 5% will have approximately 91% power to detect the difference between a 
null hypothesis (H0) of ORR = 26.4% and an alternative hypothesis (H1) of ORR = 37% when 
the sample size is 210.  Table 9.1 below displays the exact 95% CI at various ORRs.  When the 
observed ORR is greater than or equal to 32.9%, the lower bound of the 95% CI excludes 26.4%. 
Table 9.1: 
Exact 95% Confidence Intervals for Sample Size of 210 Subjects at Various 
Observed ORRs 
Sample Size  
Number of 
Responders 
Observed ORR (%) 
Exact 95% CI 
210 
63 
30.0 
23.9, 36.7 
69 
32.9 
26.6, 39.7 
70 
33.3 
27.0, 40.2 
77 
36.7 
30.1, 43.6 
84 
40.0 
33.3, 47.0 
93 
44.3 
37.5, 51.3 
105 
50.0 
43.0, 57.0 
CI = confidence interval; ORR = objective response rate 
Up to approximately 420 subjects may be randomized/enrolled depending on whether and when 
one dose arm is dropped or not during the study.  The sample size computation is performed 
using exact test for single proportion in nQuery v8.5.2.   
The exact 95% CIs for the observed ORRs are based on binomial distribution and calculated 
using SAS® v9.4. 
No formal comparison between the two treatment arms is planned, and sample size is calculated 
for each arm individually. 
9.4. 
Population for Analysis Sets 
Analysis Sets 
 The Full Analysis Set (FAS) will include all subjects who are randomized or dosed 
(for non-randomized subjects) in this study.  Following the Intent-to-Treat (ITT) 
principle, the randomized subjects will be analyzed according to the treatment 
assigned during the randomization process. 
 The Safety Analysis Set will include all subjects who received at least one dose of 
study treatment.  Subjects will be summarized according to the treatment received.  
Treatment received is the randomized/assigned treatment if the subject took at least 
1 dose of the randomized/assigned study drug; otherwise the first treatment received 
will be used. 
 The Efficacy Analysis Set (EAS) will include all subjects in the FAS who received at 
least 1 dose of study treatment.  Subjects who have been randomized but not dosed 

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will be excluded from the EAS.  In this study, the EAS is the same as the Safety 
Analysis Set.  The EAS will use the actual treated arm. 
 The PK Analysis Set will include all subjects in the Safety Analysis Set who had at 
least one PK sample with a measurable concentration of intact patritumab deruxtecan 
ADC, total anti-HER3 antibody, or released payload MAAA-1181a. 
9.5. 
Statistical Analysis 
The statistical analysis plan (SAP) will be developed and finalized before database lock 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 will be specified in the SAP.  
The EAS will be used for all efficacy analyses, unless otherwise specified.   
9.5.1.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint of ORR is defined as the proportion of subjects who achieved a 
BOR of confirmed CR or PR as assessed by BICR per RECIST v1.1.  The primary efficacy 
analysis will be based on the EAS. 
The BOR will be determined using tumor assessments at different evaluation time points until 
documented disease progression or start of any further anticancer treatment that is expected to 
affect the assessment of tumor response to study drug, whichever is earlier.  Clinical 
deterioration will not be considered as disease progression.   
ORR will be presented with exact 95% CI using the Clopper-Pearson method.47  If the lower 
bound of the 95% CI is higher than the null hypothesis of 26.4%, then the null hypothesis is 
rejected.  For the computation of ORR, subjects with BOR of NE will be considered as 
non-responders.  Data will be summarized by treatment arm.  No formal comparisons between 
the two arms are planned.   
9.5.1.2. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints include ORR as assessed by Investigator per RECIST v1.1; best 
percentage change in the sum of diameters (SoD) of measurable tumors, disease control rate 
(DCR), DoR, TTR, and PFS as assessed by BICR and Investigator per RECIST v1.1, and OS. 
A brief description of each endpoint is provided below:  
 DoR is defined as the time from the date of the first documentation of response 
(confirmed CR or PR) to the date of the first documentation of PD or death due to any 
cause, whichever occurs first.  Duration of response will be measured for responding 
subjects (subjects with confirmed CR or PR) only.  Detailed censoring rules for DoR 
will be specified in the SAP.   

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 Best percentage change in the SoD of measurable tumors is defined as the percentage 
change in the smallest SoD from all post-baseline tumor assessments, taking as 
reference the baseline SoD. 
 DCR is defined as the proportion of subjects who achieved a BOR of confirmed CR, 
confirmed PR, or SD.   
 PFS is defined as the time from the start date of study treatment to the earlier of the 
dates of the first documentation of PD or death due to any cause.  Detailed censoring 
rules for PFS will be specified in the SAP. 
 TTR is defined as the time from the start date of study treatment to the date of the 
first documentation of response (confirmed CR or PR).  The TTR will be measured 
for responding subjects (subjects with confirmed CR or PR) only.   
 OS is defined as the time from the start date of study treatment to the date of death 
due to any cause.  If there is no death reported for a subject before the DCO for the 
OS analysis, OS will be censored at the last contact date at which the subject is 
known to be alive. 
Response endpoints (ORR and DCR) will be analyzed in the same manner as the primary 
efficacy endpoint.  Distribution of time to event endpoints (DoR, PFS, and OS) will be estimated 
using the Kaplan-Meier method and results presented graphically.  Median event time with a 
2-sided 95% CI will be calculated using Brookmeyer and Crowley methods.  In addition, the 
event-free probability at different time points (eg, 3, 6, 9 months, etc.) will be estimated with 
corresponding 2-sided 95% CIs using Greenwood’s formula.  TTR will be summarized using 
descriptive statistics. 
Descriptive statistics for the best percent change from baseline in the SoD will be provided.  A 
waterfall plot of the best percentage change in the SoD for each subject will be presented. 
9.5.1.3. 
Exploratory Analyses 
Not applicable. 
9.5.1.4. 
Multiplicity Adjustment 
Not applicable. 
9.5.2. 
Safety Analyses 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics.  Safety analyses will be performed using the Safety Analysis Set 
and subjects will be analyzed according to their actual treatment received. 
The overall study period will be divided into 3 mutually exclusive segments for statistical 
analysis and reporting purposes:  
 Pre-treatment period: from date of informed consent (inclusive) to the start date of 
study treatment −1 

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 On-treatment period: from the start date of study treatment (inclusive) to 47 days after 
the end date of study treatment (inclusive) 
 Post-treatment period: starting from 48 days after the end date of study treatment. 
Only data from the on-treatment period will be summarized, unless otherwise specified, except 
in cases where data from the pre-treatment period will be used for baseline determination. 
Adverse Events 
Adverse events will be coded using MedDRA and graded using NCI-CTCAE v5.0.   
A TEAE is defined as an AE with a start or worsening date during the on-treatment period.   
The TEAEs will be summarized using system organ class (SOC) and/or PTs.  Additional 
summaries will be provided by the worst CTCAE grade, relationship to the study treatment 
(ie, regardless of relationship to study drug, study drug related), seriousness, actions taken with 
study treatment (ie, associated with dose reduction, dose interruption, study treatment 
discontinuation), and fatality.   
If a subject reports more than one AE with the same PT, the AE with the worst CTCAE grade 
will be presented.  If a subject reports more than one AE within the same primary SOC, the 
subject will be counted only once with the worst CTCAE grade at the SOC level, where 
applicable.   
AESIs will also be summarized. 
All AEs will be listed, including, but not limited to, verbatim term, PT, SOC, CTCAE grade, 
relationship to study drug, start and end dates, and outcome.  Non-TEAEs will be flagged in the 
listing.   
SAEs starting or worsening after the on-treatment period, if reported as related to the study 
treatment, will be summarized. 
Clinical Laboratory Evaluation 
Descriptive statistics will be provided for selected clinical laboratory test results (hematology 
and chemistry) and changes from baseline by scheduled time of evaluation, including the EOT 
Visit. 
Abnormal clinical laboratory results will be graded according to NCI-CTCAE v5.0, if applicable.  
A shift table, presenting the 2-way frequency tabulation for baseline and the worst post-treatment 
value according to the NCI-CTCAE grade, will be provided for selected clinical laboratory tests.  
Abnormal clinical laboratory test results that are deemed of clinical significance or of Grade 3 or 
4 will be listed. 
ECG 
A listing of ECG data will be provided. 

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Vital Signs 
Descriptive statistics will be provided for the vital sign measurements and changes from baseline 
by scheduled time of evaluation, including the EOT Visit.  A listing of vital sign data will be 
generated. 
Other 
Listings of all other safety data (eg, physical examination findings including ECOG PS, 
ECHO/MUGA, and ophthalmologic findings) will be generated.   
9.5.3. 
Other Analyses 
The following other analyses are planned in this study. 
Pharmacokinetics 
Serum concentrations for intact patritumab deruxtecan ADC, total anti-HER3 antibody and 
released payload MAAA-1181a will be listed, plotted, and summarized using descriptive 
statistics at each time point of each dosing arm using the PK Analysis Set. 
The Population PK (PopPK) analysis to evaluate the effect of intrinsic and extrinsic factors of 
intact patritumab deruxtecan ADC, and if appropriate, total anti-HER3 antibody and released 
payload MAAA-1181a may be characterized and may also include available PK data from the 
Phase 1 studies (U31402-A-J101 and U31402-A-U102).  After establishment of the PopPK 
model, a PopPK/exposure-response model may be developed to evaluate the relationship 
between exposure and efficacy and toxicity.  If conducted, the results of the nonlinear mixed 
effects PopPK and PopPK/exposure-response models will be reported separately from the CSR. 
Immunogenicity 
Immunogenicity will be assessed through characterization of prevalence, incidence and titer of 
ADA.  The number and percentage of subjects with treatment-emergent ADA will be calculated.  
Treatment-emergent ADA positive is defined as subjects who were ADA negative at baseline 
and became ADA positive (ie, confirmed positive ADA) post-treatment or ADA positive at 
baseline and post-treatment and had an increase in ADA titer from baseline to post-treatment that 
meets the cut off value of fold change, or had missing ADA data at baseline and became ADA 
positive post-treatment.  
Concentrations and PK parameters of total anti-HER3 antibody, intact patritumab deruxtecan 
ADC, and released payload MAAA-1181a may be summarized by status of ADA, if data allows.  
ADA titer will be determined for samples confirmed ADA positive.  When neutralizing antibody 
assay becomes available, confirmed ADA positive samples may be analyzed for neutralizing 
activity. 
Pharmacodynamics 
Not applicable. 

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Biomarker 
Biomarker data include IHC HER3 expression data and genomic alterations data from tumor 
tissue.  HER3 expression data will be summarized and plotted if data permits.  HER3 expression 
and genomic alteration data will be presented in listings.  Other biomarker data, if analyzed, may 
be reported separately (ie, not in the CSR). 
Inherited Genetics 
A pharmacogenomics analysis may be conducted in combination with data from other studies.  If 
conducted, results of the analysis will be reported separately.   
9.6. 
Interim Analyses 
There is no formal interim analysis planned for futility or superiority in this study. 
This Phase 2 study will start with 2 randomized dose arms (5.6 mg/kg fixed dose regimen and 
up-titration dose regimen) with a 1:1 randomization ratio.  In the ongoing U31402-A-U102 
study, the same population is being studied in multiple expansion cohorts: Cohort 3a and 3b 
(with 45 subjects planned to be randomized to each dose regimen, 5.6 mg/kg Q3W or up-
titration) and Cohort 1 (45 subjects dosed with 5.6 mg/kg Q3W).  If, during the conduct of the 
current trial (U31402-A-U201), analyses from the U31402-A-U102 study indicate that one dose 
regimen provides clear advantages over the other in terms of benefit/risk, further enrollment into 
one arm may be discontinued.   

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10. 
APPENDICES - SUPPORTING DOCUMENTATION AND 
OPERATIONAL CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory and Ethical Considerations 
10.1.1. 
Regulatory Compliance 
The study protocol, the IB, 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 Clinical Study Report 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 Harmonisation (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; 

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 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) and/or; 
 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, 
Independent Ethics Committees (IECs)/IRBs, and regulatory authorities of such information, and 
when needed, will amend the protocol and/or subject information. 
The Investigator should immediately inform the subject whenever new information becomes 
available that may be relevant to the subject’s consent or may influence the subject’s willingness 
to continue participation in the study.  The communication should be documented on medical 
records, for example, and it should be confirmed whether the subject is willing to remain in the 
study. 
If the subject information is revised, it must be re-approved by the IEC/IRB.  The Investigator 
should obtain written informed consent to continue participation with the revised written 
information even if subjects were already informed of the relevant information.  The Investigator 
or other responsible personnel who provided explanations and the subject should sign and date 
the revised ICF. 
10.1.2. 
Informed Consent 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirements, and should adhere to GCP and to the ethical principles that 
have their origin in the Declaration of Helsinki.  The ICF and any revision(s) should be approved 
by the IEC/IRB prior to being provided to potential subjects. 
The subject’s written informed consent should be documented in the subject’s medical records.  
The ICF should be signed and personally dated by the subject and by the person who conducted 
the informed consent discussion (not necessarily the Investigator).  The original signed ICF 
should be retained in accordance with institutional policy, and a copy of the signed ICF should 
be provided to the subject.  The date that informed consent was signed 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 ICF after the subject has consented to their participation.  By signing the ICF, the 
witness attests that the information in the ICF and any other written information was adequately 
explained to and apparently understood by the subject and that informed consent was freely 
given by the subject. 

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A separate special consent for inherited genetic analysis will be obtained from subjects in 
accordance with health authorities in their particular region/country. 
Suggested model text for the ICF for the study and any applicable subparts (PK, 
pharmacodynamic, etc.) is provided in the Sponsor’s ICF template for the Investigator to prepare 
the documents to be used at his or her study site.  Updates to applicable forms will be 
communicated via letter from the Sponsor. 
For study sites in the US, an additional consent is required for the Health Insurance Portability 
and Accountability Act (HIPAA). 
10.1.3. 
Subject Confidentiality 
The Investigators and the Sponsor will preserve the confidentiality of all subjects taking part in 
the study, in accordance with GCP and local regulations. 
For EU study sites, the Sponsor will observe the rules laid down in the EU 2016/679/General 
Data Protection Regulation on the protection of individuals with regard to the processing of 
personal data and the free movement of such data. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the eCRFs or other 
documents submitted to the Sponsor or the CRO, subjects should be identified by a unique 
subject identification (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. 

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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 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 adverse events 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. 

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10.1.5. 
Committees 
Interstitial Lung Disease Adjudication Committee 
An external ILD AC will be used for this study.  Details on the membership, responsibilities, and 
working procedures of the external ILD AC will be described in its own charter, provided as a 
separate document.  The ILD AC will adjudicate all cases of potential ILD on an ongoing basis.   
Adjudication of ILD cases will be based on evaluation of eCRFs and source documents 
including, but not limited to, chest high-resolution CT, arterial blood gases, and carbon 
monoxide diffusing capacity.  The ILD AC will review ongoing cases of ILD to make the final 
determination of ILD diagnoses to guide Sponsor decisions regarding study suspension or study 
discontinuation and to provide assessment of ILD prevalence at the end of the study.  Findings of 
the ILD AC with its recommendations will be provided to the Sponsor. 
Mechanisms of Safety Oversight by the Sponsor 
In Version 1.0 of U31402-A-U201 study protocol dated 26 Jun 2020, an external independent 
DMC was included to provide interim safety review of this Phase 2 U31402-A-U201 study to 
supplement safety and efficacy data obtained from the Phase 1 U31402-A-U102 study. 
Subsequently, an external independent DMC was deemed not to be necessary with the following 
rationale: the Sponsor has determined that the combined safety and efficacy data from the 
Phase 1 U31402-A-U102 study will be sufficient to support any potential selection of a preferred 
dosing regimen while the Phase 2 U31402-A-U201 study is ongoing; the primary endpoint of 
ORR as assessed by BICR in this non-comparative Phase 2 study does not require DMC 
oversight; the lack of any a priori serious safety concern, besides ILD which is accounted for by 
the ILD adjudication committee; and the robust internal pharmacovigilance oversight that is part 
of the standard Daiichi Sankyo safety monitoring for clinical studies.   
The Sponsor has in place a multi-layered process for ensuring subject safety through the Safety 
Management Team (SMT) through close collaboration of study site Investigators, the Sponsor 
study team, and the Sponsor Clinical Safety and Pharmacovigilance (CSPV).  This collaborative 
process constitutes the Data Safety Monitoring Plan for the study as detailed below: 
 Study safety is evaluated continuously by representatives of the Sponsor-CSPV, who 
operate independently from the clinical team and monitor safety across all patritumab 
deruxtecan protocols.  Adverse events are monitored continuously by CSPV.  Signal 
detection is performed at least monthly and ad hoc throughout the study by the SMT 
composed, at a minimum, of the CSPV safety physician (Chairman of the SMT) and 
CSPV single case review physician, the study Medical Monitor(s), Sponsor Clinical 
Scientist/Leader, the study biostatistician, and epidemiologist.  The SMT monitors 
actual or potential issues related to subject safety that could result in a significant 
change in the medical risk-benefit balance associated with the use of study drugs.  
Furthermore, Investigators will be kept updated of important safety information by 
the Sponsor.  If appropriate, select safety issues may be escalated to a senior level, 
multidisciplinary, Sponsor-wide Global Safety Board for further evaluation and 
action. 

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To support safety oversight, the Sponsor has established ongoing processes for collection, 
review, analysis, and submission of all AEs reported in the study and their aggregate analyses.  
Because this is an open-label study, the clinical scientist/leader, the Sponsor medical monitor, 
and the Investigators will have access to all data necessary for safety evaluation. 
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, IEC/IRB 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other Sponsor correspondence pertaining 
to the study must be kept in appropriate study files at the study site (site specific Trial Master 
File).  Source documents include all recordings and observations or notations of clinical 
activities and all reports and records necessary for the evaluation and reconstruction of the 
clinical study.  These records will be retained in a secure file for the period required by local 
laws or regulations or study site policy.  Prior to transfer or destruction of these records, the 
Sponsor must be notified in writing and be given the opportunity to provide further instruction. 
Record Keeping 
The Investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system (site specific Trial Master File) of all study-related (essential) documentation, 
suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Essential documents include: 
 Subject files containing completed eCRFs, ICFs, and supporting source 
documentation (if kept). 
 Study files containing the protocol with all amendments, IB, copies of relevant 
essential documents required prior to commencing a clinical study, and all 
correspondence to and from the independent IRB/EC and the Sponsor. 

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 Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
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 the Sponsor/CRO.  This agreement will include the financial information agreed 
upon by the parties. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 
10.1.8. 
Publication and Public Disclosure Policy 
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. 
In order to ensure compliance with the public disclosure policies and the International Council of 
Medical Journal Editors recommendations, and to protect proprietary information generated 
during the study, all publications (manuscripts, abstracts, or other public disclosure) based on 

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data generated in this study must be reviewed and approved in writing by the Sponsor prior to 
submission. 
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 IECs/IRBs. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed in this 
study except where necessary to eliminate immediate hazard(s) to the subject. 
The Sponsor must be notified in writing of all intended or unintended deviations to the protocol 
(eg, inclusion/exclusion criteria, dosing, missed study visits) within 24 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 IEC/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: 
 Failure of the Investigator to comply with the protocol, the requirements of the 
IEC/IRB or local health authorities, the Sponsor's procedures, or GCP guidelines 
 Inadequate recruitment of subjects by the Investigator 
 Discontinuation of further study intervention development 
Study termination may also be requested by (a) competent authority/ies. 
At the time of study closure, any subjects who are continuing treatment with patritumab 
deruxtecan and who are judged by the Investigator to have ongoing benefit may continue to 
receive treatment with patritumab deruxtecan through a rollover protocol or another mechanism 
consistent with local requirements. 

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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 from 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) 
bilirubin (direct and indirect) 
blood urea nitrogen (BUN)/urea 
calcium (Ca) 
chloride (Cl) 
creatinine 
estradiol (if indicated) 
FSH (follicle-stimulating hormone; if 
indicated) 
lactate dehydrogenase (LDH) 
magnesium (Mg) 
phosphorus 
potassium (K) 
protein (total) 
sodium (Na) 
 
Hematology 
hemoglobin 
hematocrit 
platelet count 
mean platelet volume (if available) 
reticulated platelet fraction (if available) 
red blood cell (RBC) count 
white blood cell (WBC) count 
mean corpuscular volume (if available) 
differential WBC count (absolute and 
percent): 
basophils  
eosinophils 
lymphocytes 
monocytes 
neutrophils 
Coagulation 
prothrombin time (PT)/international normalized ratio (INR) 
partial thromboplastin time (PTT)/activated partial thromboplastin time (aPTT) 
Urinalysis 
(abbreviated) 
 
bilirubin 
glucose 
ketone bodies 
occult blood 
microscopic assessments (if indicated) 
pH 
protein 
urobilinogen 
sediments: 
casts  
RBC 
WBC 
specific gravity 
 

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10.3. 
Appendix 3: Reference Standards 
10.3.1. 
Cockcroft-Gault Equation 
The estimated creatinine clearance (CrCl; mL/min) will be calculated using the Cockcroft-Gault 
equation based on [actual/ideal] weight in kilograms (1 kilogram = 2.2 pounds):48  
 
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) =  
Female: 
CrCl (mL/min) = 
× 0.85 
 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) =  
Female: 
CrCl (mL/min) = 
× 0.85 
10.3.2. 
New York Heart Association (NYHA) 
The NYHA classifications are summarized below.49  
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in mg/dL) × 72 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 
[140 - age (in years)] × weight (in kg) 
serum creatinine (in µmol/L) × 72 × 0.0113 

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Table 10.2: 
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.  
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of- 
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
10.3.3. 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
The ECOG performance status scale scores are summarized below.50  
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 
Male and female subjects of reproductive/childbearing potential must agree to use a highly 
effective form of contraception or avoid intercourse during and upon completion of the study for 
at least 4 months for males and for at least 7 months for females after the last dose of study drug.  
Methods considered to be highly effective contraception include:51  

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 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 
 True abstinence: when this is in line with the preferred and usual lifestyle of the 
subject 
10.4. 
Appendix 4: Response Criteria 
Response Evaluation Criteria in Solid Tumors (Version 1.1) 
Assessment of tumor responses will be performed according to revised RECIST guidelines, 
v1.1.52  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) 
 10 mm caliper measurement by clinical examination (lesions which cannot be 
accurately measured with calipers should be recorded as non-measurable) 
 20 mm by chest X-ray 
Measurable malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymph node must be ≥15 mm in the short axis when assessed by CT scan (CT scan slice 
thickness is recommended to be no greater than 5 mm).  At baseline and in follow-up, only the 
short axis will be measured and followed.  See also notes below on “Baseline documentation of 
target and non-target lesions” for information on lymph node measurement. 

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Non-measurable 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions.  Lesions considered 
truly non-measurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
Bone lesions: 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques 
to measure bone lesions.  However, these techniques can be used to confirm the 
presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above.  
However, if noncystic lesions are present in the same subject, these are preferred for 
selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other 
loco-regional therapy, are not considered measurable unless there has been 
demonstrated progression in the lesion since the therapy. 
Specifications by Methods of Measurements 
Measurement of Lesions 
All measurements should be recorded in metric notation, using calipers if clinically assessed.  All 
baseline evaluations should be performed as close as possible to the treatment start and NEVER 
more than 4 weeks before the beginning of the treatment. 

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Method of Assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation 
should always be done rather than clinical examination unless the lesion(s) being followed 
cannot be imaged but are assessable by clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment.  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (eg, for body scans). 
Tumor Response Evaluation 
Assessment of Overall Tumor Burden and Measurable Disease 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. 
In this study, only subjects with measurable disease at baseline should be included in the study. 
Baseline Documentation of ‘Target’ and ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a total of two 
lesions per organ and a maximum of five lesions total representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where subjects have only one or two organ sites involved a maximum of two and 
four lesions, respectively, will be recorded). 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements.  It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor.  As noted above, pathological nodes which are 
defined as measurable and may be identified as target lesions must meet the criterion of a short 
axis of ≥15 mm by CT scan.  Only the short axis of these nodes will contribute to the baseline 
sum.  The short axis of the node is the diameter normally used by radiologists to judge if a node 
is involved by solid tumor.  Nodal size is normally reported as two dimensions in the plane in 
which the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane 
of acquisition may be axial, sagittal, or coronal).  The smaller of these measures is the short axis.  
For example, an abdominal node which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node.  In this example, 20 mm should be 
recorded as the node measurement.  All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered non-target lesions.  Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. 

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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 of diameters.  If lymph nodes are to 
be included in the sum, then as noted above, only the short axis is added into the sum.  The 
baseline sum of diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal 
progression’.  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  (Note: the appearance of one or more new lesions is also 
considered progression.) 
Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum of 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 

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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 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing 
non-target lesions.  (Note: the appearance of one or more new lesions is also considered 
progression. 
Special Notes on Assessment of Progression of Non-target Disease 
The concept of progression of non-target disease requires additional explanation as follows, 
when the subject also has measurable disease.  In this setting, to achieve ‘unequivocal 
progression’ on the basis of the non-target disease, there must be an overall level of substantial 
worsening in non-target disease such that, even in presence of SD or PR in target disease, the 
overall tumor burden has increased sufficiently to merit discontinuation of therapy.  A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify for 
unequivocal progression status.  The designation of overall progression solely on the basis of 
change in non-target disease in the face of SD or PR of target disease will therefore be extremely 
rare. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important.  There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
unequivocal: ie, not attributable to differences in scanning technique, change in imaging 
modality, or findings thought to represent something other than tumor (for example, some ‘new’ 
bone lesions may be simply healing or flare of pre-existing lesions).  This is particularly 
important when the subject’s baseline lesions show partial or complete response.  For example, 
necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic lesion, which it is 
not. 

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A lesion identified on a follow-up study in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression.  An example of this is 
the subject who has visceral disease at baseline and while on study has a CT or MRI of the brain 
which reveals metastases.  The subject’s brain metastases are considered to be evidence of PD 
even if he/she did not have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease.  If repeat scans confirm there 
is definitely a new lesion, then progression should be declared using the date of the initial scan 
that indicated its presence. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
the EOT.  Confirmatory measurement for CR or PR is required in this study.  The subject’s best 
overall response assignment will depend on the findings of both target and non-target disease and 
will also take into consideration the appearance of new lesions. 
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 (Cycle 1 Day 1) scan. 
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 
Stable disease 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; PR = partial response; PD = progressive disease; and NE = not evaluable 
Missing Assessments and In-evaluable Designation 
When no imaging/measurement is done at all at a particular time point, the subject is 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 

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baseline sum of 50 mm with three measured lesions and at follow-up only two lesions were 
assessed, but those gave a sum of 80 mm, the subject will have achieved PD status, regardless of 
the contribution of the missing lesion. 
Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject are known.  The BOR 
when confirmation of CR or PR is required is displayed in Table 10.5. 
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; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 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 subject 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 (v1.1).  Table 3.  Euro J 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. 

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Subjects with a global deterioration of health status requiring discontinuation of patritumab 
deruxtecan without objective evidence of disease progression at that time should be reported as 
‘clinical progression.’  Every effort should be made to document objective progression even after 
discontinuation of treatment.  Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study drug.  The objective response status of such subjects is 
to be determined by evaluation of target and non-target disease.  If a radiographic tumor 
assessment has not been performed within 4 weeks of the time of clinical progression, then 
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 every 6 weeks ±7 days 
from Cycle 1 Day 1 for the first 24 weeks then every 12 weeks (±7 days) thereafter, independent 
of treatment cycle, until documented disease progression by BICR per RECIST v1.1, death, lost 
to follow-up, or withdrawal of consent as specified in the SoE or sooner if clinically indicated 
(see Table 1.1 and Table 1.2).  Tumor assessments should not be delayed by dose interruptions; 
they are timed relative to randomization.  The interval between scans is based on the last scan 
visit.  When tumor assessments at a visit are performed over multiple days, the date of response 
for that assessment (CR, PR, SD, Non-CR/Non-PD [subjects with NTL only] or NE) should be 
recorded as the date of the last radiographic evaluation included in the series for that assessment, 
and the date of progression (PD) should be recorded as the date of the earliest radiographic 
evaluation included in the series for that assessment. 
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, and CT or MRI of the brain.  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 5: General Information - Adverse Events 
10.5.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 

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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.53  
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). 
 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.  Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-harming 
intent.  Such overdoses should be reported regardless of sequelae. 
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). 
 “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE.  Such instances will be captured in the efficacy 
assessments.  However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfill the definition of an AE 
or SAE. 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 

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10.5.2. 
Serious Adverse Event 
A serious adverse event 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 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Is an important medical event 
 Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent one 
of the other outcomes listed in the above definition.  These events should usually be 
considered serious. 
 Examples of such events include invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 

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Events Exempted from SAE Reporting 
Disease progression is a component of efficacy endpoints such as PFS.  With one exception, 
disease progression should not be reported as an AE or SAE.  However, when a death occurs due 
to disease progression with no other immediate cause, then disease progression should be 
reported as an SAE and should be recorded in the designated eCRF; in this circumstance, the 
SAE will be processed and be reported as per local regulatory requirements and institutions, as 
applicable.53 
10.5.3. 
Grade Assessment 
The severity of AEs will be graded using the latest NCI-CTCAE (v5.0).  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 
Difference Between Severity and Seriousness 
The term "severe" is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache).  This is not the same as "serious," which is based 
on subject/event outcome or action criteria usually associated with events that pose a threat to a 
subject's life or functioning.  Seriousness (not severity) serves as a guide for defining regulatory 
reporting obligations. 
10.5.4. 
Causality Assessment 
The Investigator should assess causal relationship between an adverse event 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 

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 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(s) 
 Dose Not Changed: No change in study drug dosage was made. 
 Drug Withdrawn: The study drug was permanently stopped. 
 Dose Reduced: The dosage of study drug was reduced. 
 Drug Interrupted: The study drug was temporarily stopped. 
 Not Applicable: Subject died, study drug completed/permanently discontinued prior 
to reaction/event, or reaction/event occurred prior to start of treatment 
10.5.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 
 Prescription and/or over the counter medication was required to treat the adverse 
event. 
 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 

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10.6. 
Appendix 6: Key Data Analysis Requirements 
Table 10.6: 
Key Data Requirements 
Endpoint/Analysis 
Key Data Requirements 
Primary Analysis 
All electronic case report form (eCRF) collected data and key external 
source data (eg, tumor data as assessed by blinded independent central 
review [BICR], interstitial lung disease [ILD], laboratory data, 
pharmacokinetic [PK] data, protocol deviation, human epidermal growth 
factor receptor 3 [HER3] expression data) collected up to the data cut-off 
date are required for the primary analysis. 
Primary Endpoint – 
objective response rate 
(ORR) 
All tumor assessment data (eg, target, non-target, new lesion, overall 
response) as assessed by BICR and Investigator per Response Evaluation 
Criteria in Solid Tumors version 1.1 (RECIST v1.1) is required. 
10.7. 
Instructions Related to Coronavirus Disease 2019 (COVID-19) 
Due to the potential impact of coronavirus disease 2019 (COVID-19; due to severe 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 
COVID-19 while being treated with patritumab deruxtecan.  Dose modifications will be based on 
the worst CTCAE grade.  Use CTCAE version 5.0 general grading criteria to evaluate 
COVID-19.  All dose modifications (discontinuation, interruptions or reductions) must be 
recorded on the AE and drug administration eCRFs. 
Dose Modification Criteria for Suspected or Confirmed COVID-19 
If COVID-19 infection is suspected, interrupt patritumab deruxtecan and evaluate for COVID-19 
according to local standards. 
 If COVID-19 infection is ruled out, follow dose modification and management 
guidance as outlined in Table 6.4. 
 If COVID-19 infection is confirmed or is still suspected after evaluation, continue to 
delay patritumab deruxtecan dosing and manage COVID-19 infection according to 
local standards until recovery.  Recovery from COVID-19 infection is defined as the 
absence of signs or symptoms of COVID-19 infection and at least 1 negative 
real-time reverse transcription polymerase chain reaction (RT-PCR) test result.  A 
chest CT must be performed in all subjects at the time of presumed recovery, and the 
results should be taken into consideration by the investigator when confirming 
recovery of COVID-19 infection.  If recovery from COVID-19 infection is 
confirmed, follow the dose modification guidelines as summarized in Table 10.7  
below. 
 Dosing of patritumab deruxtecan may be delayed for up to 28 days from the planned 
date of administration (ie, 49 days from the last infusion date).  If a subject is judged 
by the investigator to require a dose delay of longer than 28 days, the subject must be 
discontinued from the study treatment. 

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 In addition to the recommendations outlined in Table 10.7, Investigators may 
consider dose modifications of the study drug according to the subject’s condition and 
after discussion with the study Medical Monitor or designee. 
 If an event is suspected to be a drug-related ILD, manage per protocol ILD 
management guideline (see Table 6.4). 

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Table 10.7: 
COVID-19 Dose Modification Criteria 
COVID-19 Worst Toxicity NCI-CTCAE 
(Version 5.0 Grade unless otherwise specified) 
Schedule Modification for Patritumab 
Deruxtecan 
Grade 1 
Resume study drug at the same dose level after 
the subject has recovered from COVID-19 
infection. a 
Grade 2 
Resume study drug at the same dose level after 
the subject has recovered from COVID-19 
infection and if chest CT findings thought to be 
related to this infection are completely resolved.a 
Reduce by 1 dose level after the subject has 
recovered from COVID-19 infection and if 
residual chest CT findings related to the infection 
are observed but are not indicative of active 
infection.a 
Grade 3 
Reduce by 1 dose level if chest CT findings 
related to the infection are completely resolved.a 
Discontinue study drug if chest CT findings 
related to the infection are not completely 
resolved. 
Grade 4 
Discontinue study drug. 
COVID-19 = coronavirus disease 2019; CT = computed tomography; NCI-CTCAE = National Cancer Institute 
Common Terminology Criteria for Adverse Events 
a Closely monitor signs/symptoms after resuming patritumab deruxtecan, initially with a phone call every 3 days for 
the first week and then with a weekly phone call thereafter for a total of 6 weeks. 
Prior and Concomitant Medications - Prohibited Therapies/Products 
 Chloroquine or hydroxychloroquine; 
 Concomitant treatment is not allowed during the study treatment (Section 5.2). 
 If treatment is absolutely required for COVID-19, patritumab deruxtecan must be 
interrupted. 
 If administered, then a washout period of more than 14 days is required before 
resumption of patritumab deruxtecan. 
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 COVID-19 infection, at the time points 
specified in the Schedule of Events (Table 1.1 and Table 1.2). 
The chloroquine or hydroxychloroquine administration time and the exact time of blood sample 
collection for PK analysis must be recorded on the eCRF. 

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COVID-19 Assessment(s) 
All confirmed or suspected COVID-19 infection events must be recorded in the eCRF.  If a 
subject presents to the clinic with symptoms suggestive of COVID-19, but the real-time RT PCR 
test is not available at the site, a 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 COVID-19 testing from each subject who provides consent.  
Samples will be collected prior to the study drug infusion, at the time points specified in the 
Schedule of Events (Table 1.1 and Table 1.2), shipped to a central laboratory, and stored there 
until the tests become available. 
If subjects consent, the remaining serum samples will also be stored for future analysis. 
Sample collection, preparation, handling, storage, and shipping instructions are provided in the 
Study Laboratory Manual. 
Statistical Analysis - Assessment of the Impact of COVID-19 
If deemed appropriate, analyses will be performed to explore the impact of COVID-19 on the 
safety, efficacy, and any other endpoints, as appropriate, reported for the study. 
As a result of the impact of COVID-19 on study conduct, adjustments to the statistical analysis 
and interpretation will be made, if required.  These will be described in the statistical analysis 
plan. 

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11. 
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30. Shames DS, Carbon J, Walter K, et al.  High heregulin expression is associated with 
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novel HER3-targeted antibody–drug conjugate—in EGFR TKI-resistant, EGFR-mutant 
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12. 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
Ab 
antibody 
AC 
Adjudication Committee 
ADA 
anti-drug antibody 
ADC 
antibody drug conjugate 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
Anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BICR 
blinded independent central review 
BOR 
best overall response 
cfDNA 
cell-free deoxyribonucleic acid 
cfRNA 
cell-free ribonucleic acid 
CI 
confidence interval 
Cmax 
maximum concentration 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CR 
complete response  
CrCl 
creatinine clearance 
CRO 
contract research organization 
CSPV 
Clinical Safety and Pharmacovigilance 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCO 
data cut-off 
DCR 
disease control rate 
DFCI 
Dana-Farber Cancer Institute 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
DoR 
duration of response 
EC 
Ethics Committee 

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Abbreviation 
Definition 
ECD 
extracellular domain 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group performance status 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EGFR 
epidermal growth factor receptor 
EGFRm 
epidermal growth factor receptor-mutated 
EIU 
exposure in utero 
EOS 
End of Study 
EOT 
End of Treatment 
ERBB3 
ERB-B2 receptor tyrosine kinase 3 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice 
G-CSF 
granulocyte colony stimulating factor 
GGFG 
glycine-glycine-phenylalanine-glycine 
H0 
null hypothesis 
H1 
alternative hypothesis 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HER2 
human epidermal growth factor receptor 2 
HER3 
human epidermal growth factor receptor 3 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HRT 
hormone replacement therapy 
H&E 
hematoxylin and eosin 
IB 
Investigator’s Brochure 
ICF 
informed consent form 

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Abbreviation 
Definition 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG1 
immunoglobulin G1 
IHC 
immunohistochemistry 
ILD 
interstitial lung disease 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
LVEF 
left ventricular ejection fraction 
Lyo-DP 
lyophilized-drug product 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid; 
MUGA 
multigated acquisition 
NAB 
neutralizing antidrug-antibody 
NCI 
National Cancer Institute 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
NGS 
next generation sequencing 
NSCLC 
non-small cell lung cancer 
NTL 
non-target lesion 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PDX 
patient-derived xenograft 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic 
PR 
partial response 
PT 
prothrombin time/ preferred term 
PTT 
partial thromboplastin time 
Q3W 
every 3 weeks 

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Abbreviation 
Definition 
QTc 
corrected QT interval 
QTcF 
QT interval corrected with Fridericia’s formula 
RDE 
recommended dose for expansion 
RECIST v1.1 
Response Evaluation Criteria in Solid Tumors version 1.1 
RNA 
ribonucleic acid 
ROS1 
ROS protocol-oncogene 1 
RT-PCR 
reverse transcription polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARS-CoV-2 
suspected severe acute respiratory syndrome coronavirus 2 
SAVER 
serious adverse event report 
SCr 
serum creatinine 
SD 
stable disease 
SID 
subject identification 
SMT 
Safety Management Team 
SoE 
Schedule of Events 
SOP 
standard operating procedures 
SpO2 
peripheral oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TKI 
tyrosine kinase inhibitors 
TTR 
time to response 
ULN 
upper limit of normal 
US 
United States 
v 
version