Conditions: Non-Small Cell Lung Cancer
Keywords: HER2 over-expression HER2 mutation Unresectable or metastatic Non-squamous NSCLC
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 181
Healthy volunteers: no

Brief summary:
The primary objective of this trial is to evaluate the efficacy of trastuzumab deruxtecan in HER2-overexpressing and/or HER2-mutated advanced NSCLC participants.

Detailed description:

Arms:
arm 1: Participants with HER2-overexpressing(immunohistochemistry \[IHC\] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a). arm 2: Participants with HER2-overexpressing (immunohistochemistry \[IHC\] 3+ or IHC 2+), unresectable and/or metastatic NSCLC adenocarcinoma who received 5.4 mg/kg trastuzumab deruxtecan (DS-8201a). arm 3: Participants with HER2-mutated, unresectable and/or metastatic NSCLC who received 6.4 mg/kg trastuzumab deruxtecan (DS-8201a).

Interventions: intervention 1: Trastuzumab deruxtecan
Intervention descriptions: intervention 1: Antibody component covalently conjugated to a drug component, prepared by dilution based on body weight for intravenous (IV) infusion.

Protocol document:
Prot_SAP_000.pdf: 
Proprietary and Confidential 
Page 1 
CLINICAL STUDY PROTOCOL 
 
A PHASE 2, MULTICENTER, OPEN-LABEL, 2-COHORT 
STUDY OF TRASTUZUMAB DERUXTECAN (DS-8201a), 
AN ANTI-HER2 ANTIBODY DRUG CONJUGATE (ADC), 
FOR HER2-OVER-EXPRESSING OR -MUTATED, 
UNRESECTABLE AND/OR METASTATIC NON-SMALL 
CELL LUNG CANCER (NSCLC) 
 
[DESTINY-Lung01] 
 
DS8201-A-U204 
IND NUMBER 137009 
EUDRACT NUMBER 2017-004781-94 
 
VERSION 7.0, 14 JULY 2020 
 
DAIICHI SANKYO, INC. 
211 MT. AIRY ROAD 
BASKING RIDGE, NJ 07920-2311 
UNITED STATES 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Daiichi Sankyo, Inc (DSI).  The 
information is provided to you in confidence which is requested under an agreed upon and 
signed Confidentiality and Disclosure Agreement.  Do not give this document or any copy of it 
or reveal any proprietary information contained in it to any third party (other than those in your 
organization who are assisting you in this work and are bound by the Confidentiality and 
Disclosure Agreement) without the prior written permission of an authorized representative of 
DSI. 




Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 3 
DOCUMENT HISTORY 
Version Number 
Version Date 
6.0 
21 Feb 2020 
5.0 
12 Aug 2019 
4.0 
02 May 2019 
3.0 
19 Mar 2018 
2.0 
09 Feb 2018 
1.0 
13 Nov 2017 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 4 
SUMMARY OF CHANGES 
Please refer to the comparison document for protocol Version 7.0 (dated 14 July 2020) vs. 
protocol Version 6.0 (dated 21 Feb 2020) for actual changes in text.  The summary of changes 
below is a top-line summary of major changes in the current DS8201-A-U204 clinical study 
protocol (Version 7.0) by section. 
Amendment Rationale: 
This amendment is primarily driven by the need for alignment with the latest safety information 
on trastuzumab deruxtecan; additional information on Coronavirus disease 2019 (COVID-19) 
and update to interstitial lung disease (ILD) management.  
This and other changes are briefly described in the table below. 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it does not significantly impact the safety or physical/mental integrity of subjects 
nor the scientific value of the study. 
CONVENTIONS USED IN THIS SUMMARY OF CHANGES 
All locations (Section numbers and/or paragraph/bullet numbers) refer to the current protocol 
version, which incorporates the items specified in this Summary of Changes document. 
Minor edits, such as update to language that does not alter original meaning, update to version 
numbering, formatting, change in font color, corrections to typographical errors, use of 
abbreviations, moving verbiage within a section or table, change in style, or change in case, are 
not noted in the following table. 
Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis 
 
 
 
Destiny number was added. 
 
The description of the statistical 
analyses was updated 
To provide clarification 
 
To align with the 
planned interim 
analyses 
1.1.3.3.  DS8201-A-U204: 
Treatment Emergent Events 
 
Table 1.3: Serious Treatment-
Emergent Adverse Events in Study 
DS8201-A-U204 through 08 Jun 
2019 
 
1.1.3.4.  DS8201-A-U204: Deaths, 
Serious Treatment-Emergent 
Adverse Events, and Dose 
Modifications Due to Treatment-
Emergent Adverse Events 
These subsections were deleted. 
The safety data 
provided is now 
outdated 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 5 
Section # and Title 
Description of Change 
Brief Rationale 
Protocol Synopsis 
 
4.1.  
Inclusion Criteria 
Presentation of the Cockcroft-Gault 
equation  in criterion 10 was updated. 
 
 Use of 
chloroquine/hydroxychloroquine was 
added to criterion 11.   
 
Criteria 2 and 11 were also updated 
 
To align with the latest 
safety information 
Protocol Synopsis 
 
4.1.  
Exclusion Criteria 
Exclusion criterion 5 was deleted and 
criteria 11 and 14 updated 
 
 
To align with the latest 
safety information 
Table 5.1 
Sample Dose Reduction Levels of 
Trastuzumab Deruxtecan 
Dose Level -2 was changed from 3.4 
mg/kg to 3.2 mg/kg 
To align with the dose 
reduction used in other 
studies 
5.4.1.  
Dose Reduction and Interruption 
Guidelines 
The following sentence was added: 
All confirmed or suspected 
Coronavirus disease 2019 (COVID-
19), adverse events must be recorded 
on the electronic case report form 
(eCRF).  Please refer to Section 16.7  
for additional information on dose 
modification 
To include management 
guidelines for 
COVID-19 
5.4.1.1. Dose Modifications 
Tables 5.2, 5.3, 5.4 and 5.5 were 
updated.    
To align with the latest 
safety information 
5.6. 
Prior and Concomitant Medications 
This section was updated. 
To align with the latest 
safety information 
6.4.1.1  Day 1 Before Infusion (All 
Cycles, Unless Otherwise Noted) 
Collection of serum samples for 
COVID-19 testing was added 
To align with the latest 
safety information 
6.7 
Additional PK assessments due to 
COVID-19 
 
Table 8.2  
Schedule of PK Sample Collections 
in case of Chloroquine and 
Hydroxychloroquine Treatment 
The section and table were added.  
To monitor potential 
drug-drug interactions 
between 
investigational/study 
drug treatment and 
COVID-19 specific 
treatment 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 6 
Section # and Title 
Description of Change 
Brief Rationale 
9.3.2.1  
Interstitial Lung Disease 
Adjudication Committee 
This section was updated 
To align with the latest 
safety information 
10.1. 
 
General Statistical Considerations 
This section was updated 
To align with the 
planned interim 
analyses 
10.4 Efficacy Analyses 
10.4 .2 
Key Secondary Efficacy Analyses 
These sections were updated  
To align with the 
planned interim 
analyses 
10.4.6.  
Immunogenicity (Anti-Drug 
Antibody [ADA]) Analyses 
This section was updated 
To provide further 
clarification 
10.5.2.  
Adverse Event Analyses 
This section was updated  
To provide clarification 
15. 
References 
Reference 32 was deleted 
To align with the latest 
safety information 
Table 16.1  
Schedule of Events 
The table and footnotes were updated 
To provide clarification 
To align with the latest 
safety information 
16.7 
Instructions Related to Coronavirus 
diesease 2019 (COVID-19) 
This section was added. 
To provide management 
guidelines for 
COVID-19 
Throughout the protocol 
The phrase, “interstitial lung disease 
(ILD)” was replaced by “interstitial 
lung disease (ILD)/pneumonitis” 
To align with the latest 
safety information 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 7 
PROTOCOL SYNOPSIS 
IND Number: 
137009   
Protocol Number: 
DS8201-A-U204 
Investigational Product: 
Trastuzumab deruxtecan 
Active Ingredient(s)/ 
International Non-proprietary 
Name: 
trastuzumab deruxtecan 
Study Title: 
A Phase 2, multicenter, open-label, 2-cohort study of 
trastuzumab deruxtecan (DS-8201a), an anti-HER2 antibody 
drug conjugate (ADC), for HER2-over-expressing or -mutated, 
unresectable and/or metastatic non-small cell lung cancer 
(NSCLC)    
[DESTINY-Lung01] 
Study Phase: 
Phase 2 
Indication Under Investigation: Human epidermal growth factor receptor 2 (HER2) over-
expressing or -mutated, unresectable and/or metastatic non-
squamous non-small cell lung cancer (NSCLC) 
Study Objectives: 
Primary Objective: 
The primary objective is to evaluate the overall response rate 
(ORR) of trastuzumab deruxtecan in HER2-over-expressing 
and/or –HER2 mutated advanced NSCLC subjects. 
Secondary Objectives: 
The secondary objectives are:  
 To evaluate duration of response (DoR), disease 
control rate (DCR), progression-free survival (PFS), 
and overall survival (OS)  
 To further evaluate the safety of trastuzumab 
deruxtecan 
 To determine the pharmacokinetics (PK) of 
trastuzumab deruxtecan 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 8 
Exploratory Objective: 
The exploratory objectives are: 
 To evaluate time to response (TTR) and best percent 
change in the sum of the diameters for all target 
lesions 
 To evaluate potential biomarkers for HER2 
 To evaluate exposure-response relationships for 
efficacy and safety endpoints 
Study Design: 
This is a multicenter, open-label, 2-cohort, Phase 2 study to 
investigate the safety and efficacy of trastuzumab deruxtecan in 
HER2-over-expressing or -mutated non-small-cell lung cancer 
(NSCLC) subjects. 
Cohort 1 will enroll approximately 40 subjects with HER2-over-
expressing (immunohistochemistry IHC 3+ or IHC 2+), 
unresectable and/or metastatic NSCLC with 6.4 mg/kg of 
trastuzumab deruxtecan dosing.  Another approximately 40 
subjects will receive 5.4 mg/kg of trastuzumab deruxtecan in 
Cohort 1a.  
Cohort 2 will enroll approximately 90 subjects with HER2-
mutated, unresectable and/or metastatic NSCLC with 6.4 mg/kg 
of trastuzumab deruxtecan dosing. 
There will be follow-up visits after permanent discontinuation of 
study drug to obtain information about subsequent treatment(s) 
and survival status. 
Study Duration: 
Enrollment is planned to occur over approximately 31 mo. 
The total anticipated duration of the overall study is 
approximately 43 mo.  There will be a 40-Day Follow-up visit 
(+7 d), followed by Long-Term Follow-up visits every 3 mo 
(±14 d) from the date of 40-Day Follow-up Visit, until death, 
withdrawal of consent, loss to follow-up, or study closure; 
whichever occurs first. 
Study Centers and Location: 
Approximately 170 subjects enrolled (40 in each Cohorts 1 and 
1a and 90 in Cohort 2) in up to 30 sites in North America, Japan, 
and Europe 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 9 
Eligibility Criteria: 
Inclusion Criteria: 
1. Must have provided informed consent for study 
participation (see Section 14.3) before performance of 
any study-specific procedure or test. 
2. Age ≥20 y old in Japan, ≥18 y old in other countries.  
3. Pathologically documented unresectable and/or 
metastatic non-squamous NSCLC. 
4. Has relapsed from or is refractory to standard treatment 
or for which no standard treatment is available. 
5. For Cohort 1 and Cohort 1a only: HER2-overexpression 
(IHC 2+ or 3+) status must be assessed and confirmed by 
Clinical Laboratory Improvement Amendments-certified 
laboratory or equivalent, from an archival tumor tissue 
sample. 
For Cohort 2 only: subject has any known documented 
activating HER2 mutation from an archival tumor tissue 
sample analyzed by CLIA laboratory or equivalent, 
specifically exon 20 insYVMA (Y772_A775dup), 
insGSP (G778_P780dup), insTGT (G776delinsVC), 
single base pair substitutions L755S, V777L, or S310F 
or another HER2 mutation listed in the appendix (see 
Table 16.5). Note: HER2 mutation documented only 
from a liquid biopsy sample cannot be used for 
enrollment. 
6. Presence of at least 1 measurable lesion assessed by the 
investigator and based on Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1. 
7. Is willing and able to provide an adequate archival tumor 
tissue sample. Fine needle aspirates are not acceptable 
8. Is willing to undergo a tissue biopsy, after the 
completion of the most recent treatment regimen. 
9. Has Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) of 0 to 1. 
10. Has adequate organ function within 14 d before 
enrollment, defined as: 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count  
 100 000/mm3  
(Platelet transfusion is not allowed within 1 
wk prior to screening assessment) 
Hemoglobin  
≥ 9.0 g/dL 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 10 
(Red blood cell transfusion is not allowed 
within 1 wk prior to screening assessment) 
Absolute neutrophil count 
(ANC) 
 1500/mm3  
(G-CSF administration is not allowed within 
1 wk prior to screening assessment) 
Adequate renal function 
Creatinine Clearance 
Creatinine clearance ≥ 30 mL/min as 
calculated using the Cockcroft-Gault 
equation: 
CLcr (mL/min) =   
(140 - age [years]) × weight (kg)   {× 0.85 for females}   
(72 × serum creatinine [mg/dL])       
Adequate hepatic function 
ALT/AST 
< 2.5 × ULN per institutional standards or < 
5 × ULN if liver metastases are present 
Total bilirubin (TBL) 
≤ 1.5 × ULN if no liver metastases or  < 3 × 
ULN in the presence of documented 
Gilbert’s syndrome (unconjugated 
hyperbilirubinemia) or liver metastases at 
baseline 
Adequate blood clotting function 
International normalized 
ratio (INR)/Prothrombin 
time (PT) and either partial 
thromboplastin (PTT) or 
activated partial 
thromboplastin time 
(aPTT) 
≤ 1.5 × ULN 
11. Has adequate treatment washout period before 
enrollment, defined as: 
Treatment 
Washout Period 
Major surgery 
> 4 wk 
Radiation therapy including 
palliative stereotactic radiation to 
chest  
> 4 wk (palliative stereotactic 
radiation therapy to other areas, > 2 
weeks) 
Anti-cancer chemotherapy 
[Immunotherapy (non antibody 
based therapy)], retinoid therapy 
> 3 wk (> 2 wk or 5 half-lives, 
whichever is longer, for small-
molecule targeted agents such as 5-
fluorouracil-based agents, folinate 
agents, weekly paclitaxel; > 6 wk 
for nitrosureas or mitomycin C, ≥ 1 
wk for TKIs approved for the 
treatment of NSCLC - baseline CT 
scan must be completed after 
discontinuation of TKI) 
Antibody-based anti-cancer therapy  > 4 wk 
Chloroquine/Hydroxychloroquine 
>14 d 
12. Subjects of reproductive/childbearing potential must 
agree to use a highly effective form of contraception or 
avoid intercourse during and upon completion of the 
study and for at least 4.5 mo for male subjects, for at 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 11 
least 7 mo for female subjects, after the last dose of study 
drug. 
Methods considered as highly effective methods of 
contraception include:  
 Combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of 
ovulation: 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated 
with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence defined as refraining 
from heterosexual intercourse during and upon 
completion of the study and for at least 4.5 mo for 
male subjects, for at least 7 mo for female subjects 
after the last dose of study drug.  Periodic abstinence 
(calendar, symptothermal, post-ovulation methods) is 
not an acceptable method of contraception. 
Non-child-bearing potential defined as pre-menopausal 
females with a documented tubal ligation or 
hysterectomy; or postmenopausal defined as 12 mo of 
spontaneous amenorrhea (in questionable cases, a blood 
sample with simultaneous follicle-stimulating hormone 
[FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 
pmol/L] is confirmatory). Females on hormone 
replacement therapy (HRT) and whose menopausal 
status is in doubt will be required to use one of the 
contraception methods outlined for women of child-
bearing potential if they wish to continue their HRT 
during the study.  Otherwise, they must discontinue HRT 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 12 
to allow confirmation of postmenopausal status prior to 
study enrollment. For most forms of HRT, at least 2 to 4 
wk will elapse between the cessation of therapy and the 
blood draw; this interval depends on the type and dosage 
of HRT. Following confirmation of their postmenopausal 
status, they can resume use of HRT during the study 
without use of a contraceptive method. 
13. Male subjects must not freeze or donate sperm starting at 
Screening and throughout the study period, and at least 
4.5 mo after the final study drug administration.  
Preservation of sperm should be considered prior to 
enrollment in this trial. 
14. 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 mo after the 
final study drug administration. 
15. Subjects should be willing and able to comply with 
protocol visits and procedures. 
Exclusion Criteria: 
1. Previously treated with HER2-targeted therapies, except 
for pan-HER class tyrosine kinase inhibitors. 
2. For Cohort 1 and Cohort 1a only: Has known HER2 
mutation. 
3. Uncontrolled or significant cardiovascular disease, 
including any of the following:  
a. Medical history of myocardial infarction within 6 mo 
prior to enrollment 
b. Symptomatic congestive heart failure (CHF) (New 
York Heart Association Class II to IV) 28 d prior to 
enrollment 
c. Troponin levels consistent with myocardial infarction 
(as defined by the manufacturer) 28 d prior to 
enrollment 
d. History of unstable angina, or serious cardiac 
arrhythmia requiring treatment 
e. Left ventricular ejection fraction (LVEF) < 50% 
within 28 d prior to enrollment 
f. Has a QT interval corrected by Fridericia’s Formula 
(QTcF) prolongation to > 470 ms (females) or >450 
ms (males) based on average of the screening 
triplicate12-lead electrocardiogram (ECG). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 13 
4. Has a history of (non-infectious) interstitial lung disease 
(ILD) /pneumonitis that required steroids or, current ILD 
/pneumonitis, or suspected ILD /pneumonitis that cannot 
be ruled out by imaging at screening. 
5. Has spinal cord compression or clinically active central 
nervous system metastases, defined as untreated and 
symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms.  
Subjects with clinically inactive brain metastases may be 
included in the study. Subjects with treated brain 
metastases that are no longer symptomatic and who 
require no treatment with corticosteroids or 
anticonvulsants may be included in the study if they have 
recovered from the acute toxic effect of radiotherapy.  A 
minimum of 2 wk must have elapsed between the end of 
whole brain radiotherapy and study enrollment. 
6. Has multiple primary malignancies within 3 y, except 
adequately resected non-melanoma skin cancer, 
curatively treated in-situ disease, or other solid tumors 
curatively treated. 
7. Has a history of severe hypersensitivity reactions to 
either the drug substances or inactive ingredients in the 
drug product. 
8. Has history of severe hypersensitivity reactions to other 
monoclonal antibodies. 
9. Has an uncontrolled infection requiring IV antibiotics, 
antivirals, or antifungals.  
10. Has substance abuse or any other medical conditions 
such as clinically significant cardiac or psychological 
conditions, that may, in the opinion of the investigator, 
interfere with the subject’s participation in the clinical 
study or evaluation of the clinical study results.  
11. Has known human immunodeficiency virus (HIV) 
infection, or active hepatitis B  or C infection. Patients 
positive for hepatitis C (HCV) antibody are eligible only 
if polymerase chain reaction is negative for HCV RNA.  
Subjects should be tested for HIV prior to enrollment if 
required by local regulations or institutional review 
board (IRB)/ethics committee (EC). 
12. Has unresolved toxicities from previous anticancer 
therapy, defined as toxicities (other than alopecia) not 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 14 
yet resolved to Grade ≤ 1 or baseline.  Subjects with 
chronic Grade 2 toxicities may be eligible per the 
discretion of the investigator after consultation with the 
Sponsor Medical Monitor or designee (eg, Grade 2 
chemotherapy-induced neuropathy). 
13. Is a female subject who is pregnant or breastfeeding or 
planning to become pregnant. 
14. Clinically severe pulmonary compromise resulting from 
intercurrent pulmonary illnesses including, but not 
limited to, any underlying pulmonary disorder (i.e. 
pulmonary emboli within three months of the study 
enrollment, severe asthma, severe COPD, restrictive lung 
disease, pleural effusion etc.), and any autoimmune, 
connective tissue or inflammatory disorders with 
pulmonary involvement (i.e. Rheumatoid arthritis, 
Sjogren's, sarcoidosis etc.), or prior pneumonectomy. 
15. Has undergone prior treatment with an ADC which 
consists of an exatecan derivative that is a topoisomerase 
I inhibitor. 
16. Has social, familial, or geographical factors that would 
interfere with study participation or follow-up. 
17. Has a concomitant medical condition that would increase 
the risk of toxicity, in the opinion of the investigator.  
18. Is a family member of the study site personnel or of the 
Sponsor personnel. 
19. Is otherwise considered inappropriate for the study by 
the investigator. 
Dosage Form, Dose and Route 
of Administration: 
Trastuzumab deruxtecan for injection 100 mg, lyophilized 
powder (Lyo-DP): A trastuzumab deruxtecan sterile lyophilized 
powder containing 100 mg of trastuzumab deruxtecan in a glass 
vial.  
The drug for IV infusion is prepared by dilution of the required 
volume of the drug product calculated based on the subject’s 
body weight in a volume of 100 mL, by the study site 
pharmacist.  The study drug will be administered as an IV 
infusion every 3 wk ±2 d, initially for approximately 90 min, 
then, if there is no infusion-related reaction, for approximately 
30 min thereafter. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 15 
Study Endpoints: 
Primary Efficacy Endpoint: 
The primary efficacy endpoint (primary outcome measure) is 
ORR assessed by independent central review (ICR) based on 
RECIST Version 1.1 for each cohort. 
Secondary Efficacy Endpoints: 
- DoR based on investigator assessment and ICR 
- DCR based on investigator assessment and ICR 
- PFS based on investigator assessment and ICR 
- OS  
- ORR based on investigator assessment 
Secondary outcome measures include: ORR, DoR, PFS, and OS. 
Safety Endpoints: 
The safety endpoints will include: 
 Serious adverse events (SAEs) 
 Treatment-emergent adverse events (TEAEs) 
 Physical examination findings (including ECOG PS) 
 Vital sign measurements 
 Standard clinical laboratory parameters (troponin) 
 ECG parameters 
 Echocardiogram (ECHO) or multigated acquisition 
(MUGA) scan findings 
 Ophthalmologic findings 
 Anti-drug antibody (ADA) 
Pharmacokinetic (PK) Endpoints: 
The PK endpoints (trastuzumab deruxtecan, total anti-HER2 
antibody and MAAA-1181a) will include: 
 PK parameters: maximum serum concentration 
(Cmax), time to Cmax (Tmax), area under the 
concentration time-curve to the (AUClast) and from 
time 0 to 21 d (AUC0-21d) 
 Serum concentrations  


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 16 
Exploratory and Biomarker Endpoints: 
The exploratory efficacy endpoints are: 
 
TTR  
 Best percent change from baseline in the sum of the 
diameters for all target lesions 
 Analysis of biopsied materials for mechanisms of 
resistance to trastuzumab deruxtecan 
 To evaluate exposure-response relationships for 
efficacy and safety endpoints 
Biomarker endpoints are: 
 Analysis of tissue and/or blood for mechanisms of 
response/resistance to trastuzumab deruxtecan 
 To evaluate potential biomarkers of response 
  Biomarker analysis using cell-free DNA  
(cfDNA) 
Planned Sample Size: 
Approximately 40 subjects will be enrolled in each of Cohorts 1 
and 1a and approximately 90 subjects will be enrolled in Cohort 
2. In total, approximately 170 subjects will be enrolled in the 
study. 
Statistical Analyses: 
Efficacy analyses will be performed on the Full Analysis Set 
(FAS).  In addition, select efficacy analyses will also be 
performed on the Response Evaluable Set (RES.  Safety 
analyses will be performed using the Safety Analysis Set.  
Analysis of PK parameters will be based on the PK Analysis 
Set.  All other exploratory analyses will be performed on the 
basis of the RES. 
A sample size of 40 response evaluable subjects each in Cohorts 
1 and 1a is required so that the average distance from the limits 
of the respective 95% confidence intervals (CIs) to the observed 
ORR is approximately 0.14, assuming the expected ORR is 0.3. 
A sample size of 90 subjects in Cohort 2 ensures that the 
average distance from the limits of a 95% CI to the observed 
ORR is approximately 0.09, assuming the expected ORR is 0.3. 
The probability of the lower bound of the 95% CI exceeding 0.3 
is more than 49% when the true ORR is 0.4 and the probability 
increases to more than 96% when the true ORR is 0.5. The 
upper 95% confidence limit of the ORR for the current standard 
of care (SOC) Docetaxel was observed to be under 0.2 or 20% 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 17 
(CheckMate057 study). The threshold of 0.3 or 30% was 
decided by benchmarking against this estimate of the upper limit 
of 20% and allowing a further increment of 10% to account for 
the sparseness of the available data. 
ORR and DCR will be summarized by cohort for FAS and RES, 
and their 95% exact CIs will be provided.  
For time to event endpoints (DoR, PFS, OS), Kaplan-Meier 
method will be used to estimate the survival distribution and 
present the results graphically. Additionally, estimates of 
medians and their corresponding 95% CIs using Brookmeyer and 
Crowley method will be reported.  


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 18 
TABLE OF CONTENTS 
INVESTIGATOR AGREEMENT...................................................................................................2 
DOCUMENT HISTORY.................................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................7 
LIST OF ABBREVIATIONS ........................................................................................................27 
1. 
INTRODUCTION ...........................................................................................................31 
1.1. 
Background ......................................................................................................................31 
1.1.1. 
Investigational Product ....................................................................................................31 
1.1.1.1. Name ................................................................................................................................31 
1.1.1.2. Description ......................................................................................................................31 
1.1.1.3. Intended Use Under Investigation ...................................................................................32 
1.1.1.4. Nonclinical Studies of Trastuzumab Deruxtecan ............................................................32 
1.1.2. 
Nonclinical Studies ..........................................................................................................32 
1.1.2.1. Pharmacology ..................................................................................................................32 
1.1.2.2. Safety Pharmacology .......................................................................................................32 
1.1.2.3. Pharmacokinetics and Drug Metabolism .........................................................................33 
1.1.2.4. Toxicology .......................................................................................................................34 
1.1.3. 
Clinical Experience .........................................................................................................35 
1.1.3.1. Efficacy: DS8201-A-J101 (Ongoing) ..............................................................................35 
1.1.3.2. Safety: DS8201-A-J101 (Ongoing) .................................................................................38 
1.1.4. 
Summary of Clinical Pharmacokinetics ..........................................................................41 
1.2. 
Study Rationale ...............................................................................................................42 
1.2.1. 
Rationale for Expansion ..................................................................................................43 
1.3. 
Risks and Benefits for Study Subjects .............................................................................44 
2. 
STUDY OBJECTIVES AND HYPOTHESIS ................................................................46 
2.1. 
Study Objectives ..............................................................................................................46 
2.1.1. 
Primary Objectives ..........................................................................................................46 
2.1.2. 
Secondary Objectives ......................................................................................................46 
2.1.3. 
Exploratory Objectives ....................................................................................................46 
2.2. 
Study Hypothesis .............................................................................................................46 
2.3. 
Study Endpoints ...............................................................................................................46 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 19 
2.3.1. 
Primary Endpoint(s) ........................................................................................................46 
2.3.2. 
Key Secondary Endpoint(s) .............................................................................................46 
2.3.3. 
Exploratory and Biomarker Endpoint(s) .........................................................................47 
3. 
STUDY DESIGN ............................................................................................................48 
3.1. 
Overall Design .................................................................................................................48 
3.1.1. 
Overview .........................................................................................................................48 
3.1.2. 
Duration of the Study ......................................................................................................49 
3.1.3. 
Duration of Subject Participation ....................................................................................49 
3.1.3.1. Screening Phase ...............................................................................................................49 
3.1.3.2. Treatment Phase ..............................................................................................................49 
3.1.4. 
Follow-up Phase ..............................................................................................................49 
3.2. 
Discussion of Study Design .............................................................................................49 
3.3. 
Selection of Dose and Usage ...........................................................................................49 
3.4. 
Interim Analyses ..............................................................................................................51 
4. 
STUDY POPULATION ..................................................................................................52 
4.1. 
Inclusion Criteria .............................................................................................................52 
4.2. 
Exclusion Criteria ............................................................................................................55 
4.3. 
Subject Rescreening Procedures ......................................................................................56 
5. 
STUDY TREATMENT(S) ..............................................................................................57 
5.1. 
Assigning Subjects to Treatments and Blinding .............................................................57 
5.1.1. 
Treatment Group(s)/Sequences .......................................................................................57 
5.1.2. 
Method of Treatment Allocation .....................................................................................57 
5.1.3. 
Blinding ...........................................................................................................................57 
5.1.4. 
Emergency Unblinding Procedure ..................................................................................57 
5.2. 
Study Drug .......................................................................................................................57 
5.2.1. 
Description ......................................................................................................................57 
5.2.2. 
Labeling and Packaging ..................................................................................................57 
5.2.3. 
Preparation .......................................................................................................................57 
5.2.4. 
Administration .................................................................................................................58 
5.2.5. 
Storage .............................................................................................................................58 
5.2.6. 
Drug Accountability ........................................................................................................58 
5.3. 
Control Treatment ...........................................................................................................59 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 20 
5.4. 
Management Guidelines for trastuzumab deruxtecan .....................................................59 
5.4.1. 
Dose Reduction and Interruption Guidelines ..................................................................59 
5.4.1.1. Dose Modifications .........................................................................................................60 
5.5. 
Method of Assessing Treatment Compliance ..................................................................67 
5.6. 
Prior and Concomitant Medications ................................................................................67 
5.7. 
Prohibited Medications and Treatments ..........................................................................68 
5.7.1. 
Restricted products ..........................................................................................................68 
5.8. 
Removal of Subjects from Treatment and/or Study ........................................................68 
5.8.1. 
Reasons for Discontinuation of Study Drug ....................................................................68 
5.8.2. 
Reasons for Discontinuation of Study Participation .......................................................69 
5.8.3. 
Withdrawal Procedures ...................................................................................................69 
6. 
STUDY PROCEDURES .................................................................................................70 
6.1. 
Tissue Screening (For Cohort 1 and Cohort 1a Only) .....................................................70 
6.2. 
Screening .........................................................................................................................70 
6.3. 
Randomization .................................................................................................................72 
6.4. 
Treatment Period .............................................................................................................72 
6.4.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles .....................................................................72 
6.4.1.1. Day 1; Before Infusion (All Cycles, Unless Otherwise Noted): .....................................72 
6.4.1.2. Day 1; Dosing and End of Infusion (All Cycles, unless otherwise noted): .....................74 
6.4.1.3. Cycle 1 - Day 8 and Day 15 (±1 d): ................................................................................74 
6.4.2. 
Every 6 Wk (±7 d) ...........................................................................................................74 
6.4.3. 
Fresh Tumor Biopsy During Treatment ..........................................................................74 
6.5. 
End of Treatment .............................................................................................................75 
6.6. 
Follow-up ........................................................................................................................76 
6.6.1. 
40-Day Follow-up (within + 7 d) ....................................................................................76 
6.6.2. 
Long-Term Follow-up Visits ...........................................................................................76 
6.7. 
Additional PK assessments due to COVID-19 infection ................................................77 
7. 
EFFICACY ASSESSMENTS .........................................................................................78 
7.1. 
Assessments for Efficacy Endpoint(s) .............................................................................78 
7.1.1. 
Primary Efficacy Endpoint ..............................................................................................78 
7.1.2. 
Secondary Efficacy Endpoints ........................................................................................78 
7.1.3. 
Exploratory Efficacy Endpoints ......................................................................................78 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 21 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS ...........................79 
8.1. 
Pharmacokinetic Assessment(s) ......................................................................................79 
8.2. 
Biomarker Assessment(s) ................................................................................................80 
8.2.1. 
Tumor and Blood Biomarker Assessments .....................................................................80 
8.2.2. 
Additional Biomarker Assessments ................................................................................80 
8.3. 
Immunogenicity ...............................................................................................................80 
8.4. 
Pharmacogenomic Analysis ............................................................................................81 
8.4.1. 
Genomic or Genetic Banking and Analysis ....................................................................81 
8.4.1.1. Disclosure of the Results of Genomic or Genetic Analysis ............................................81 
8.4.1.2. Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis ...........................................................................................................................81 
9. 
SAFETY EVALUATION AND REPORTING ..............................................................82 
9.1. 
Assessment of Safety Endpoint(s) ...................................................................................82 
9.2. 
Adverse Event Collection and Reporting ........................................................................82 
9.3. 
Adverse Events of Special Interest ..................................................................................83 
9.3.1. 
LVEF Decrease ...............................................................................................................83 
9.3.2. 
Interstitial Lung Disease ..................................................................................................83 
9.3.2.1. Interstitial Lung Disease Adjudication Committee .........................................................84 
9.4. 
Adverse Event .................................................................................................................84 
9.4.1. 
Definition of Adverse Event ............................................................................................84 
9.4.2. 
Serious Adverse Event ....................................................................................................85 
9.4.3. 
Severity Assessment ........................................................................................................85 
9.4.4. 
Causality Assessment ......................................................................................................86 
9.4.5. 
Action Taken Regarding Study Drug(s) ..........................................................................86 
9.4.6. 
Other Action Taken for Event .........................................................................................86 
9.4.7. 
Adverse Event Outcome ..................................................................................................87 
9.5. 
Serious Adverse Events Reporting–Procedure for Investigators ....................................87 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional Review 
Board/Ethics Committee .................................................................................................89 
9.7. 
Exposure In Utero During Clinical Studies .....................................................................89 
9.8. 
Clinical Laboratory Evaluations ......................................................................................89 
9.9. 
Vital Signs .......................................................................................................................90 
9.10. 
Electrocardiograms ..........................................................................................................90 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 22 
9.11. 
Physical Examinations .....................................................................................................90 
9.12. 
Other Examinations .........................................................................................................91 
9.12.1. Cardiac Assessments .......................................................................................................91 
9.12.2. Pulmonary Assessments ..................................................................................................91 
10. 
STATISTICAL METHODS ...........................................................................................92 
10.1. 
General Statistical Considerations ...................................................................................92 
10.2. 
Analysis Sets ...................................................................................................................92 
10.2.1. Full Analysis Set ..............................................................................................................92 
10.2.2. Safety Analysis Set ..........................................................................................................92 
10.2.3. Response Evaluable Set ...................................................................................................93 
10.2.4. Pharmacokinetic Analysis Set .........................................................................................93 
10.3. 
Study Population Data .....................................................................................................93 
10.4. 
Efficacy Analyses ............................................................................................................93 
10.4.1. Primary Efficacy Analyses ..............................................................................................93 
10.4.2. Key Secondary Efficacy Analyses ..................................................................................93 
10.4.3. Exploratory Efficacy Analyses ........................................................................................93 
10.4.4. Pharmacokinetic and Pharmacodynamic Analyses .........................................................94 
10.4.4.1. Pharmacokinetic Analyses ...............................................................................................94 
10.4.4.2. Pharmacodynamic Analyses ............................................................................................94 
10.4.5. Biomarker Analyses ........................................................................................................94 
10.4.6. Immunogenicity (Anti-Drug Antibody [ADA]) Analyses ..............................................94 
10.5. 
Safety Analyses ...............................................................................................................94 
10.5.1. Study drug exposure ........................................................................................................95 
10.5.2. Adverse Event Analyses ..................................................................................................95 
10.5.3. Clinical Laboratory Evaluation Analyses ........................................................................95 
10.5.4. Vital Sign Analyses .........................................................................................................95 
10.5.5. Electrocardiogram Analyses ............................................................................................95 
10.5.6. Other Safety Analysis ......................................................................................................96 
10.5.7. Other Analyses - Assessment of the Impact of COVID-19 ............................................96 
10.6. 
Interim Analyses ..............................................................................................................96 
10.7. 
Sample Size Determination .............................................................................................97 
10.8. 
Statistical Analysis Process .............................................................................................97 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 23 
11. 
DATA INTEGRITY AND QUALITY ASSURANCE ..................................................98 
11.1. 
Monitoring and Inspections .............................................................................................98 
11.2. 
Data Collection ................................................................................................................98 
11.3. 
Data Management ............................................................................................................99 
11.4. 
Study Documentation and Storage ..................................................................................99 
11.5. 
Record Keeping .............................................................................................................100 
12. 
FINANCING AND INSURANCE ................................................................................101 
12.1. 
Finances .........................................................................................................................101 
12.2. 
Reimbursement, Indemnity, and Insurance ...................................................................101 
13. 
PUBLICATION AND PUBLIC DISCLOSURE OF CLINICAL TRIAL 
INFORMATION ...........................................................................................................102 
14. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION .................................103 
14.1. 
Compliance Statement, Ethics, and Regulatory Compliance ........................................103 
14.2. 
Subject Confidentiality ..................................................................................................103 
14.3. 
Informed Consent ..........................................................................................................103 
14.4. 
Regulatory Compliance .................................................................................................104 
14.5. 
Protocol Deviations .......................................................................................................104 
14.6. 
Supply of New Information Affecting the Conduct of the Study .................................105 
14.7. 
Protocol Amendments ...................................................................................................105 
14.8. 
Study Termination .........................................................................................................106 
14.9. 
Data Monitoring Committee ..........................................................................................106 
14.10. 
Address List ...................................................................................................................106 
15. 
REFERENCES ..............................................................................................................107 
16. 
APPENDICES ...............................................................................................................110 
16.1. 
Appendix 1: Schedule of Events ...................................................................................110 
16.2. 
Appendix 2: Cockcroft-Gault Equation .........................................................................115 
16.3. 
Appendix 3: New York Heart Association (NYHA) ....................................................116 
16.4. 
Appendix 4: Eastern Cooperative Oncology Group (ECOG) Performance Status .......116 
16.5. 
Appendix 5: Response Evaluation Criteria in Solid Tumors, Version 1.1 ....................117 
16.5.1. Measurability of Tumor at Baseline ..............................................................................117 
16.5.1.1. Definitions .....................................................................................................................117 
16.5.1.2. Specifications by Methods of Measurements ................................................................118 
16.5.2. Tumor Response Evaluation ..........................................................................................118 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 24 
16.5.2.1. Assessment of Overall Tumor Burden and Measurable Disease ..................................118 
16.5.2.2. Baseline Documentation of “Target” and “Non-target” Lesions ..................................118 
16.5.2.3. Response Criteria ...........................................................................................................119 
16.5.2.4. Evaluation of Best Overall Response ............................................................................122 
16.5.2.5. Frequency of Tumor Re-evaluation ...............................................................................123 
16.6. 
Appendix 6: Relevant HER2 Mutations ........................................................................124 
16.7. 
Appendix 7: Instructions Related to Coronavirus disease 2019 (COVID-19) ..............125 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 25 
LIST OF TABLES 
Table 1.1: Efficacy Results in NSCLC Cancers in Study DS8201-A-J101 (Enrolled 
Analysis Set) ...............................................................................................................37 
Table 1.2: Summary of Treatment-Emergent Adverse Events (≥20% of Subjects) in 
Study DS8201-A-J101 ................................................................................................40 
Table 1.3: Mean Pharmacokinetic Parameters of Trastuzumab Deruxtecan Following 
Cycle 1 (± Standard Deviation) ..................................................................................41 
Table 1.4: Mean Pharmacokinetic Parameters of Total Antibody Following Cycle 1 (± 
Standard Deviation) ....................................................................................................42 
Table 1.5: Mean Pharmacokinetic Parameters of MAAA-1181a Following Cycle 1 
(± Standard Deviation) ...............................................................................................42 
Table 5.1: Sample Dose Reduction Levels of Trastuzumab Deruxtecan ....................................60 
Table 5.2: Management Guidelines for Cardiac Toxicities .........................................................60 
Table 5.3: Management Guidelines for Hematologic Toxicities .................................................62 
Table 5.4: Management Guidelines for Hepatic Toxicity ...........................................................63 
Table 5.5: Management Guidelines for Non-Hematologic Toxicities .........................................64 
Table 8.1: Blood Sampling for Pharmacokinetic Analysis ..........................................................79 
Table 8.2: Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment ..................................................................................79 
Table 10.1: Operating Characteristics for Single Arm Expansion Design with 90 
Subjects .......................................................................................................................97 
Table 16.1: Schedule of Events ...................................................................................................111 
Table 16.2: New York Heart Association Functional Classification ...........................................116 
Table 16.3: Eastern Cooperative Oncology Group Performance Status Scale ............................116 
Table 16.4: Overall Response: Subjects with Target (± Non-target) Disease .............................122 
Table 16.5: List of HER2 Mutations............................................................................................124 
Table 16.6: COVID-19 Dose Modification Criteria ....................................................................125 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 26 
LIST OF FIGURES 
Figure 3.1: Study Design Schema for DS8201-A-U204 ...............................................................48 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 27 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AC 
Adjudication Committee 
ADA 
Anti-drug Antibody(ies) 
ADC 
Antibody Drug Conjugate 
ADCC 
Antibody-dependent Cell-mediated Cytotoxicity 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ANC 
Absolute Neutrophil Count 
Akt 
Protein Kinase b 
ALK 
Anaplastic Lymphoma Kinase 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Aminotransferase 
AMI 
Acute Myocardial Infarction 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
ARDS 
Acute Respiratory Distress Syndrome 
AUC0-a 
Area Under the Concentration-Time Curve 
AUC0-21d 
Area Under the Concentration-Time Curve from the Time 0 to 21 d  
AUCinf 
Area Under the Concentration-Time Curve from 0 Extrapolated to 
Infinity 
AUClast 
Area Under the Concentration-Time Curve from time zero to time of last 
measurable concentration  
BI 
Before Infusion 
BRAF 
Proto-Oncogene B-raf 
BUN 
Blood Urea Nitrogen 
cfDNA 
Cell-free Deoxyribonucleic Acid 
CHF 
Congestive Heart Failure 
CI 
Confidence Interval 
CHO 
Chinese Hamster Ovary 
CLIA 
Clinical Laboratory Improvement Amendments 
Cmax 
Maximum Serum Concentration 
COVID-19 
Coronavirus disease 2019 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 28 
ABBREVIATION 
DEFINITION 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
Ctrough 
Trough serum concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
d 
Day(s) 
DAR 
Drug-to-Antibody Ratio 
DCR 
Disease Control Rate 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DoR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
Estimated Glomerular Filtration Rate 
EGFR 
Epidermal Growth Factor Receptor 
EIU 
Exposure In Utero 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice  
HER2 
Human Epidermal Growth Factor Receptor 2 
hERG 
Human Ether a-go-go Related Gene 
HRT 
Hormone Replacement Therapy 
IB 
Investigator’s Brochure 
IC50 
50% inhibition 
ICF 
Informed Consent Form 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 29 
ABBREVIATION 
DEFINITION 
ICH 
International Conference on Harmonisation of Technical Requirements 
for Registration of Pharmaceuticals for Human Use 
IHC 
Immunohistochemistry 
ILD 
Interstitial Lung Disease 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IV 
Intravenous 
IXRS 
Interactive Web/Voice Response System 
LDH 
Lactate Dehydrogenase 
LVEF 
Left ventricular Ejection Fraction 
MAPK 
Mitogen-activated Protein Kinase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
MSI 
Microsatellite Instability 
MTD 
Maximum Tolerated Dose 
MUGA 
Multigated Acquisition (scan) 
NCI 
National Cancer Institute 
NSAID 
Nonsteroidal Anti-Inflammatory Drugs 
NSCLC 
Non-Small Cell Lung Cancer 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease  
PFS 
Progression-free Survival 
PK 
Pharmacokinetic 
PR 
Partial Response 
PS 
Performance Status 
PT 
Preferred Term 
Q3W 
Once Every 3 Wk 
QTc 
Corrected QT Interval 
QTcF 
QT Interval Corrected for Heart Rate by Fridericia’s Formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RES 
Response Evaluable Set 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 30 
ABBREVIATION 
DEFINITION 
ROS1 
ROS Proto-Oncogene 1 
SAVER 
Serious Adverse Event Report 
SID 
Subject Identification 
SMQ 
Standardised MedDRA Query 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SpO2 
Peripheral Oxygen Saturation 
TBL 
Total Bilirubin 
TEAE 
Treatment-emergent Adverse Event 
Tmax 
Time to maximum serum concentration 
TMF 
Trial Master File 
TTR 
Time to Response 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAVER 
Serious Adverse Event Report 
SD 
Stable Disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal Elimination Half-life 
TKI 
Tyrosine Kinase Inhibitors 
ULN 
Upper Limit of Normal 
Vss 
Volume of Distribution at Steady-State 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 31 
1. 
INTRODUCTION 
1.1. 
Background 
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related mortality 
worldwide; accounting for approximately 18% of all cancer deaths.1 For years, platinum-based 
chemotherapy has been the cornerstone of treatment for NSCLC in the first-line.  However, the 
5-year survival with conventional chemotherapy regimens is around only 5%.2 
In recent years, several targeted therapies have been approved and recommended for use in 
patients with advanced/metastatic NSCLC including those with non-squamous disease.  In 
particular, the advent of targeted therapies for specific driver mutations such as epidermal growth 
factor receptor (EGFR) and well immune checkpoint inhibitors have significantly changed the 
outlook for this disease.  Despite these recent advances, however, a significant number of 
patients are either not eligible for the new therapies or eventually progress on these treatments.  
Hence, a significant unmet need exists for patients with advanced/metastatic NSCLC. 
Human epidermal growth factor receptor 2 (HER2) overexpression has been reported in 
approximately 10% to15% of NSCLC, with a reported incidence as high as 30% in 
adenocarcinoma.3, 4  This overexpression is also associated with poor disease prognosis and 
shortened overall survival (OS).4, 5, 6  HER2 activating mutation is also reported in approximately 
2% to 3% of all NSCLC adenocarcinoma, particularly in patients who are Asian, women, and 
nonsmokers.7, 8, 9, 10, 11, 12  HER2 mutations and other driver oncogene abnormalities are reported 
to be mutually exclusive.7  
Results from clinical studies suggest a potential role of HER2-targeting antibody drug conjugate 
(ADC) in NSCLC.  A recent study of trastuzumab emtansine (T-DM1) in NSCLC based on 
HER2 immunohistochemistry (IHC) expression showed an objective response rate (ORR) of 0% 
for IHC 2+ tumors, but did demonstrate efficacy with ORR 20% in IHC 3+ tumors.13  A separate 
T-DM1 study reported an ORR of 44% in patients with HER2-mutant NSCLC.14  While there is 
no direct HER2-targeted therapies approved for NSCLC, further investigation of HER2-targeting 
strategies are warranted in this patient population. 
1.1.1. 
Investigational Product 
1.1.1.1. 
Name 
Trastuzumab deruxtecan 
1.1.1.2. 
Description 
Trastuzumab deruxtecan is an ADC targeting HER2.  Trastuzumab deruxtecan consists of an 
antibody component, MAAL-9001, covalently conjugated via a maleimide tetrapeptide linker, to 
a drug component, MAAA-1181a.  MAAL-9001 is an in-house humanized immunoglobulin G1 
monoclonal antibody with the same amino acid sequence as trastuzumab.  MAAA-1181a, an 
exatecan derivative, is a topoisomerase I inhibitor that is cell-membrane permeable, and more 
potent than SN-38 (active metabolite of irinotecan).15,16,17  This ADC achieves a high 
drug-to-antibody ratio (DAR) (7 - 8:1) with homogeneous conjugation with MAAA-1181a.18  


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 32 
Trastuzumab deruxtecan is cleaved by lysosomal enzymes and releases MAAA-1181a in the 
cytoplasm after it binds to the HER2 receptor, which gets internalized in tumor cells.  
Three forms of trastuzumab deruxtecan drug product being investigated in clinical trials include: 
FL-DP1, FL-DP2, and lyophilized powder (Lyo-DP).  Only the Lyo-DP form will be 
administered in this trial. 
The trastuzumab deruxtecan Phase 1 clinical study, DS8201-A-J101, was initiated with the 
antibody component, MAAL-9001, produced using the Chinese hamster ovary (CHO)
 cell 
line (FL-DP1).  To support this study, as well as commercial development, transition has been 
made to MAAL-9001 production by using a Chinese hamster ovary
cell line 
(FL-DP2/Lyo-DP).  Analytic comparison of the 2 cell line products has shown comparability 
across a wide range of variables.  Minor differences have been observed in glycan profile, charge 
variants, size variants, FcgRIIIA binding, FcRn binding, and antibody-dependent cellular 
cytotoxic (ADCC) activity.  Following single intravenous (IV) administration of trastuzumab 
deruxtecan to cynomolgus monkeys, mean maximum plasma concentration (Cmax) of 
trastuzumab deruxtecan was similar, while area under the concentration-time curve (AUC) was 
approximately 15% lower, for FL-DP2 material as compared to FL-DP1 material.  However, in a 
xenograft model, no difference was seen in cytotoxicity between the 2 products.  
1.1.1.3. 
Intended Use Under Investigation 
This study will investigate the safety and efficacy of trastuzumab deruxtecan in 
HER2-over-expressing or -mutated NSCLC subjects. 
1.1.1.4. 
Nonclinical Studies of Trastuzumab Deruxtecan  
In nonclinical studies for MAAA-1181a (free form), MAAA-1181c (additive form [3/10 
MeCN 2/5 MeOH 3/10 H2O]) or MAAA-1181d (monohydrate) were used.  The doses and 
concentrations of MAAA-1181c and MAAA-1181d are expressed as those of MAAA-1181a, the 
free form. 
1.1.2. 
Nonclinical Studies 
1.1.2.1. 
Pharmacology 
In studies on the mechanism of action of trastuzumab deruxtecan, trastuzumab deruxtecan was 
confirmed to have an HER2-mediated protein kinase b (Akt) phosphorylation inhibition and an 
ADCC activity, and has also been confirmed to cause DNA damage and induce apoptosis, effects 
that are assumed to be the result of MAAA-1181c, which has topoisomerase I inhibitory activity. 
Therefore, trastuzumab deruxtecan is considered to exhibit HER2-specific cell growth inhibition 
and antitumor activity via a novel mechanism of action that combined the pharmacological 
activities of MAAL-9001, the antibody component, with those of MAAA-1181a, the drug 
component.  
1.1.2.2. 
Safety Pharmacology 
In a safety pharmacology study in monkeys treated with single IV doses of trastuzumab 
deruxtecan, no effects on the cardiovascular system, the respiratory system, or the central 
CCI
CCI


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 33 
nervous system were observed under the study condition.  In addition, in human ether- a-go-go-
related gene (hERG) studies of MAAA-1181a, MAAA-1181a did not inhibit the hERG channel 
current. 
1.1.2.3. 
Pharmacokinetics and Drug Metabolism 
In cynomolgus monkeys, the clearance of trastuzumab deruxtecan was much lower than the 
hepatic flow, and it decreased with increasing dose, suggesting a non-linear process.  The 
volume of distribution at steady state (Vss) was close to the plasma volume.  Both trastuzumab 
deruxtecan and the total antibody, bound and unbound antibody combined, exhibited similar 
pharmacokinetics (PK) profiles, indicating that the majority of the administered trastuzumab 
deruxtecan circulates in plasma unchanged.  The plasma concentrations of MAAA-1181a, the 
drug that is released from trastuzumab deruxtecan, were quite low.  No anti-trastuzumab 
deruxtecan antibody was detected in any animals.  
After a single IV administration of 3H-labeled trastuzumab deruxtecan (3H-trastuzumab 
deruxtecan, antibody portion [MAAL-9001] was 3H-labeled) or 14C-labeled trastuzumab 
deruxtecan (14C-trastuzumab deruxtecan, drug portion [MAAA-1181a] was 14C-labeled) to 
cynomolgus monkeys, the highest radioactivity was observed in the blood during the study 
period.  The concentrations of radioactivity in all tissues declined in proportion to the decline in 
the blood concentration, suggesting no accumulation and retention in specific tissues.  The 
plasma protein binding ratios of MAAA-1181a (10 ng/mL to 100 ng/mL) were 90.3% to 92.5% 
in mice, 94.2% to 96.7% in rats, 86.5% to 89.1% in monkeys, and 96.8% to 98.0% in humans, 
respectively. 
In vitro release rates of MAAA-1181a from trastuzumab deruxtecan in mouse, rat, monkey, and 
human plasma up to 3 wk were 3.9% or less. Cytochrome P450 (CYP) 3A4 was the primary 
CYP enzyme involved in the metabolism of MAAA-1181a.  No human specific metabolites were 
detected in vitro.  The major peaks inferred to be metabolites were MAAA-1181a, a 
methylglycinamide form of MAAA-1181a, a cysteine conjugate of the drug and linker moieties 
of trastuzumab deruxtecan and its isomer, a succinimide form of the linker and the drug 
conjugate of trastuzumab deruxtecan, and a thiomethylate of the linker and the drug conjugate of 
trastuzumab deruxtecan.  
In monkeys, excretion of radioactivity from administered 14C-trastuzumab deruxtecan into feces 
was predominant.  In rats, excretion of radioactivity from administered 14C-labeled 
MAAA-1181a (14C-MAAA-1181a) into feces via bile was predominant. 
MAAA-1181d did not show any inhibition potential to CYP1A2, CYP2B6, CYP2C8, CYP2C9, 
CYP2C19, CYP2D6, and CYP3A (concentration producing 50% inhibition [IC50] >50 μmol/L).  
MAAA-1181d did not show any induction potential to CYP3A4, CYP1A2, and CYP2B6 up to 
30 μmol/L.  MAAA-1181d did not inhibit organic anion transporter (OAT) 3, organic cation 
transporter (OCT) 1, OCT2, organic anion- transporting polypeptide (OATB) 1B3, multidrug 
and toxin extrusion protein (MATE) 1, MATE2-K, P-glycoprotein, breast cancer resistance 
protein, and bile salt export pump (IC50 >30 μmol/L).  MAAA-1181d inhibited OAT1 and 
OATP1B1 with the IC50 values of 12.7 μmol/L and 14.4 μmol/L, respectively; however, the 
values were much higher than the Cmax of MAAA-1181a in humans (9.25 ng/mL 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 34 
[0.019 μmol/L] at 8.0 mg/kg of trastuzumab deruxtecan).  In addition, OATPs were considered 
to contribute to the human hepatic uptake of MAAA-1181a. 
The plasma concentration time profiles following repeated administration of trastuzumab 
deruxtecan once every 3 weeks (Q3W) for 3 cycles (Q3W × 3) to humans were simulated on the 
basis of the PK of trastuzumab deruxtecan in cynomolgus monkeys.  These estimates were 
compared to the plasma concentrations of trastuzumab deruxtecan in the studies in tumor-bearing 
mice.  As a result, the minimum effective dose and the pharmacologically active dose were 
expected to be 0.8 and 4.8 mg/kg, respectively, with a Q3W dosage in humans. 
1.1.2.4. 
Toxicology 
In a study of intermittent IV dosing of trastuzumab deruxtecan in rats (Q3W × 2), no deaths or 
moribund animals were found at dose levels up to 197 mg/kg, the maximum dose.  The major 
observed findings included testicular and intestinal toxicity at dose levels of 20 mg/kg and 
greater, and lymphatic/hematopoietic, skin, incisor tooth, and renal toxicity at dose levels of 
60 mg/kg and greater.  Except for the testicular and incisor tooth changes, these changes were all 
found to recover.  
In an intermittent IV dosing study of trastuzumab deruxtecan in cynomolgus monkeys 
(Q3W × 2), 1 female was sacrificed moribund at 78.8 mg/kg, the highest dose level.  The major 
toxicity findings in this moribund animal were observed in the intestine, hematopoietic system, 
skin, and kidney.  The cause of the moribundity appeared to be the deteriorated condition of the 
animal from decreased body weight and food consumption, as well as bone marrow toxicity and 
intestinal toxicity.  The major findings of toxicity in the surviving animals were observed in the 
intestine at dose levels of 10 mg/kg and greater, and in the lung, testes, and skin at dose levels of 
30 mg/kg and greater.  In addition, hematopoietic system toxicity, renal toxicity, and 
electrocardiogram (ECG) abnormalities (shortened PR interval and corrected QT interval [QTc] 
prolongation) were found at 78.8 mg/kg.  Except for the pulmonary and skin toxicity 
(pigmentation), these findings tended to recover.  
Thus, as described above, the severely toxic dose in 10% of the animals in a rat intermittent IV 
dosing study of trastuzumab deruxtecan was found to be greater than 197 mg/kg.  In the monkey 
study, due to observed moribundity at 78.8 mg/kg and evidence of critical pulmonary toxicity 
(eg, interstitial inflammation and/or alveolar edema) in the surviving animals, it was concluded 
that the highest non-severely toxic dose is 30 mg/kg.  
In an intermittent IV dose toxicity study of MAAA-1181a (morning dosing for 4 wk), findings in 
the lymphatic/hematopoietic system, intestinal tract, and the cornea of the eye were observed at 
3 mg/kg and greater in rats and there was no death or moribundity at up to 30 mg/kg.  Findings 
similar to those in rats were observed in cynomolgus monkeys at dose levels of 1 mg/kg and 
greater.  In addition, one female monkey died and one male monkey was sacrificed moribund at 
12 mg/kg.  Although effects on the heart (focal myocardial cell degeneration/necrosis) were 
found in the moribund male along with the above-mentioned toxicities, there were no abnormal 
heart findings in the female that died, even though both animals exhibited worsening clinical 
conditions associated with sustained decreases in food consumption, bone marrow toxicity, and 
intestinal toxicity.  These changes were considered to be the cause of the death and moribundity.  
The common adverse findings in both trastuzumab deruxtecan and MAAA-1181a studies were 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 35 
intestinal and lymphatic/hematopoietic system toxicities.  For trastuzumab deruxtecan treatment, 
pulmonary, testicular, skin, and renal toxicities were observed while heart, liver, and corneal 
toxicities were found only when MAAA-1181a was administered.  
In a human cross-reactivity study of trastuzumab deruxtecan with a panel of human tissues, 
trastuzumab deruxtecan-related cell membrane staining was found only in the placenta.  In a 
cross-reactivity study of trastuzumab deruxtecan with selected cynomolgus monkey tissues 
(eg, brain, liver, kidney, lung, heart, intestines, lymphoid organs, testes, and skin), neither 
membranous nor cytoplasmic staining was noted in any tissues.  
In an in vitro 3T3 NRU phototoxicity study, MAAA-1181a was found to be phototoxic to Balb/c 
3T3 mouse fibroblasts.  However, in an in vivo single dose phototoxicity study of MAAA-1181d 
in pigmented rats, no phototoxic reaction was noted at 3 mg/kg, the highest dose tested.  For 
additional nonclinical data supporting trastuzumab deruxtecan use in nonclinical studies, please 
refer to the current Investigator’s Brochure (IB). 
1.1.3. 
Clinical Experience 
As of 08 Jun 2019, trastuzumab deruxtecan has been evaluated in 12 company-sponsored clinical 
studies (11 monotherapy studies and 1 combination therapy study) in multiple oncology 
indications, with an estimated 1036 subjects exposed to at least 1 dose of trastuzumab 
deruxtecan.   
The trastuzumab deruxtecan first-in-human study (Protocol DS8201-A-J101) is an open-label, 
dose finding study to assess the safety and tolerability of trastuzumab deruxtecan in subjects with 
advanced solid tumors.  Part 1 (dose escalation) enrolled subjects with either advanced breast 
cancer or gastric/gastroesophageal junction adenocarcinoma that is refractory or intolerant to 
standard treatment, or for which no standard treatment is available.  Part 2 is the expansion phase 
and focuses on HER2-expressing breast (previously treated ado- T-DM1 HER2-positive breast 
cancer) and gastric/gastroesophageal junction adenocarcinoma, HER2-low-expressing breast 
cancer, as well as other HER2-expressing solid cancers. 
As of the data cutoff date of 01 Feb 2019, in the Study DS8201-A-J10134 there were 289 subjects 
in total who received at least 1 dose of trastuzumab deruxtecan (27 subjects during the Dose 
Escalation Phase [Part 1] and 262 subjects during the Dose Expansion Phase [Part 2]) across all 
tumor types and doses.  Median duration of treatment across all tumor types and doses is 
7.4 months, and 25.3% of subjects had ≥12 months of treatment.  Across tumor types by dose, 
the median duration of treatment was similar between 5.4 mg/kg (7.1 months) and 6.4 mg/kg 
(7.8 months).  Median duration of treatment was longest in HER2 positive breast cancer 
(8.5 months in subjects dosed with 5.4 mg/kg and 9.0 months in subjects dosed with 6.4 mg/kg). 
1.1.3.1. 
Efficacy: DS8201-A-J101 (Ongoing) 
Preliminary efficacy results34 as of 01 Feb 2019 showed confirmed  ORR by independent central 
review (ICR) of 52.5% (95% confidence interval [CI]: 43.1, 61.8) among the 118 subjects with 
HER2-positive breast cancer, with confirmed ORR of 51.0% (95% CI: 36.6 to 65.2) for the 
51 subjects in the 5.4-mg/kg dose group and confirmed ORR of 53.7% (95% CI: 41.1 to 66.0) 
for the 67 subjects in the 6.4 mg/kg dose group.  The median confirmed duration of response 
(DoR) by ICR was 13.3 months, 12.7 months, and 13.6 months for the pooled, 5.4 mg/kg, and 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 36 
6.4-mg/kg dose groups, respectively.  The median progression-free survival (PFS) by ICR was 
13.7 months, 13.7 months, and 14.1 months for the pooled, 5.4 mg/kg, and 6.4-mg/kg dose 
groups, respectively.  Median OS was not reached as of the data cutoff.  
Among the 54 subjects with HER2-low breast cancer, confirmed ORR by ICR was 37.0% (95% 
CI: 24.3 to 51.3) by ICR.  Median confirmed DoR by ICR was 10.4 months (95% CI: 8.8 to not 
estimable).  Median PFS by ICR was 11.1 months (95% CI: 7.6 to not estimable).  Median OS 
was 29.4 months (95% CI: 12.9 to 29.4).  
Among the 61 subjects with other cancers, confirmed ORR by ICR was 29.5% (95% CI: 18.5 to 
42.6) and median confirmed DoR by ICR was 11.5 months (95% CI: 7.0 to not estimable).  
Median PFS by ICR was 7.2 months (95% CI: 4.8 to 11.1) and median OS was 23.4 months 
(95% CI: 15.6 to not estimable). 
As of the data cutoff date of 01 Feb 2019, efficacy results for all subjects with NSCLC in the 
Study DS8201-A-J101 are summarized in Table 1.1.  
In the Enrolled Analysis Set, a confirmed ORR by ICR was observed in 55.6% (95% CI: 30.8 to 
78.5) of subjects with NSCLC, 5.0% (95% CI: 0.1 to 24.9) of subjects with colorectal cancer, 
and 30.4% (95% CI: 13.2 to 52.9) of subjects with cancer of other tumor type.  In subjects with 
other cancers, 18 subjects had best overall responses of CR (2 [3.3%] subjects) or partial 
response [PR) (16 [26.2%]subjects). 
The median confirmed DoR based on complete response (CR) (calculated using the 
Kaplan-Meier [KM] method) was 10.7 months in subjects with NSCLC and 13.4 months in 
subjects with colorectal cancer and was not reached in subjects with cancer of other tumor type.  
Of the 18 subjects with confirmed response by ICR assessment, 7 (38.9%) subjects had 
progressed and none had died as of the data cutoff.  Based on the KM estimate of confirmed 
CR/PR by ICR assessment, the estimated proportion of subjects remaining in response was 
88.5% at 6 months, 46.8% at 12 months, and 31.2% at 18 months. 
At the time of the data cutoff, 38 of 61 (62.3%) subjects had PD based on ICR assessment and/or 
death.  The median PFS by ICR was 11.3 months (95% CI: 7.2 to 14.3) in subjects with NSCLC, 
4.0 months (95% CI 2.7 to 5.6) in subjects with colorectal cancer, and 11.0 months (95% CI: 2.8 
to not estimable) in subjects with cancer of other tumor type.  
At the time of the data cutoff, 21 of 61 (34.4%) subjects in the Enrolled Analysis Set had died.  
The median OS was 23.4 months in all subjects with other cancers.  Based on the KM analysis, 
the estimated proportion of subjects alive was 77.8% at 6 months, 69.9% at 12 months, 61.2% at 
18 months, and 46.7% at 24 months.  
Overall, 52 of 61 (85.2%) subjects with other cancers had baseline and postbaseline tumor 
assessments by ICR.  The mean tumor shrinkage of target lesions was -30.65% (30.793).  Most 
subjects had tumor shrinkage by ICR (80.8% [42/52]), which occurred at the first postbaseline 
tumor assessment in 92.9% (39/42) of subjects. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 37 
Table 1.1: 
Efficacy Results in NSCLC Cancers in Study DS8201-A-J101 (Enrolled 
Analysis Set) 
Efficacy Variable 
NSCLC 
(N = 18) 
Confirmed ORR, n (%) (95% CIa) 
 
ORR by ICR 
10 (55.6) 
(30.8, 78.5) 
ORR by investigator 
10 (55.6) 
(30.8, 78.5) 
ORR by ICR in response evaluable set, n/N 
10/17 (58.8) 
(32.9, 81.6) 
- 
CR 
0 
- 
PR 
10 (55.6) 
- 
Stable disease 
5 (27.8) 
- 
PD 
2 (11.1) 
- 
NE 
1 (5.6) 
Confirmed best overall response by investigator, n (%) 
 
CR 
0 
PR 
10 (55.6) 
Stable disease 
4 (22.2) 
PD 
3 (16.7) 
NE 
1 (5.6) 
Confirmed DoR, medianb (95% CI) (months) 
 
DoR by ICR 
10.7 
(6.9, 11.5) 
DoR by investigator 
9.9 
(6.9, 11.5) 
Confirmed DCR,c n (%) (95% CIa) 
 
DCR by ICR 
15 (83.3) 
(58.6, 96.4) 
DCR by investigator 
14 (77.8) 
(52.4, 93.6) 
Time to confirmed response by ICR, medianb (95% CI) (months) 
1.4 
(1.2, 2.8) 
Duration of confirmed stable disease by ICR, medianb (95% CI) (months) 
- 
(2.1, -) 
PFS 
 
PFS by ICR 
 
Events, n (%) 
9 (50.0) 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 38 
Efficacy Variable 
NSCLC 
(N = 18) 
Confirmed ORR, n (%) (95% CIa) 
 
Medianb (95% CI) (months) 
11.3 
(7.2, 14.3) 
PFS by investigator 
 
Events, n (%) 
11 (61.1) 
Medianb (95% CI) (months) 
11.3 
(5.5, 14.1) 
Events, n (%) 
4 (22.2) 
Medianb (95% CI) (months) 
Not reached 
(17.3, -) 
Survival at 6 months, % (95% CId) 
88.9 
(62.4, 97.1) 
Survival at 12 months, % (95% CId) 
83.3 
(56.8, 94.3) 
Survival at 18 months, % (95% CId) 
66.7 
(26.2, 88.4) 
Survival at 24 months, % (95% CId) 
- 
(-, -) 
CI = confidence interval; CR = complete response; DCR = disease control rate; DoR = duration of response; HER2 
= human epidermal growth factor receptor 2; ICR = independent central review; NE = nonevaluable; NSCLC = non-
small cell lung cancer; ORR = objective response rate; PD = progressive disease; PFS = progression-free survival; 
PR = partial response  
a 95% exact binomial CI. 
b Median was from Kaplan-Meier estimate.  CI for median as computed using the Brookmeyer-Crowley method. 
c DCR was calculated as the proportion of subjects demonstrating CR, PR, or stable disease for a minimum of 
6 weeks (±1 week) from the first dosing date. 
d CI for the rate at a fixed time point was computed by applying asymptotic normality to the log-log transformation 
of the rate. 
Dashes (-) represent data that are not estimable 
The range includes the censored observations where using “+” after the value indicates censoring.  Months were 
calculated as days × 12/365.25. 
Part 2 subjects are included. 
Data cutoff date: 01 Feb 2019.   
Source: Preliminary data as of 01 Feb 201934. 
1.1.3.2. 
Safety: DS8201-A-J101 (Ongoing) 
As of 01 Feb 2019, a total of 288 (99.7%) subjects experienced at least 1 TEAE, with most of the 
common TEAEs being gastrointestinal or hematological in nature.   
No dose limiting toxicities (DLTs) were reported, and the maximum tolerated dose (MTD) was 
not reached in the Dose Escalation Phase. 
 Gastrointestinal: Nausea was most frequently reported, was predominantly Grade 1 or 
Grade 2, occurred early in the treatment (the majority occurring in the first 1 to 3 
cycles), and was manageable under routine clinical practice.   


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 39 
 Hematological: Events were predominantly Grade 1 or Grade 2, occurred early in 
treatment (the majority occurring in the first 1 to 3 cycles), and were manageable 
under routine clinical practice.  Platelet count decrease (grouped term for preferred 
terms [PTs] platelet count decreased and thrombocytopenia) was commonly seen.  
Treatment-emergent adverse events reported in ≥20% of total subjects (N = 289) by PT and 
grouped term, tumor type, and dose are provided in Table 1.2.  
The TEAEs of Grade ≥3 were reported in 168 (58.1%) subjects.  The most frequently (≥5% of 
subjects) reported TEAEs of Grade ≥3 in any tumor type and dose by PT were anaemia (60 
[20.8%] subjects), neutrophil count decreased (53 [18.3%] subjects), white blood cell (WBC) 
count decreased (37 [12.8%] subjects), platelet count decreased (33 [11.4%] subjects), and 
hypokalaemia (18 [6.2%] subjects). 
Across all tumor types, a numerically higher proportion of subjects in the 6.4-mg/kg dose group 
than in the 5.4-mg/kg group experienced AEs of Grade ≥3 (overall and causally related), SAEs 
(including causally related), AEs leading to drug withdrawal (overall and causally related), and 
AEs leading to dose reduction (overall and causally related). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 40 
Table 1.2: 
Summary of Treatment-Emergent Adverse Events (≥20% of Subjects) in Study DS8201-A-J101 
MedDRA 
Preferred Term 
Number (%) of Subjectsa 
HER2-Positive 
Breast Cancer 
HER2-Low 
Breast Cancer 
HER2-Positive 
Gastric/GEJ Cancer 
Other 
Cancersb 
Total 
(N = 274) 
Total 
(N = 289) 
5.4 mg/kg 
(N = 50) 
6.4 mg/kg 
(N = 66) 
5.4 mg/kg 
(N = 21) 
6.4 mg/kg 
(N = 33) 
5.4mg/kg 
(N = 19) 
6.4 mg/kg 
(N = 25) 
6.4 mg/kg 
(N = 59) 
5.4 mg/kg 
(N = 91) 
6.4 mg/kg 
(N = 183) 
All Doses 
Subjects with any 
TEAEs 
50 (100.0) 
66 (100.0) 
20 (95.2) 
33 (100.0) 
19 (100.0) 
25 (100.0) 
59 (100.0) 
90 (98.9) 
183 (100.0) 
288 (99.7) 
Nausea 
43 (86.0) 
52 (78.8) 
15 (71.4) 
26 (78.8) 
12 (63.2) 
19 (76.0) 
44 (74.6) 
71 (78.0) 
141 (77.0) 
222 (76.8) 
Decreased appetite 
23 (46.0) 
47 (71.2) 
7 (33.3) 
20 (60.6) 
8 (42.1) 
22 (88.0) 
35 (59.3) 
38 (41.8) 
124 (67.8) 
168 (58.1) 
Vomiting 
28 (56.0) 
35 (53.0) 
10 (47.6) 
14 (42.4) 
3 (15.8) 
8 (32.0) 
31 (52.5) 
41 (45.1) 
88 (48.1) 
133 (46.0) 
Alopecia 
19 (38.0) 
45 (68.2) 
6 (28.6) 
18 (54.5) 
4 (21.1) 
4 (16.0) 
20 (33.9) 
29 (31.9) 
87 (47.5) 
120 (41.5) 
Anaemiac 
24 (48.0) 
30 (45.5) 
7 (33.3) 
14 (42.4) 
4 (21.1) 
14 (56.0) 
23 (39.0) 
35 (38.5) 
81 (44.3) 
118 (40.8) 
Fatigue 
24 (48.0) 
32 (48.5) 
11 (52.4) 
9 (27.3) 
4 (21.1) 
3 (12.0) 
21 (35.6) 
39 (42.9) 
65 (35.5) 
111 (38.4) 
Diarrhoea 
18 (36.0) 
28 (42.4) 
9 (42.9) 
16 (48.5) 
3 (15.8) 
5 (20.0) 
19 (32.2) 
30 (33.0) 
68 (37.2) 
102 (35.3) 
Constipation 
18 (36.0) 
30 (45.5) 
7 (33.3) 
14 (42.4) 
5 (26.3) 
7 (28.0) 
16 (27.1) 
31 (34.1) 
67 (36.6) 
100 (34.6) 
Platelet count 
decreased 
15 (30.0) 
24 (36.4) 
3 (14.3) 
14 (42.4) 
5 (26.3) 
12 (48.0) 
22 (37.3) 
24 (26.4) 
72 (39.3) 
100 (34.6) 
Neutrophil count 
decreasee 
12 (24.0) 
25 (37.9) 
3 (14.3) 
13 (39.4) 
2 (10.5) 
12 (48.0) 
21 (35.6) 
18 (19.8) 
71 (38.8) 
91 (31.5) 
White blood cell 
count decreasef 
9 (18.0) 
22 (33.3) 
4 (19.0) 
13 (39.4) 
3 (15.8) 
11 (44.0) 
17 (28.8) 
17 (18.7) 
63 (34.4) 
82 (28.4) 
Aspartate 
aminotransferase 
increased 
9 (18.0) 
23 (34.8) 
3 (14.3) 
10 (30.3) 
1 (5.3) 
3 (12.0) 
12 (20.3) 
13 (14.3) 
48 (26.2) 
63 (21.8) 
Malaise 
6 (12.0) 
19 (28.8) 
2 (9.5) 
13 (39.4) 
3 (15.8) 
5 (20.0) 
13 (22.0) 
11 (12.1) 
50 (27.3) 
62 (21.5) 
Pyrexia 
10 (20.0) 
7 (14.0) 
18 (27.3) 
9 (27.3) 
3 (15.8) 
8 (32.0) 
9 (15.3) 
14 (15.4) 
44 (24.0) 
60 (20.8) 
Stomatitisg 
 
 
4 (19.0) 
13 (39.4) 
1 (5.3) 
4 (16.0) 
10 (16.9) 
12 (13.2) 
45 (24.6) 
58 (20.1) 
GEJ = gastroesophageal junction; HER2 = human epidermal growth factor receptor 2; MedDRA = Medical Dictionary for Regulatory Activities; PT = preferred term; 
TEAE = treatment-emergent adverse event  
a Part 1 and Part 2 subjects are included.  Percentage was calculated using the number of subjects in the column heading as the denominator. 
b Does not include 1 subject with HER2-low gastric cancer who received trastuzumab deruxtecan at 5.4 mg/kg. 
c Grouped term that includes PTs anaemia, hemoglobin count decreased, and red blood cell count decreased. 
d Grouped term that includes PTs platelet count decreased and thrombocytopenia. 
e Grouped term that includes PTs neutrophil count decreased and neutropenia. 
f Grouped term that includes PTs white blood count decreased and leukopenia. 
g Grouped term that includes PTs stomatitis, aphthous stomatitis, mouth ulceration, oral mucosa erosion, and oral mucosal blistering. 
Adverse events were coded using MedDRA Version 20.1. 
Table is presented by decreasing order of preferred terms within the Total (N = 289) All Doses column. 
Data cutoff date: 01 Feb 2019. 
Source: DS8201-A-J101 CSR, Table 10.6.  


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 41 
1.1.4. 
Summary of Clinical Pharmacokinetics 
Following a single IV administration of trastuzumab deruxtecan, the systemic exposure of 
trastuzumab deruxtecan increased approximately proportional to dose across the dose range of 
0.8 to 8.0 mg/kg evaluated in the dose escalation part of Study DS8201-A-J101.  The 
trastuzumab deruxtecan PK parameters at 5.4, 6.4, and 8.0 mg/kg in Cycle 1 are shown in 
Table 1.3. 
The Cmax of trastuzumab deruxtecan was achieved with a median time to Cmax (Tmax) 
approximately 2 h.  The Cmax and AUClast from time 0 to 21 days (AUC0-21d), at 5.4 mg/kg 
were 127 μg/mL and 544 μg•d/mL, respectively, and at 6.4 mg/kg were 181 μg/mL and 
901μg•d/mL, respectively. 
The systemic exposures at 5.4 and 6.4 mg/kg doses in subjects in Cycle 1 were observed to 
exceed the systemic efficacious exposure observed during the nonclinical pharmacology 
evaluation34.  The mean terminal elimination half-life (t1/2) of trastuzumab deruxtecan was 
approximately 6.0 to 7.0  days  
The PK parameters of total antibody were close to that of trastuzumab deruxtecan. 
The Cmax and AUC of MAAA-1181a for the dosing interval were quite low compared with the 
corresponding values for trastuzumab deruxtecan. 
The t1/2 of MAAA-1181a was similar to that of trastuzumab deruxtecan. 
Table 1.3: 
Mean Pharmacokinetic Parameters of Trastuzumab Deruxtecan Following 
Cycle 1 (± Standard Deviation) 
Trastuzumab 
deruxtecan 
Dose 
(mg/kg) 
Cmax 
(g/mL) 
 
Tmax 
(h) 
Median 
(range) 
AUC0-21d 
(μgd/mL) 
 
AUCinf 
(μgd/mL) 
 
t1/2 
(d) 
 
CL 
(mL/d/kg) 
 
Vss 
(mL/kg) 
 
5.4 
(N=6) 
127±17.2 
2.02 
(1.87, 2.07) 
544±165 
590±186 
6.03±0.603 
10.1±3.90 
75.2±24.2 
6.4 
(N=6) 
181±33.1 
2.06 
(1.50, 3.97) 
901±155 
1030±209 
7.33±1.64 
6.41±1.12 
58.6±11.0 
8.0 
(N=5) 
224±41.0 
1.97 
(1.70, 6.80) 
996±229 
1100±259 
6.44±0.793 
7.60±1.73 
62.1±14.0 
AUC = area under the concentration-time curve; AUC0-21d = AUC from the time 0 to 21 d; AUCinf = AUC from time 0 
extrapolated to infinity; CL = clearance; Cmax = maximum serum concentration; d = day, N = number of evaluable subjects; 
t1/2 = terminal elimination half-life; Tmax = time to Cmax; Vss = volume of distribution at steady-state. 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 42 
Table 1.4: 
Mean Pharmacokinetic Parameters of Total Antibody Following Cycle 1 (± 
Standard Deviation) 
Trastuzumab 
deruxtecan 
Dose 
(mg/kg) 
Cmax (μg/mL) 
mean±SD 
Tmax (h) 
(min, max) 
Median (range) 
AUC0-21d 
(μgd/mL) 
 
AUCinf 
(μgd/mL) 
 
t1/2 (day) 
 
5.4 
(N=6) 
116±13.9 
2.03 
(1.87, 6.88) 
609±151 
682±172 
6.78±2.39 
6.4 
(N=6) 
146±18.9 
3.94  
(2.05, 6.87) 
878±97.1 
1050±149 
8.25±2.16 
8.0 
(N=5) 
188±23.3 
2.07  
(1.97, 6.83) 
1120±213 
1270±261 
6.79±0.821 
AUC = area under the concentration-time curve; AUC0-21d = AUC from the time 0 to 21 d; AUCinf = AUC from 0 
extrapolated to infinity; Cmax = maximum serum concentration; d = day; N = number of evaluable subjects; 
t1/2 = terminal elimination half-life; Tmax = time to Cmax. 
 
Table 1.5: 
Mean Pharmacokinetic Parameters of MAAA-1181a Following Cycle 1 
(± Standard Deviation) 
Trastuzumab 
deruxtecan Dose 
(mg/kg) 
Cmax 
(μg/mL) 
 
Tmax (h) 
(min, max) 
Median (range) 
AUC0-21d 
(μgd/mL) 
 
AUCinf 
(μgd/mL) 
 
t1/2 (d) 
 
5.4 
(N=6) 
10.8±7.56 
5.38 
(3.83, 23.75) 
40.6±19.8 
43.6±21.2 
6.11±0.811 
6.4 
(N=6) 
6.80±1.72 
6.83 
(4.05, 7.15) 
31.0±5.11 
34.2±5.63 
6.28±1.17 
8.0 
(N=5) 
9.65±2.56 
6.80 
(2.07, 7.00) 
40.3±5.66 
44.5±7.03 
6.456±1.56 
AUC = area under the concentration-time curve; AUC0-21d = AUC from the time 0 to 21 d; AUCinf = AUC from 0 
extrapolated to infinity; Cmax = maximum serum concentration; d = day; N = number of evaluable subjects; 
t1/2 = terminal elimination half-life; Tmax = time to Cmax. 
1.2. 
Study Rationale 
HER2 is a member of the HER superfamily that initiates signal transduction via the 
phosphatidylinositol-3 kinase Akt and Ras/mitogen-activated protein kinase pathways.19  In 
human advanced solid tumors, expression of HER2 protein has been reported in various tumor 
tissues and in a variety of cultured tumor cell lines including breast cancer,20 gastric cancer,21, 22 
lung cancer,23 pancreatic cancer,24 colorectal cancer,25 and ovarian cancer.26  
HER2 overexpression is an established target of treatments for patients with breast or gastric 
cancer; however, no direct HER2-targeted therapy is approved for NSCLC.  In a CALGB 39810 
study to assess the antitumor activity of trastuzumab in patients with HER2 overexpressing 
NSCLC, ORR was 5%, and median PFS was 2.6 mo (95% CI, 2.2-4.2).27  
Targeted therapies (eg, EGFR, anaplastic lymphoma kinase, ROS proto-oncogene 1  tyrosine 
kinase inhibitor [TKI]) are recommended during the course of treatment as systemic treatments 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 43 
for a subset of patients with NSCLC who have those driver mutations/rearrangements.  However, 
the current unmet medical needs in NSCLC remains in patients who have no known mutation or 
mutations without approved targeted therapy.  HER2 mutation is also considered a distinct 
molecular target since few overlap with other driver oncogene abnormalities were reported.  
Several pan-class HER family TKIs were investigated in HER2-mutated NSCLC; however, 
clinical activity of those treatments were very limited, with ORR range of 0% to 19%.28, 29, 30, 31  
Additionally, once subjects have developed acquired resistance to the various TKIs, there are 
limited treatment options.  Platinum- or Taxane-based chemotherapy or immune checkpoint 
inhibitor remain the treatment options for no known mutation or after disease progression against 
molecular targeted therapy. 
Results from clinical studies suggest a potential role of HER2-targeting ADC in NSCLC.  A 
recent study of T-DM1 in NSCLC based on HER2 IHC expression showed an ORR of 0% for 
IHC 2+ tumors, but did demonstrate efficacy with ORR 20% in IHC 3+ tumors.13  A separate 
T-DM1 study reported an ORR of 44% in patients with HER2-mutant NSCLC.14  While there is 
no direct HER2-targeted therapies approved for NSCLC, further investigation of HER2 targeting 
strategies are warranted in this patient population. 
Trastuzumab deruxtecan is a HER2-targeting ADC with a high drug to antibody ratio (7 to 8), 
and a novel topoisomerase I inhibitor.  Trastuzumab deruxtecan is expected to inhibit tumor 
growth on the basis of the following reasons: it exhibits ADCC activities and Akt 
phosphorylation inhibition similar to those of trastuzumab when it binds to HER2; and the 
MAAA-1181a that is released from trastuzumab deruxtecan after the internalization induces 
apoptosis by inhibiting topoisomerase I.  Nonclinical evidence demonstrates that the HER2 
targeting of trastuzumab deruxtecan is highly specific.  In a study conducted in tumor-bearing 
mouse models, trastuzumab deruxtecan has antitumor activity against HER2 overexpressing 
NSCLC. 
In the Phase 1 study, DS8201-A-J101, the preliminary results as of 08 Jun 2017, indicates that 
trastuzumab deruxtecan has acceptable safety and PK profiles, and antitumor activity.  There 
have been no reported dose-limiting toxicities, the maximum tolerated dose was not reached in 
the 0.8 to 8.0 mg/kg Q3W dose range, and 5.4 mg/kg or 6.4 mg/kg are being considered as the 
recommended Phase 2 dose.  In Part 1 of the Phase 1 study, several doses of trastuzumab 
deruxtecan were administered in a total of 24 subjects and the ORR was 34.8% and the disease 
control rate (DCR) was 91%.  One out of 5 evaluable subjects with NSCLC achieved confirmed 
PR and 2 subjects had stable disease (SD). 
Based on the non-clinical and the clinical observations in the Phase 1 study (DS8201-A-J101), 
trastuzumab deruxtecan was well tolerated and efficacy is suggested by the data in HER2 
overexpressing NSCLC subjects.  Therefore a Phase 2, multicenter, open-label study will be 
conducted to determine the efficacy and safety profile of trastuzumab deruxtecan for HER2 
overexpressing or mutated NSCLC. 
1.2.1. 
Rationale for Expansion 
Given the high level of activity32observed in Phase 1 study DS8201-A-J101, further 
understanding of safety and efficacy of trastuzumab deruxtecan in subjects in Cohort 1 is of 
interest. The increased sample size will facilitate the computation of more precise safety and 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 44 
efficacy estimates.  Cohort 2 expansion has been initiated to include 50 additional subjects.  The 
addition of Cohort 1a of subjects treated at 5.4 mg/kg is required for a preliminary assessment of 
the safety and efficacy of this dose vis-à-vis the slightly higher dose of 6.4 mg/kg that had been 
administered in the other cohorts. 
1.3. 
Risks and Benefits for Study Subjects 
Trastuzumab deruxtecan is under development for the treatment of HER2-expressing cancers 
and HER2-mutant tumors.  Based on the preliminary clinical observations in the Phase 1 study 
(Study DS8201-A-J101), trastuzumab deruxtecan demonstrates antitumor activity in HER2 
expressing cancers, including breast cancer and gastric cancer. 
As of 01 Feb 2019 from the ongoing study DS8201-A-J101, the overall efficacy results in 
subjects with HER2-positive breast cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed 
ORR by ICR of 52.5%.  Among the subjects with HER2-low breast cancer, confirmed ORR by 
ICR was 37.0%.  The overall efficacy results in subjects with HER2-positive 
gastric/gastroesophageal junction cancer at 5.4 mg/kg or 6.4 mg/kg demonstrated a confirmed 
ORR by ICR of 29.5%.  The overall efficacy results in subjects with other cancers demonstrated 
a confirmed ORR by ICR of 29.5%.  In the Enrolled Analysis Set, a confirmed ORR by ICR was 
observed in 55.6% (95% CI: 30.8 to 78.5) of subjects with NSCLC, 5.0% (95% CI: 0.1 to 24.9) 
of subjects with colorectal cancer, and 30.4% (95% CI: 13.2 to 52.9) of subjects with cancer of 
other tumor type.   
As of 08 Jun 2019, based on the cumulative review of the safety data, including available 
nonclinical, clinical, and epidemiologic information and scientific literature (published and 
unpublished) and taking into consideration biological plausibility, ILD /pneumonitis, anemia, 
neutrophil count decrease including febrile neutropenia, and platelet count decrease are classified 
as important identified risks.  LVEF decrease is classified as an important potential risk.  
Infusion-related reactions, which were previously classified as an important potential risk, are 
reclassified as an identified risk.  QT prolongation is no longer considered an important potential 
risk and has been removed from the list of safety concerns for trastuzumab deruxtecan. 
In the trastuzumab deruxtecan clinical program, the inclusion/exclusion criteria and 
monitoring/management guidelines are currently in place in all protocols to mitigate the 
important identified risks of ILD /pneumonitis, anemia, neutrophil count decrease including 
febrile neutropenia, and platelet count decrease, and important potential risk of LVEF decrease.  
ILD /pneumonitis is a known serious risk of trastuzumab deruxtecan, and cases with fatal 
outcomes have been reported.  Most events were Grade 1 or Grade 2 and were manageable by 
dose modification and following clinical treatment guidelines for drug-induced ILD 
/pneumonitis, with specific recommendations including close monitoring of signs/symptoms of 
ILD (eg, cough, fever, and dyspnea) to identify potential ILD /pneumonitis and proactively 
managing ILD /pneumonitis with dose modification and treatment (eg, steroids).  ILD 
/pneumonitis requires proper monitoring, dose modification, and supportive care instituted in a 
timely fashion.   
Other identified risks of trastuzumab deruxtecan in order of descending frequencies are nausea, 
decreased appetite, alopecia, vomiting, fatigue, constipation, diarrhoea, WBC count decrease, 
stomatitis, aspartate aminotransferase increased, cough, headache, abdominal pain, alanine 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 45 
aminotransferase increased, hypokalaemia, epistaxis, dyspnoea, dyspepsia, dizziness, dry eye, 
upper respiratory tract infection, asthenia, and infusion-related reactions.  
These identified risks were generally manageable through dose modification and routine clinical 
practice. 
Trastuzumab deruxtecan has demonstrated a generally acceptable safety profile in the treated 
populations.   
In conclusion, given the data available on the efficacy and safety of trastuzumab deruxtecan, the 
overall benefit/risk remains positive for clinical development. 
For current details on safety and tolerability profile of trastuzumab deruxtecan and assessments 
of risks and benefits to subjects, please refer to the current IB for trastuzumab deruxtecan. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 46 
2. 
STUDY OBJECTIVES AND HYPOTHESIS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
The primary objective is to evaluate the ORR of trastuzumab deruxtecan in HER2-
overexpressing and/or –HER2 mutated advanced NSCLC subjects. 
2.1.2. 
Secondary Objectives 
The secondary objectives are: 
 To evaluate DoR, DCR, PFS, and OS.  
 To further evaluate the safety of trastuzumab deruxtecan  
 To determine the PK of trastuzumab deruxtecan  
2.1.3. 
Exploratory Objectives 
The exploratory objectives are:  
 To evaluate time to response (TTR) and best percent change in the sum of the 
diameters for all target lesions 
 To evaluate potential biomarkers 
 To evaluate exposure-response relationships for efficacy and safety endpoints 
2.2. 
Study Hypothesis 
Trastuzumab deruxtecan confers an ORR benefit in HER2-overexpressing and/or –mutated 
NSCLC subjects. 
2.3. 
Study Endpoints 
The efficacy endpoints based on tumor assessments will be based on ICR unless otherwise 
stated. 
2.3.1. 
Primary Endpoint(s) 
The primary efficacy endpoint is ORR. 
2.3.2. 
Key Secondary Endpoint(s) 
The secondary efficacy endpoints are: 
 DoR  
 DCR  
 PFS  
 OS 
 ORR per investigator’s assessments 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 47 
The safety endpoints will include: 
 SAEs 
 TEAEs 
 Physical examination findings (including Eastern Cooperative Oncology Group 
Performance Status [ECOG PS]) 
 Vital sign measurements 
 Standard clinical laboratory parameters 
 ECG parameters 
 Echocardiogram (ECHO)/multigated acquisition (MUGA) findings 
 Ophthalmologic findings 
 • 
Antidrug antibody (ADA) 
The PK Endpoints (trastuzumab deruxtecan, total anti-HER2 antibody and MAAA-1181a) will 
include: 
 PK parameters: Cmax, Tmax, AUC from time 0 to the last measurable 
concentration (AUClast), and AUC0-21d 
 Serum concentrations  
2.3.3. 
Exploratory and Biomarker Endpoint(s) 
The exploratory efficacy endpoints are: 
 TTR 
 Best percentage change from baseline in the sum of the diameters for all target lesions 
 Analysis of biopsied materials for mechanisms of resistance to trastuzumab 
deruxtecan  
 Exposure-response relationships for efficacy and safety endpoints 
Biomarker endpoints are: 
 Analysis of tissue and/or blood for mechanisms of response/resistance to trastuzumab 
deruxtecan  
 To evaluate potential biomarkers of response 
 Biomarker analysis by cell-free deoxyribonucleic acid (cfDNA) 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 48 
3. 
STUDY DESIGN 
3.1. 
Overall Design 
3.1.1. 
Overview  
This is a multicenter, open-label, 2-cohort, Phase 2 study to investigate the safety and efficacy of 
trastuzumab deruxtecan in HER2-overexpressing or -mutated NSCLC subjects. 
Cohort 1 will enroll approximately 40 subjects with HER2-overexpressing (IHC 3+ or IHC 2+), 
unresectable and/or metastatic non-squamous NSCLC with 6.4 mg/kg of trastuzumab deruxtecan 
dosing.  Another approximately 40 subjects will receive 5.4 mg/kg of trastuzumab deruxtecan in 
Cohort 1a. 
Cohort 2 will enroll approximately 90 subjects with HER2-mutated, unresectable and/or 
metastatic non-squamous NSCLC after the planned expansion adding 50 subjects to the original 
40 subject cohort. 
Trastuzumab deruxtecan will be administered as a sterile IV solution at a dosage of 6.4 mg/kg 
Q3W or 5.4 mg/kg Q3W. 
The study treatment will be continued according to the dosing criteria to derive clinical benefit in 
the absence of withdrawal of subject consent, progressive disease (PD), or unacceptable toxicity.  
If the study treatment is delayed more than 28 d from the planned date of administration, the 
subject will be withdrawn from the study treatment (see Section 5.4). 
Figure 3.1: 
Study Design Schema for DS8201-A-U204 
 
HER = human epidermal growth factor receptor; IHC = immunohistochemistry; IXRS = Interactive Web/Voice 
Response System; Q3W = every 3 weeks 
*Central lab testing of archival/fresh tissue sample is not utilized for enrollment in Cohort 2. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 49 
3.1.2. 
Duration of the Study 
Enrollment is planned to occur over approximately 31 mo.  The anticipated duration of the study 
is approximately 43 mo. 
There will be a 40-Day (+7d) Follow-up visit, followed by Long-Term Follow-up visits every 
3 mo (±14 d) from the date of 40-Day Follow-up visit, until death, withdrawal of consent, loss to 
follow-up, or study closure, whichever occurs first. 
The Sponsor may terminate the study at any time and study termination may also be requested by 
(a) competent authority(ies). 
3.1.3. 
Duration of Subject Participation 
3.1.3.1. 
Screening Phase 
The screening period is up to 28 d after the Main Informed Consent Form (ICF) is signed. 
3.1.3.2. 
Treatment Phase 
Each cycle of treatment of trastuzumab deruxtecan will be every 21 d.  The number of treatment 
cycles with trastuzumab deruxtecan is not fixed.  Upon commencing study drug, subjects may 
continue receiving the study drug until the occurrence of any of the events defined in Section 5.8. 
3.1.4. 
Follow-up Phase 
Regardless of reason for discontinuation from study drug, all subjects should be contacted for 
follow-up every 3 mo (±14 d) from the date of 40-Day (+7 d) Follow-Up Visit until death, 
withdrawal of consent, lost to follow-up, or study closure, whichever occurs first, OR until 
follow-up data collection is no longer of scientific value or otherwise needed (at the Sponsor’s 
discretion), to obtain information about subsequent treatment(s) and survival status. 
The end of the study is defined as approximately 6 mo after the last subject is registered. 
3.2. 
Discussion of Study Design 
This study will be conducted in up to 30 study sites in North America, Japan, and Europe. 
The target sample size will be approximately 170 subjects: 40 in Cohort 1, 40 in Cohort 1a, and 
90 in Cohort 2. 
3.3. 
Selection of Dose and Usage 
The dose selection was based on the efficacy, safety, tolerability and pharmacokinetic data of 
trastuzumab deruxtecan from prior clinical studies in subjects with breast cancer (BC), NSCLC 
and other solid tumors.   
In the dose escalation part (Part 1) of the first-in-human study DS8201-A-J101, no dose-limiting 
toxicities were observed, and the maximum tolerated dose was not reached in the evaluated dose 
range of 0.8 to 8.0 mg/kg. Based on the efficacy and safety data in Part 1 of Study 
DS8201-A-J101, the 5.4 and 6.4 mg/kg doses exhibited clinical activity with a qualitatively 
similar safety profile, and therefore were selected for the dose expansion portion (Part 2) of 
Study DS8201-A-J101 in subjects with metastatic breast cancer (mBC), gastric/GEJ cancer, 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 50 
NSCLC, colorectal cancer and other solid tumors; subjects with NSCLC received only a 
6.4 mg/kg dose of trastuzumab deruxtecan in Study DS8201-A-J101 (Part 2d).   
A dose of 6.4 mg/kg was selected for Study DS8201-A-U204, based on available efficacy data 
from subjects with NSCLC in Part 2d of Study DS8201-A-J101 and a preliminary 
logistic-regression analysis for efficacy from Part 1 of Study DS8201-A-J101, which indicated a 
numeric trend of achieving higher ORR (approximately 7% higher) with trastuzumab deruxtecan 
dose of 6.4 mg/kg compared to a dose of 5.4 mg/kg.  Prior to the initiation of Study 
DS8201-A-U204, 1 out of 5 evaluable subjects with NSCLC achieved a confirmed partial 
response (PR) and 2 patients were in SD at the 6.4 mg/kg dose in Part 2d of Study 
DS8201-A-J101.  As of the most recent data-cut (01 Feb 2019) in subjects with NSCLC in 
Part 2d of Study DS8201-A-J101, 18 evaluable subjects, in the Enrolled Analysis Set had 
confirmed ORR of 55.6% (10/18; 95% CI for ORR: 30.8% - 78.5%) with median DoR of 
10.7 months (95% CI: 6.9 – 11.5 months) and median PFS of 11.3 months (95% CI: 7.2 – 
14.3 months; based on 9 events) has been achieved at trastuzumab deruxtecan dose of 6.4 mg/kg.  
Consistent promising efficacy was observed in the subset of NSCLC subjects with HER2 
mutation (N =11).  From a safety perspective, trastuzumab deruxtecan dose of 6.4 mg/kg was 
generally tolerated with an acceptable and manageable safety profile consistent with the safety 
profile observed in other solid tumors.  These results support evaluation of trastuzumab 
deruxtecan dose of 6.4 mg/kg in subjects with NSCLC in current study. 
Trastuzumab deruxtecan dose of 5.4 mg/kg has been evaluated in Study DS8201-A-J101 and a 
Phase 2 study (DS8201-A-U201) in subjects with HER2-positive, unresectable and/or mBC.  
The dose of 5.4 mg/kg has shown robust efficacy with confirmed ORR (by Independent Central 
Review) of 58.3% (137/235; 95%CI: 51.7% - 64.7%) in subjects with mBC.  From safety 
perspective, a numeric trend for better safety profile was seen at the 5.4 mg/kg dose compared to 
higher doses (≥ 6.4 mg/kg).  The trastuzumab deruxtecan dose of 5.4 mg/kg is currently being 
evaluated in the ongoing Phase 3 studies in subjects with mBC. Based on these efficacy and 
safety data in subjects with mBC, trastuzumab deruxtecan dose of 5.4 mg/kg was also selected 
for evaluation in this study in subjects with HER2-expressing NSCLC to assess the benefit/risk 
profile of the 5.4 mg/kg dose in this patient population. 
From the PK perspective, the systemic exposures parameters (Cmax, AUC0-21d [AUC over 
21 days of dosing cycle] and trough serum concentration in Cycle 1) of intact trastuzumab 
deruxtecan and MAAA-1181a were comparable across subjects with mBC and HER2-expressing 
or -mutant NSCLC at 6.4 mg/kg dose of trastuzumab deruxtecan. The systemic exposure of 
intact trastuzumab deruxtecan at 5.4 and 6.4 mg/kg doses in patients with solid tumors in Cycle 1 
were observed to exceed the systemic efficacious exposure observed during the nonclinical 
pharmacology evaluation.  Based on the exposure response (ER) analyses for efficacy, the mean 
(90% CI) probability of ORR in subjects with mBC was predicted to be 63% (55%- 70%) and 
68% (58% - 77%) for the 5.4 and 6.4 mg/kg dose groups, respectively.  Hence, the ER analyses 
support clinically meaningful efficacy for trastuzumab deruxtecan at both the 5.4 and 6.4 mg/kg 
doses and a small improvement in ORR at 6.4 mg/kg compared to the 5.4 mg/kg dose level in 
subjects with mBC.  The ER analyses for safety estimated, a numerically higher incidence 
(approximately 1% to 7%) of the safety endpoints (adverse event [AE] related discontinuation, 
dose reduction or drug interruption), AEs ≥ Grade 3, SAE, anemia, neutropenia or 
thrombocytopenia and ILD (any grade and ≥ Grade 3), and decreased LVEF (≥ Grade 2) at 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 51 
6.4 mg/kg dose compared to 5.4 mg/kg dose.  Overall, these ER results for efficacy and safety 
indicate that while both 5.4 and 6.4 mg/kg doses showed a positive benefit/risk profile, the 
6.4 mg/kg dose showed a numerical trend for an increase in the ORR as well as a numerical 
increase in the incidence of adverse events compared to the 5.4 mg/kg dose.  These findings 
along with the observed efficacy and safety data in subjects with NSCLC in Study 
DS8201-A-J101 support the selection of 5.4 and 6.4 mg/kg doses in subjects with NSCLC in the 
current study.   
Based on the efficacy, tolerability and PK profile of trastuzumab deruxtecan, doses of 5.4 mg/kg 
and 6.4 mg/kg were evaluated in previous Phase 2 studies as well as in the ongoing Phase 2 and 
Phase 3 studies in patients with solid tumors. These doses have demonstrated to be efficacious 
and have a manageable safety profile. On the basis of these data, trastuzumab deruxtecan doses 
of 5.4 mg/kg and 6.4 mg/kg administered Q3W were selected for this study. 
3.4. 
Interim Analyses 
Efficacy and safety interim analyses will be performed on cohorts 1 and 2 when approximately 
20 subjects in cohort 2 have had at least 18 weeks of follow-up after initiation of therapy [usually 
three computed tomography [CT] scans post baseline] or discontinued treatment. The purpose of 
the interim analysis is to guide the future strategy for trastuzumab deruxtecan in this patient 
population. 
A second interim analysis will be conducted when at least 60 subjects in Cohort 2 have had at 
least 12 weeks of follow-up after initiation of therapy or discontinued treatment.  This interim 
analysis will also be performed on Cohorts 1 and 2. 
A third interim analysis will be performed when at least 20 subjects in Cohort 1a have had at 
least 18 weeks of follow-up after initiation of therapy [usually 3 CT scans post baseline] or 
discontinued treatment.  This interim analysis will be performed on cohorts 1, 1a, and 2. 
The main purpose of this interim analysis is to get an early idea about the safety and efficacy of 
the administered dose in Cohort 1a. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 52 
4. 
STUDY POPULATION 
Each subject will sign a study Main ICF provided by the site.  A subject is considered enrolled in 
the study upon the Investigator or designee obtaining written Main ICF from the subject at the 
time of screening and upon determination that all inclusion and exclusion criteria have been 
satisfied. 
Investigators will maintain a confidential screening log of all potential study candidates that 
includes limited subject information (initials, age, gender, date) and outcome of screening 
process (ie, enrollment in the study, reason for ineligibility, withdrew consent). 
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 (SID) code list.  This confidential 
list of the names of all subjects, allocated study numbers on enrolling in the study, allows the 
investigator to reveal the identity of any subject when necessary. 
4.1. 
Inclusion Criteria 
Subjects must satisfy all of the following criteria to be included in the study: 
1. Must have provided informed consent for study participation (see Section 14.3) before 
performance of any study-specific procedure or test. 
2. Age ≥20 y old in Japan, ≥18 y old in other countries.  
3. Pathologically documented unresectable and/or metastatic non-squamous NSCLC. 
4. Has relapsed from or is refractory to standard treatment or for which no standard 
treatment is available. 
5. For Cohort 1 and Cohort 1a only: HER2-overexpression status must be assessed and 
confirmed by Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory 
or equivalent, from an archival tumor tissue sample. 
For Cohort 2 only: suject has any known documented activating HER2 mutation from an 
archival tumor tissue sample analyzed by Clinical Laboratory Improvement Amendment 
(CLIA)-certified laboratory or equivalent, specifically exon 20 insYVMA 
(Y772_A775dup), insGSP (G778_P780dup), insTGT (G776delinsVC), single base pair 
substitutions L755S, V777L, or S310F or another HER2 mutation listed in the appendix 
(see Table 16.5). Note: HER2 mutation documented only from a liquid biopsy sample 
cannot be used for enrollment.  
6. Presence of at least one measurable lesion assessed by the investigator based on RECIST 
version 1.1. 
7. Is willing and able to provide an adequate archival tumor tissue sample. Fine needle 
aspirates are not acceptable 
8. Is willing to undergo a tissue biopsy, taken after the completion of the most recent 
treatment regimen. 
9. Has ECOG PS of 0 to 1. 
10. Has adequate organ function within 14 d before enrollment, defined as: 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 53 
Parameter 
Laboratory value 
Adequate bone marrow function 
Platelet count  
 100 000/mm3  
(Platelet transfusion is not allowed within 1 wk prior to screening 
assessment) 
Hemoglobin  
≥ 9.0 g/dL 
(Red blood cell transfusion is not allowed within 1 wk prior to 
screening assessment) 
Absolute neutrophil count (ANC) 
 1500/mm3  
(G-CSF administration is not allowed within 1 wk prior to screening 
assessment) 
Adequate renal function 
Creatinine Clearance 
Creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-
Gault equation: 
 CLcr (mL/min) =   
(140 - age [years]) × weight (kg)  {× 0.85 for females}   
(72 × serum creatinine [mg/dL])     
Adequate hepatic function  
ALT/AST 
< 2.5 × ULN per institutional standards or < 5 × ULN if liver 
metastases are present 
Total bilirubin (TBL) 
≤ 1.5 × ULN if no liver metastases or  < 3 × ULN in the presence of 
documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) 
or liver metastases at baseline 
Adequate blood clotting function 
International normalized ratio 
(INR)/Prothrombin time (PT) and either 
partial thromboplastin (PTT) or activated 
partial thromboplastin time (aPTT) 
≤ 1.5 × ULN 
11. Has adequate treatment washout period before enrollment, defined as: 
Treatment 
Washout Period 
Major surgery 
> 4 wk 
Radiation therapy including palliative stereotactic 
radiation to chest  
> 4 wk (palliative stereotactic radiation therapy to other 
areas, > 2 wk) 
Anti-cancer chemotherapy [Immunotherapy (non 
antibody based therapy)] retinoid therapy 
> 3 wk (> 2 wk or 5 half-lives, whichever is longer, for 
small-molecule targeted agents such as 5-fluorouracil-
based agents, folinate agents, weekly paclitaxel; > 6 wk 
for nitrosureas or mitomycin C, ≥1 wk for TKIs 
approved for the treatment of NSCLC - baseline CT 
scan must be completed after discontinuation of TKI) 
Antibody-based anti-cancer therapy  
> 4 wk 
Chloroquine/Hydroxychloroquine 
>14 d 
12. Subjects of reproductive/childbearing potential must agree to use a highly effective form 
of contraception or avoid intercourse during and upon completion of the study and for at 
least 4.5 mo for male subjects, for at least 7 mo for female subjects, after the last dose of 
study drug. 
Methods considered as highly effective methods of contraception include:  
 Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 54 
 Oral 
 Intravaginal 
 Transdermal 
 Progestogen-only hormonal contraception associated with inhibition of ovulation: 
 Oral 
 Injectable 
 Implantable 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Complete sexual abstinence defined as refraining from heterosexual intercourse 
during and upon completion of the study and for at least 4.5 mo for male subjects, for 
at least 7 mo for female subjects after the last dose of study drug.  Periodic abstinence 
(calendar, symptothermal, post-ovulation methods) is not an acceptable method of 
contraception. 
Non-child-bearing potential defined as pre-menopausal females with a documented tubal 
ligation or hysterectomy; or postmenopausal defined as 12 mo of spontaneous 
amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating 
hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory). 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the contraception methods outlined for women of 
child-bearing potential if they wish to continue their HRT during the study.  Otherwise, 
they must discontinue HRT to allow confirmation of postmenopausal status prior to study 
enrollment. For most forms of HRT, at least 2 to 4 wk will elapse between the cessation 
of therapy and the blood draw; this interval depends on the type and dosage of HRT. 
Following confirmation of their postmenopausal status, they can resume use of HRT 
during the study without use of a contraceptive method. 
13. Male subjects must not freeze or donate sperm starting at Screening and throughout the 
study period, and at least 4.5 mo after the final study drug administration.  Preservation of 
sperm should be considered prior to enrollment in this trial. 
14. 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 mo after the final 
study drug administration. 
15. Subjects should be willing and able to comply with protocol visits and procedures. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 55 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria will be disqualified from entering the study: 
1. Had been previously treated with HER2-targeted therapies, except for pan-HER class 
tyrosine kinase inhibitors. 
2. For Cohort 1 and Cohort 1a only: Has known HER2 mutation. 
3. Has uncontrolled or significant cardiovascular disease, including any of the following:  
a. Medical history of myocardial infarction within 6 months before enrollment 
b. Symptomatic congestive heart failure (CHF) (New York Heart Association Class II to 
IV) 28 d prior to enrollment 
c. Troponin levels consistent with myocardial infarction (as defined by the 
manufacturer) 28 d prior to enrollment 
d. History of unstable angina, or serious cardiac arrhythmia requiring treatment 
e. LVEF < 50% within 28 d prior to enrollment 
f. Has a QT interval corrected by Fridericia’s Formula (QTcF) prolongation to > 470 ms 
(females) or >450 ms (males) based on average of the screening triplicate 12-lead 
ECG. 
4. Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD, 
or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening. 
5. Has spinal cord compression or clinically active central nervous system metastases, 
defined as untreated and symptomatic, or requiring therapy with corticosteroids or 
anticonvulsants to control associated symptoms.  Subjects with clinically inactive brain 
metastases may be included in the study.  Subjects with treated brain metastases that are 
no longer symptomatic and who require no treatment with corticosteroids or 
anticonvulsants may be included in the study if they have recovered from the acute toxic 
effect of radiotherapy.  A minimum of 2 wk must have elapsed between the end of whole 
brain radiotherapy and study enrollment. 
6. Has multiple primary malignancies within 3 y, except adequately resected non-melanoma 
skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated. 
7. Has a history of severe hypersensitivity reactions to either the drug substances or inactive 
ingredients in the drug product. 
8. Has history of severe hypersensitivity reactions to other monoclonal antibodies. 
9. Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals.  
10. Has substance abuse or any other medical conditions such as clinically significant cardiac 
or psychological conditions, that may, in the opinion of the investigator, interfere with the 
subject’s participation in the clinical study or evaluation of the clinical study results.  
11. Has known human immunodeficiency virus (HIV) infection, or active hepatitis B  or C 
infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase 
chain reaction is negative for HCV RNA.  Subjects should be tested for HIV prior to 
randomization/enrollment if required by local regulations or institutional review board 
(IRB)/ethics committee (EC). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 56 
12. Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other 
than alopecia) not yet resolved to Grade ≤ 1 or baseline.  Subjects with chronic Grade 2 
toxicities may be eligible per the discretion of the investigator after consultation with the 
Sponsor Medical Monitor or designee (eg, Grade 2 chemotherapy-induced neuropathy). 
13. Is a female subject who is pregnant or breastfeeding or planning to become pregnant. 
14. Clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses 
including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli 
within three months of the study enrollment, severe asthma, severe COPD, restrictive 
lung disease, pleural effusion etc.), and any autoimmune, connective tissue or 
inflammatory disorders with pulmonary involvement (i.e. Rheumatoid arthritis, Sjogren's, 
sarcoidosis etc.), or prior pneumonectomy. 
15. Has undergone prior treatment with an ADC which consists of an exatecan derivative that 
is a topoisomerase I inhibitor. 
16. Has social, familial, or geographical factors that would interfere with study participation 
or follow-up. 
17. Has a concomitant medical condition that would increase the risk of toxicity, in the 
opinion of the investigator.  
18. Is a family member of the study site personnel or of the Sponsor personnel. 
19. Is otherwise considered inappropriate for the study by the investigator. 
4.3. 
Subject Rescreening Procedures 
Rescreening is permitted for any subject who failed to meet the eligibility criteria in the initial 
screening.  The limit of re-screening is 1 time.  The site SID must remain the same at the time of 
re-screening.  The initial screening information and the reason why the subject was ineligible for 
the initial evaluation will be recorded in the Screening Log.  No data from the initial evaluation 
will be entered into the clinical database for a subject who is rescreened. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 57 
5. 
STUDY TREATMENT(S) 
5.1. 
Assigning Subjects to Treatments and Blinding 
5.1.1. 
Treatment Group(s)/Sequences 
There will be subjects allocated to 2 different cohorts (see Section 3.1) according to the centrally 
confirmed HER2 IHC status and documented HER2 mutation status.  All subjects will receive 
trastuzumab deruxtecan treatment at the 6.4 mg/kg Q3W or 5.4 mg/kg Q3W dosages. 
5.1.2. 
Method of Treatment Allocation 
Subjects are enrolled in Interactive Web/Voice Response System (IXRS) for Cohort 1 and 
Cohort 1a (HER2-overexpressing [IHC 3+ or IHC 2+]) and for Cohort 2 (HER2 mutation) after 
signing the tissue screening ICF for Cohort 1 and Cohort 1a subjects or the Main ICF for Cohort 
2 subjects.  
5.1.3. 
Blinding  
This is an open-label study; therefore, no blinding will be performed. 
5.1.4. 
Emergency Unblinding Procedure  
Not applicable. 
5.2. 
Study Drug 
5.2.1. 
Description 
Lyophilized powder (Lyo-DP) 
Trastuzumab deruxtecan for injection 100 mg will be provided as a sterile lyophilized powder 
containing 100 mg of Trastuzumab deruxtecan in a glass vial (Lyo-DP).  Each glass vial should 
be reconstituted with 5 mL water for injection to a concentration of 20 mg/mL (ie, 100 mg/5 
mL).  Trastuzumab deruxtecan will be administered with 5% dextrose as an IV infusion.  Each 
vial is designed for single use only and is not to be used to treat more than one subject.  
5.2.2. 
Labeling and Packaging  
Trastuzumab deruxtecan for injection 100 mg will be supplied by the Sponsor.  Trastuzumab 
deruxtecan for injection 100 mg will be labeled in compliance with regulatory requirements and 
packaged.  The packaging will clearly display the name of the study drug, the lot number, 
storage condition, and other required information in accordance with local regulations. 
5.2.3. 
Preparation  
The study drug for IV infusion is prepared by dilution of the required volume of the study drug 
calculated on the basis of the subject’s body weight in a volume of 100 mL, by the study site 
pharmacist.  Prepared study drug solutions should be used as directed in the pharmacy 
instructions.  The preparation will be conducted in accordance with the pharmacy instructions 
provided by the Sponsor.  Procedures for proper handling and disposal of anticancer drugs 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 58 
should be followed in compliance with the standard operating procedures (SOPs) of the study 
site. 
5.2.4. 
Administration  
The study drug will be administered as an IV infusion over 30 to 90 min every 3 wk ±2 d.  The 
initial dose of study drug will be infused for 90±10 min.  If there is no infusion-related reaction, 
after the initial dose, the next dose of trastuzumab deruxtecan may be infused over 30 ±5 min.  
The subject’s weight at screening (baseline) will be used to calculate the initial dose.  If during 
the course of treatment, the subject’s weight changes by ≥10% of the baseline weight, the 
subject’s dose will be recalculated on the basis of the subject’s updated weight.  Refer to the 
pharmacy instructions for detailed information about administration of study drug. 
5.2.5. 
Storage  
Trastuzumab deruxtecan must be stored in a secure, limited access storage area under the storage 
conditions listed below: 
 Stored at 2 to 8 °C (protected from light) for lyophilized powder  
If storage conditions are not maintained per specified requirements, the Sponsor or Contract 
Research Organization (CRO) should be contacted. 
See pharmacy instructions for storage conditions of the infusion solution. 
5.2.6. 
Drug Accountability  
When a drug shipment is received, the investigator or designee will check the amount and 
condition of the drug, check for appropriate local language in the label, drug expiration date, and 
acknowledge receipt in IXRS.  In addition, the investigator or designee shall contact the Sponsor 
as soon as possible if there is a problem with the shipment.  
A Drug Accountability Record will be provided for study drug (trastuzumab deruxtecan).  The 
record must be kept current and should contain the following: 
 Dates and quantities of drug received,  
 SID and/or initials or supply number (as applicable),  
 The date and quantity of study drug dispensed and remaining (if from individual 
subject drug units),  
 The initials or seal of the dispenser.  
At the end of the study, as per local laws and/or directed by the Sponsor, all unused study drug 
will be returned or destroyed as per local laws or site policy and only after the study monitor has 
completed a final inventory.  As applicable, the study site must file a copy of the appropriate 
institution policy within their investigator site file and provide a copy to the Sponsor.  See 
pharmacy instructions for details.  
At the end of the study, a final study drug reconciliation statement must be completed by the 
investigator or designee and provided to the Sponsor.  Unused drug supplies may be destroyed 
by the investigator when approved in writing by the Sponsor and the Sponsor has received copies 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 59 
of the study site’s drug handling and disposition SOPs and it is assured that the sponsor will 
receive copies of the certificate of destruction which is traceable to the study drug. 
All study drug forms must be made available for inspection by the Sponsor’s authorized 
representative or designee and regulatory agency inspectors. 
5.3. 
Control Treatment  
Not applicable. 
5.4. 
Management Guidelines for trastuzumab deruxtecan 
The investigator will evaluate which toxicities are attributed to the study drug and adjust the dose 
of the drug as recommended below for study drug.  All dose modifications should be based on 
the worst preceding toxicity (Common Terminology Criteria for Adverse Events [CTCAE] 
version 5.0).  Specific criteria for interruption, re-initiation, dose reduction and/or 
discontinuation of trastuzumab deruxtecan are listed in Table 5.2, Table 5.3, Table 5.4, 
Table 5.5, which are applicable only to TEAEs that are assessed as related to use of trastuzumab 
deruxtecan by the investigator(s). For non-drug related TEAEs, follow standard clinical practice. 
Appropriate clinical experts should be consulted as deemed necessary.   
Investigators may consider dose reductions or discontinuations of the study drug according to the 
subject’s condition and after discussion with the Sponsor Medical Monitor. 
For Grade 3 or Grade 4 events, monitoring (including local lab tests when appropriate) should be 
performed at intervals no greater than 7 d until AE is determined to be resolving or subject is 
discontinued at end of treatment (EOT). 
Prophylactic or supportive treatment for expected toxicities, including management of 
study-drug induced AEs will be as per treating physician discretion and institutional guidelines.  
5.4.1. 
Dose Reduction and Interruption Guidelines 
Note: There will be no dose modifications for Grade 1 or Grade 2 AEs unless specified in 
Section 5.4.1.1. 
One initial starting dose of trastuzumab deruxtecan will be used in this study.  This starting dose 
of trastuzumab deruxtecan Lyo-DP formulation will be 6.4 mg/kg or 5.4 mg/kg.  A dose can be 
delayed for up to 28 d (49 d from the last infusion date) from the planned date of administration.  
If a subject is assessed as requiring a dose delay of longer than 28 d, the subject will be 
withdrawn from the study.  
Treatment cycles for a subject for whom trastuzumab deruxtecan dosing is temporarily withheld 
for any reason may have future cycles scheduled based on the date of the last trastuzumab 
deruxtecan dose. 
Up to two dose reductions will be permitted.  The adjustments for reduced dosing of trastuzumab 
deruxtecan depending on the initial starting dose are shown in Table 5.1. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 60 
Table 5.1: 
Sample Dose Reduction Levels of Trastuzumab Deruxtecan  
Starting Dose 
Dose Level -1 
Dose Level -2 
6.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
5.4 mg/kg 
4.4 mg/kg 
3.2 mg/kg 
Once the dose of study drug has been reduced because of toxicity, all subsequent cycles should 
be administered at that lower dose level unless further dose reduction is required.  More than 
2 dose reductions are not allowed and the subject will be withdrawn from the study treatment if 
further toxicity meeting the requirement for dose reduction occurs.  Study drug dose increases 
are not allowed in the study. 
Dose can be interrupted for up to 28 d from the planned date of administration.  If a subject 
requires a dose delay longer than 28 d, the subject will permanently discontinue study drug, but 
will be followed for survival. 
Treatment cycles for a subject for whom study drug dosing was temporarily withheld for any 
reason may have future cycles scheduled based on the date of the last study drug dose. 
All confirmed or suspected COVID-19, adverse events must be recorded in the eCRF.  Please 
refer to Section 16.7  for additional information on dose modification.  
Investigators may contact the Sponsor’s Medical Monitor or designee to discuss questions 
regarding dose modification or discontinuation of study drug. 
5.4.1.1. 
Dose Modifications 
5.4.1.1.1. Cardiac Toxicities 
Table 5.2: 
Management Guidelines for Cardiac Toxicities  
CTCAE v5.0 Grade 
Management Guidelines for trastuzumab deruxtecan 
Left Ventricular Ejection Fraction  
Symptomatic CHF 
Discontinue subject from study drug 
Decrease in LVEF 10 to 20% (absolute 
value), but LVEF > 45% 
Continue treatment with study drug 
LVEF 40% to ≤ 45% and decrease is < 
10% (absolute value) from baseline 
Continue treatment with study drug 
Repeat LVEF assessment within 3 wk 
LVEF 40% to ≤ 45% and decrease is  10-
20% (absolute value) from baseline 
Interrupt study drug dosing 
Repeat LVEF assessment within 3 wk. 
If LVEF has not recovered to within 10% (absolute value) from 
baseline, discontinue subject from study drug 
If LVEF recovers to within 10% from baseline, resume treatment 
with study drug 
LVEF < 40% or > 20% (absolute value) 
drop from baseline 
Interrupt study drug dosing 
Repeat LVEF assessment within 3 wk. 
If LVEF < 40% or > 20% drop from baseline is confirmed, 
discontinue subject from study drug 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 61 
CTCAE v5.0 Grade 
Management Guidelines for trastuzumab deruxtecan 
Electrocardiogram QT Prolonged 
Grade 3 (average QTc>500 ms or >60 ms 
change from baseline) 
Delay dose until resolved to ≤ Grade 1 (QTc ≤ 480 ms), determine if 
another medication the subject was taking may be responsible and 
can be adjusted or if there is any changes in serum electrolytes that 
can be corrected, then if attributed to study drug, reduce by one dose 
level 
Grade 4 (Torsade de pointes or 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia) 
Discontinue subject from study drug 
Troponin 
Grade 1  
(Levels above the upper limit of normal 
and below the level of myocardial 
infarction as defined by the manufacturer) 
 
If troponin levels are above the upper limit of normal and below the 
level of myocardial infarction as defined by the manufacturer 
(CTCAE Grade 1) at baseline, no repeat testing is required if the 
troponin level is not Grade 3.  
 
For newly diagnosed Grade 1 events, repeat troponin testing at 3 ± 1 
hours (h) after initial troponin test. If repeat troponin level at 3 ± 1 h 
rises significantly per institutional guidelines,  
- perform ECG in triplicate; 
- repeat troponin testing at 6 ± 1 h after initial troponin test; 
- follow institutional guidelines for management of detectable 
troponin testing. 
 
If repeat troponin level at 3 ± 1 h does not rise  significantly per 
institutional guidelines,  
- repeat troponin testing at 6 ± 1 h or at 24 ± 2 h after initial troponin 
test.  
 
Continue treatment with trastuzumab deruxtecan. 
Grade 3  
(Levels consistent with myocardial 
infarction as defined by the manufacturer) 
 
Perform ECG in triplicate. 
Repeat troponin testing at 6 h (±1 h) and 12 h (±1 h) after initial 
troponin test. 
Follow institutional guidelines for management of detectable 
troponin testing.  
If AMI confirmed, discontinue subject from study therapy.  
Otherwise, delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, maintain dose. 
If resolved in > 7 d from day of onset, reduce dose 1 level. 
AMI = acute myocardial infarction; CHF = congestive heart failure; CTCAE = Common Terminology Criteria for 
Adverse Events; ECG = electrocardiogram; LVEF = left ventricular ejection fraction; QTc = corrected QT interval; 
ULN = upper limit of normal 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 62 
5.4.1.1.2. Hematologic Toxicity 
Table 5.3: 
Management Guidelines for Hematologic Toxicities 
CTCAE v5.0 Grade 
Management Guidelines for trastuzumab deruxtecan 
Neutrophil Count Decreased and/or White Blood Cell Count Decreased 
Grade 3  
 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4  
 
Delay dose until resolved to ≤ Grade 2,  
Reduce by one dose level 
Febrile Neutropenia (absolute 
neutrophil count < 1 × 109/L, 
fever > 38.3°C or a sustained 
temperature of ≥ 38 °C for more 
than one h) 
Delay dose until resolved,  
Reduce by one dose level 
Lymphocyte Count Decreased 
Grade 1 to Grade 3 
lymphopenia 
No dose modification 
Grade 4  
(< 0.2 × 109/L) 
Delay dose until resolved to ≤ Grade 2: 
If resolved in ≤ 14 d from day of onset, maintain dose 
If resolved in > 14 d from day of onset, reduce dose one level 
Anaemia 
Grade 3 (Hemoglobin 
<8.0 g/dL); transfusion 
indicated 
Delay dose until resolved to ≤ Grade 2, then maintain dose 
Grade 4 (Hemoglobin 
<8.0 g/dL) Life-threatening 
consequences; urgent 
intervention indicated 
Delay dose until resolved to ≤ Grade 2, then reduce dose one level 
Platelet Count Decreased 
Grade 3 
 (<50 to 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose one level 
Grade 4  
(< 25 × 109/L) 
Delay dose until resolved to ≤ Grade 1, then reduce dose one level 
CTCAE = Common Terminology Criteria for Adverse Events 
5.4.1.1.3. Non-Hematologic Toxicity 
The following guidelines should be followed for subjects who develop Grade 3 or 4 
non-hematologic toxicity unless otherwise noted in Table 5.4. 
Other Laboratory and Non Laboratory TEAEs: 
 Grade 3: delay dose until resolved to ≤ Grade 1 or baseline level:  
 If resolved in ≤ 7 d from day of onset, maintain dose 
 If resolved in > 7 d from day of onset, reduce by one dose level 
 Grade 4:  discontinue subject from study drug 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 63 
5.4.1.1.3.1. Hepatic Toxicity 
Dose and schedule modifications for hepatic toxicities in subjects with normal hepatic function 
and mild/moderate hepatic impairment at baseline (ie, the last measurement prior to study drug 
administration on Cycle 1 Day 1) should be followed as outlined in Table 5.4. 
Table 5.4: 
Management Guidelines for Hepatic Toxicity 
CTCAE v5.0 Grade 
Management Guidelines for trastuzumab deruxtecan 
Aspartate amino transaminase (AST) or Alanine amino transaminase (ALT) with Simultaneous Blood  
Bilirubin  Increased 
AST/ALT ≥3.0 × ULN with 
simultaneous TBL >2.0 × ULN 
Delay study medication until drug-induced liver injury can be ruled out.  
If drug-induced liver injury is ruled out, the subject should be treated 
accordingly, and resumption of study drug may occur after discussion 
between the Investigator and Sponsor.  
If drug-induced liver injury cannot be ruled out from diagnostic workup, 
permanently discontinue study treatment. 
Monitor AST/ALT and blood bilirubin twice weekly until resolution or return 
to baseline. 
AST or ALT Increased 
Grade 2  (>3.0 - 5.0 × ULN if 
baseline was normal; >3.0 - 5.0 
× baseline, if baseline was 
abnormal) 
No action for Grade 2 AST/ALT  
Grade 3 (>5.0 - 20.0 × ULN if 
baseline was normal; >5.0 - 20.0 
x baseline if baseline was 
abnormal).  
In subjects without liver 
metastases and subjects with 
liver metastases and baseline 
level ≤ 3 × ULN 
Repeat testing within 3 d.  Delay dose until resolved to ≤ Grade 1, if baseline 
≤3 × ULN, otherwise delay dose until resolved to ≤ baseline, then: 
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 3: (>8.0 - 20.0 × ULN if 
baseline was normal; >8.0 - 20.0 
x baseline if baseline was 
abnormal). 
In subjects with liver 
metastases, if the baseline level 
was > 3 × ULN 
Repeat testing within 3 d.  Delay dose until resolved to ≤ baseline level, then: 
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 4 (>20.0 x ULN if 
baseline was normal; >20.0 × 
baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Total Bilirubin 
Grade 2 (>1.5 - 3.0 × ULN if 
baseline was normal; >1.5 - 3.0 
x baseline if baseline was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at baseline delay 
dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose 1 level 
 
If documented Gilbert’s syndrome or liver metastases at baseline, continue 
study treatment 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 64 
CTCAE v5.0 Grade 
Management Guidelines for trastuzumab deruxtecan 
Grade 3 (>3.0 - 10.0 × ULN if 
baseline was normal; >3.0 - 10.0 
× baseline if baseline was 
abnormal) 
If no documented Gilbert’s syndrome or liver metastases at baseline, repeat 
testing within 3 d.  Delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, reduce dose 1 level 
If resolved in > 7 d from day of onset, discontinue trastuzumab deruxtecan  
 
If documented Gilbert’s syndrome or liver metastases at baseline, repeat 
testing within 3 d.  Delay dose until resolved to < Grade 2: 
If resolved in ≤ 7 d from day of onset, reduce dose 1 level 
If resolved in > 7 d from day of onset, discontinue trastuzumab deruxtecan 
Grade 4 (>10.0 × ULN if 
baseline was normal; >10.0 × 
baseline if baseline was 
abnormal) 
Discontinue subject from study treatment 
Blood Alkaline Phosphatase Increased 
Grade 3 (>5.0 - 20.0 × ULN if 
baseline was normal; >5.0 - 20.0 
× baseline if baseline was 
abnormal) 
or  
Grade 4 (>20.0 × ULN if 
baseline was normal; >20.0 × 
baseline if baseline was 
abnormal) 
No modification unless determined by the Investigator to be clinically 
significant or life-threatening. 
ALT = alanine transaminase; AST = aspartate transaminase; CTCAE = Common Terminology Criteria for Adverse 
Events; d = days; SAE = serious adverse event; TBL = total bilirubin; ULN = upper limit of normal 
5.4.1.1.3.2. Other Non-Hematologic Toxicity 
Table 5.5: 
Management Guidelines for Non-Hematologic Toxicities 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Infusion Reaction 
Grade 1 (Mild transient 
reaction; infusion interruption 
not indicated; intervention not 
indicated) 
If infusion-related reaction (such as fever and chills [with and without 
nausea/vomiting], pain, headache, dizziness, dyspnea, hypotension) is 
observed during administration, the infusion rate should be reduced by 50% 
and subjects should be closely monitored.  
If no other reactions appear, the subsequent infusion rate could be resumed at 
the initial planned rate.  
Grade 2 (Therapy or infusion 
interruption indicated but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, nonsteroidal 
anti-inflammatory drugs 
(NSAIDs), narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h) 
Administration of study drug should be interrupted and symptomatic 
treatment started (eg, antihistamines, NSAIDs, narcotics, IV fluids). 
If the event resolves or improves to Grade 1, infusion can be restarted at a 
50% reduced infusion rate. 
Subsequent administrations should be conducted at the reduced rate. 
Grade 3 or 4 (Prolonged or life-
threatening consequences, 
urgent intervention indicated) 
Administration of study drug should be discontinued immediately and 
permanently. 
Urgent intervention indicated.  Antihistamines, steroids, epinephrine, 
bronchodilators, vasopressors, IV fluid therapy, oxygen inhalation etc., should 
be administered. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 65 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Pulmonary Toxicity 
 
 
If a subject develops radiographic changes potentially consistent with 
ILD/pneumonitis or develops  an acute onset of new or worsening pulmonary 
or other related signs/symptoms such as dyspnea, cough or fever, rule out 
ILD/pneumonitis.  
If the AE is confirmed to have an etiology other than ILD/pneumonitis, follow 
the management guidance outlined in the “Other Non-Laboratory Adverse 
Events” in the dose modification section of the study protocol.  
If the AE is suspected to be ILD/pneumonitis, treatment with study drug 
should be interrupted pending further evaluation.  
Evaluations should include: 
• 
high resolution CT  
• 
pulmonologist consultation (Infectious Disease consultation as clinically 
indicated) 
• 
Blood culture and complete blood count (CBC). Other blood tests could 
be considered as needed 
• 
Consider bronchoscopy and bronchoalveolar lavage if clinically indicated 
and feasible 
• 
pulmonary function tests and pulse oximetry (SpO2)  
• 
arterial blood gases if clinically indicated  
•      one blood sample collection for PK    
       analyses as soon as ILD/pneumonitis is suspected, if feasible.   
Other tests could be considered, as needed. 
If the AE is confirmed to be ILD/pneumonitis, follow the ILD/pneumonitis  
management guidance as outlined below. 
All events of ILD/pneumonitis regardless of severity or seriousness will be 
followed until resolution including after drug discontinuation.  
 
Grade 1 
The administration of trastuzumab deruxtecan must be interrupted for any 
ILD/pneumonitis events regardless of grade.  
• 
Monitor and closely follow-up in 2 to 7 d for onset of clinical symptoms 
and pulse oximetry 
• 
Consider follow-up imaging in 1-2 weeks (or as clinically indicated). 
• 
Consider starting systemic steroids (e.g. at least 0.5 mg/kg/day 
prednisone or equivalent) until improvement, followed by gradual taper 
over at least 4 weeks. 
• 
If worsening of diagnostic observations despite initiation of 
corticosteroids, then follow Grade 2 guidelines. * 
 
For Grade 1 events, trastuzumab deruxtecan can be restarted only if the event 
is fully resolved to Grade 0: 
• 
If resolved in ≤ 28 d from day of onset, maintain dose 
• 
If resolved in > 28 d from day of onset, reduce dose 1 level 
However, if the event of Grade 1 ILD/pneumonitis occurs beyond Day 22 and 
has not resolved within 49 d from the last infusion, the study drug should be 
discontinued. 
 
* If subject is asymptomatic, then subject should still be considered as Grade 
1 even if steroid treatment is given 
Grade 2 
Permanently discontinue subject from study treatment. 
• 
Promptly start and treat with systemic steroids (e.g., at least 1mg/kg/day 
prednisone or equivalent) for at least 14 d or until complete resolution of 
clinical and chest CT findings, then followed by a gradual  taper over at least 
4 weeks.  


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 66 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
• 
Monitor symptoms closely. 
• 
Re-image as clinically indicated. 
• 
If worsening or no improvement in clinical or diagnostic observations in 
5 d,  
- 
Consider increasing dose of steroids (eg., 2 mg/kg/day prednisone or 
equivalent) and administration may be switched to intravenous (eg. 
methylprednisolone). 
- 
Re-consider additional work-up for alternative etiologies as 
described above. 
- 
Escalate care as clinically indicated. 
Grades 3 and 4 
Permanently discontinue subject from study treatment. 
• 
Hospitalization required. 
• 
Promptly initiate empiric high-dose methylprednisolone IV treatment 
(e.g., 500-1000 mg/day for 3 d), followed by at least 1.0 mg/kg/day of 
prednisone (or equivalent) for at least 14 d or until complete resolution of 
clinical and chest CT findings, then followed by a gradual taper over at 
least 4 weeks.. 
• 
Re-image as clinically indicated. 
• 
If still no improvement within 3 to 5 d,  
- 
Re-consider additional work-up for alternative etiologies as 
described above. 
- 
Consider other immuno-suppressants and/or treat per local practice. 
Ocular 
Grade 3 
Delay dose until resolved to ≤ Grade 1: 
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose by 1 level 
Grade 4 
Discontinue subject from study treatment 
Blood Creatinine Increased 
Grade 3 (> 3.0 to 6.0 × ULN) 
Delay dose until resolved to ≤ Grade 2 or baseline, then reduce dose one level 
Grade 4 (> 6.0 × ULN) 
Discontinue subject from study drug 
Gastrointestinal 
Nausea 
Grade 3  
Delay dose until resolved to ≤ Grade 1  
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose one level 
Diarrhea/Colitis 
Grade 3 
Delay dose until resolved to ≤ Grade 1 
If resolved in ≤ 3 d from day of onset, maintain dose 
If resolved in > 3 d from day of onset, reduce dose one level 
Grade 4 
Discontinue subject from study drug 
Other Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline level:  
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose 1 level 
Grade 4 
Discontinue subject from study treatment 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 67 
CTCAE v5.0 Grade 
Management Guidelines for Trastuzumab Deruxtecan 
Other Non-Laboratory Adverse Events 
Grade 3 
Delay dose until resolved to ≤ Grade 1 or baseline:  
If resolved in ≤ 7 d from day of onset, maintain dose 
If resolved in > 7 d from day of onset, reduce dose 1 level  
Grade 4 
Discontinue subject from study treatment 
AEs = adverse events; CT = computed tomography; CTCAE = Common Terminology Criteria for Adverse Events; 
d = days; IV = intravenous; NSAIDs = nonsteroidal anti-inflammatory drugs; SAE = serious adverse event; 
ULN = upper limit of normal; SpO2 = peripheral oxygen saturation 
In addition, the Investigator may consider dose reductions or discontinuations of the study drug 
according to the subject’s condition and after discussion with the Sponsor’s Medical Monitor or 
designee. 
5.5. 
Method of Assessing Treatment Compliance 
Trastuzumab deruxtecan will be administered IV only to subjects participating in the study and 
under the supervision of clinical study personnel at the study site.  Therefore, treatment 
compliance will be guaranteed as long as the subject attends each visit for administration of the 
study treatment.  Start and stop date/time of injection, amount of drug administered, and reason 
for change or interruption (if applicable) must be recorded in medical record by clinical study 
personnel.  These data will be recorded in the eCRF. 
5.6. 
Prior and Concomitant Medications 
Medications used from the time the subject signs the Main ICF for study participation to the visit 
40-Day Follow-up (+7 d) after the last administration of trastuzumab deruxtecan will be 
recorded.  Prophylactic treatment for the study treatment and all concomitant medications will be 
recorded in the eCRF.  
Permitted Therapies/Products: 
1. Hematopoietic growth factor may be used for prophylaxis or treatment based on the 
clinical judgment of the investigator. 
2. Concomitant use of dietary supplements, medications not prescribed by the Investigator, 
and alternative/complementary treatments is discouraged, but not prohibited. 
3. Prophylactic or supportive treatment of study-drug induced AE will be otherwise as per 
investigator’s discretion and the institutional guidelines. 
4. Based on the currently available clinical safety data, it is recommended that subjects 
patients receive prophylactic anti-emetic agents prior to infusion of trastuzumab 
deruxtecan and on subsequent days. Antiemetics such as 5-hydroxytryptamine receptor 
(5-HT3) antagonists or Neurokinin-1 (NK1) receptor antagonists and/or steroids 
(eg, dexamethasone) should be considered and administered in accordance with the 
prescribing information or institutional guidelines. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 68 
5.7. 
Prohibited Medications and Treatments 
The following medications and products will be prohibited during the treatment period: 
1. Other anticancer therapy, including cytotoxic, targeted agents, immunotherapy, antibody, 
retinoid, or anti-cancer hormonal treatment [concurrent use of hormones for 
noncancer-related conditions (e.g. insulin for diabetes and hormone replacement therapy) 
is acceptable].  
2. Other investigational therapeutic agents. 
3. Radiotherapy (except for palliative radiation to known metastatic sites as long as it does 
not affect assessment of response or interrupt treatment for more than the maximum time 
specified in dose modification section).  
4. Concomitant use of chronic systemic (IV or oral) corticosteroids or other 
immunosuppressive medications except for managing AEs; (Inhaled steroids or intra 
articular steroid injections are permitted in this study.) 
 Subjects with bronchopulmonary disorders who require intermittent use of 
bronchodilators (such as albuterol) will not be excluded from this study.  
5.  Radiotherapy to the thorax. 
6.  Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during 
the study treatment. Refer to Section 16.7  for further details. 
5.7.1. 
Restricted products 
1. Use of e-cigarettes and vaping is strongly discouraged but not prohibited.   
5.8. 
Removal of Subjects from Treatment and/or Study 
5.8.1. 
Reasons for Discontinuation of Study Drug 
Subjects may be withdrawn from study drug for the following reasons: 
 PD per RECIST version 1.1 assessed by the investigator; 
 Clinical progression (definitive clinical signs of disease progression, but a recent 
radiographic assessment did not meet the criteria for PD according to RECIST 
version 1.1);  
 AE; 
 Death; 
 Pregnancy; 
 Protocol deviation; 
 Withdrawal of consent by subject; 
 Lost to follow-up; 
 Physician decision; 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 69 
 Study terminated by the Sponsor; 
 Other, specify. 
All subjects who are withdrawn from the study treatment should complete protocol-specified 
withdrawal procedures (Section 5.8.3) and follow-up procedures (Section 6.6). 
Record the reason for any subject who discontinues study treatment.  Discontinued subjects will 
be followed for survival, either through direct contacts or by collecting public records (eg, death 
certificates) unless prohibited by local laws. 
5.8.2. 
Reasons for Discontinuation of Study Participation 
The duration of subject participation in the study will be until one of the following occurs: 
 Subject dies;  
 Study is terminated by the Sponsor;  
 Subject withdraws consent to participate in study procedures; 
 Subject is lost to follow-up; 
 Others, specify. 
Note: All subjects will be followed for survival status even after consent for study procedures is 
withdrawn.  Subjects discontinued from the study because of withdrawal of consent will be 
followed for survival by collecting public records (eg, death certificates) unless prohibited by 
local laws. 
5.8.3. 
Withdrawal Procedures 
If a subject is withdrawn from 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 
treatment and the reason for withdrawal.  
If the subject is withdrawn due to an AE, the investigator will follow the subject until the AE has 
resolved or stabilized, post-cancer treatment, or lost to follow-up.  
All subjects who are withdrawn from the study drug should complete protocol-specified 
withdrawal procedures.  Protocol-specified withdrawal procedures will be obtained during the 
EOT visit (within +7 d) and the 40-Day Follow-up Visit (within +7 d) conducted after date that 
Principal Investigator decides subject discontinuation of treatment (Section 6.5 and Section 6.6). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 70 
6. 
STUDY PROCEDURES 
A study visit schedule in tabular format is provided in Section 16.1.  A signed and dated Main 
ICF will be obtained before any study-related procedures or assessments are conducted. For 
Cohort 1 and Cohort 1a, a separate tissue screening ICF may be used to obtain consent to send 
the sample to the central laboratory.  
After signing the tissue screening ICF for Cohort 1 and Cohort 1a subject or the Main ICF for 
Cohort 2 subjects, the investigator or designee will assign an SID and enter subject’s background 
data in the IXRS.  
Informed consent for optional pharmacogenomics study will be obtained separately. 
6.1. 
Tissue Screening (For Cohort 1 and Cohort 1a Only) 
To determine eligibility, subjects must meet tumor biomarker criteria. 
Note: A separate tissue screening ICF may be used to obtain consent to send the sample to the 
central laboratory.  Subjects may continue on prior therapy while tissue testing takes place. 
Please refer to the study laboratory manual for required tumor tissue sample specifications and 
shipping instructions. 
The following procedures will be conducted: 
 Obtain a signed and dated written consent from the subject to collect archival tumor 
tissue sample. 
 Register the subject in the IXRS and assign an SID. 
 Obtain adequate archival tumor tissue sample for HER2 IHC testing.  Slides or 
adequate paraffin-embedded tissue blocks of formalin-fixed tissue specimens can be 
submitted for this analysis. Fine needle aspirates are not acceptable. 
 Send the sample to the central laboratory to assess and confirm HER2 IHC status 
If subject is ineligible during the tissue screening period, the subject is not eligible for screening. 
6.2. 
Screening 
A signed and dated Main ICF will be obtained before any study-related procedures or 
assessments are conducted.  After eligibility is confirmed, the subject will be enrolled to IXRS as 
ineligible or eligible and assigned to the cohort. 
The following activities and/or assessments will be performed within the screening period: 
 For Cohort 1, Cohort 1a and Cohort 2, fresh tumor biopsy must be obtained after 
discontinuation of the most recent treatment regimen and before treatment with 
trastuzumab deruxtecan.  The detailed procedures for preparing and submitting tumor 
tissue samples will be provided in the laboratory manual.  There is no need to perform 
fresh tumor biopsy if a subject already has an adequate tumor tissue sample which 
was taken after the completion of the most recent treatment regimen and available to 
be submitted. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 71 
 For Cohort 1, Cohort 1a and Cohort 2, tumor tissue samples for the specimen used to 
determine HER2 status for screening should be provided. Central laboratory 
confirmation is required prior to enrollment for Cohort 1 and Cohort 1a, but not for 
Cohort 2.  Further details will be provided in the laboratory manual. 
Within 28 d before enrollment: 
 Perform ophthalmologic assessment, including visual acuity testing, slit lamp 
examination, and fundoscopy. 
 Perform an ECHO or MUGA (Note: The same test must be used for the subject 
throughout the study). 
 Perform tumor assessment by CT or magnetic resonance imaging (MRI) scans of the 
chest, abdomen, pelvis, and any other sites of disease.  A CT or MRI of the brain is to 
be included for all subjects. Baseline CT scan must be completed after 
discontinuation of TKI.  
 Perform an HIV antibody test.  It is optional unless required by local regulations or 
IRB/ECs. 
 Perform hepatitis B surface antigen test, and hepatitis C antibody test. 
Note: To assess objective response or future progression, it is necessary to estimate the overall 
tumor burden at baseline and use it as comparator for subsequent measurement.  Therefore, all 
lesions (target and non-target) have to be assessed at Screening according to RECIST version 
1.1. 
The following activities and/or assessments will be performed during the Screening period 
within 14 d before enrollment except as indicated: 
 Record concomitant medications and AEs, (from the time the subject signed the Main 
ICF).  For details on AE collection and reporting, refer to Section 9. 
 Confirm subject eligibility 
 Obtain demographics (eg, birth date, sex, race, ethnicity), medical and surgical 
history, including all previous, now resolved, significant medical conditions, smoking 
history, histology (eg, adenocarcinoma, large cell carcinoma) date of diagnosis, extent 
of disease, disease staging, primary tumor site (eg, right upper lobe, right middle lobe, 
right lower lobe, left upper lobe, left lower lobe), previous cancer therapies (including 
prior radiation therapy), historical gene abnormality status (eg, EGFR, proto 
oncogene B-raf mutation, ALK, ROS proto-oncogene 1 fusion, microsatellite 
instability status) and oncology surgical history. 
 Perform a complete physical examination (see Section 9.11) including weight and 
height. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
and body temperature) and peripheral oxygen saturation (SpO2). 
 Assess functional status using the ECOG PS (see Section 16.4). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 72 
 Collect and send blood and urine samples to the laboratory for the following tests: 
 Hematology; 
 Chemistry; 
 Troponins (preferably high-sensitivity troponin-T), the test used to test troponin 
should remain the same throughout the course of a subject’s time on study;  
 Coagulation; 
 Urinalysis 
 Perform triplicate 12-lead ECG. 
 ECGs will be taken in close succession, initiated approximately 3 min apart, after 
the subject has been in a supine/semi-recumbent position. 
Within 72 h prior to enrollment: 
 For women of childbearing potential, perform a serum or urine pregnancy test and 
document the results.  Test must be confirmed negative within 72 h prior to 
enrollment.  For subjects who are of non-childbearing potential, no pregnancy test 
will be required. 
6.3. 
Randomization 
Not applicable. 
6.4. 
Treatment Period 
Treatment will begin as soon as possible after a subject is enrolled to IXRS. 
6.4.1. 
Cycle 1 to Cycle 4 and Subsequent Cycles 
Treatment and procedures performed on Cycle 1 Day 1 and beyond are specified in Section 16.1 
and further described below.  Procedures are to be performed within 3 d of the Day 1 visit of 
each cycle unless otherwise specified. 
Note: Vital sign (including SpO2) evaluations, 12-lead ECG, hematology, chemistry, physical 
examination, weight, and ECOG PS determination need not be repeated if they were performed 
within 3 d of the first dose of Cycle 1, Day 1. 
6.4.1.1. 
Day 1; Before Infusion (All Cycles, Unless Otherwise Noted): 
 Perform a physical examination (Section 9.11), including weight.  More frequent 
examinations may be performed at the discretion of the investigator and if medically 
indicated. 
 Perform ophthalmologic assessment, including visual acuity testing, slit lamp 
examination, and fundoscopy on Day 1: Cycles 2, 6, 10, 14, etc  (- 7 d).  If the 
planned date of study drug administration is delayed after examination of 
ophthalmologic assessments, and there are no abnormal findings on the examination, 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 73 
it is up to the investigator’s judgment as to whether ophthalmologic assessments need 
to be repeated. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature, and SpO2).  More frequent examinations may be performed at the 
discretion of the investigator and if medically indicated. 
 Collect blood samples for the following tests (see Section 9.8) 
 Hematology; 
 Chemistry 
 Perform an ECHO or MUGA scan assessment (Note: The same test must be used for 
the subject throughout the study) every 4 cycles (-7 d) starting with Cycle 5 (ie, Cycle 
5, 9, 13, etc).  If the planned date of study drug administration is delayed after 
examination of ECHO or MUGA, and there are no abnormal findings on the 
examination, it is up to the investigator’s judgment as to whether ECHO or MUGA 
need to be repeated. 
 Assess functional status using the ECOG PS (see Section 16.4)  
 Perform triplicate 12-lead ECG.  ECGs will be taken in close succession, initiated 
approximately 3 minutes apart, while in a supine/semi-recumbent position.  ECGs 
should be performed before PK blood draws 
 Obtain blood samples for:  
 Serum will be obtained before infusion (BI) (within -8 h) on Day 1: Cycles 1, 2, 
3, 4, and 6 for PK assessments;  
 Pharmacogenetic assessment, Cycle 1 only, if the subject provides consent by 
signing the pharmacogenetics sample banking ICF.  (This sample is not required 
for study participation.) 
 ADA will be obtained BI (within -8 h) at Cycles 1, 2 and 4, then every 4 cycles 
(ie, Cycles 8, 12, 16, etc.) 
 If a subject provides consent once protocol version 7.0 is applied, leftover samples 
after ADA testing would be used for future central laboratory analysis for COVID-19 
testing at Cycles 1, 4 and every 4 cycles thereafter.  For subjects with suspected or 
confirmed COVID-19, follow the dose modifications in Section 16.7  
 Obtain blood samples for exploratory biomarkers, such as cfDNA analysis, before 
treatment on Day 1 of every cycle. 
 Record concomitant medications and AEs at every visit 
 Serum or urine sample for pregnancy testing in women of childbearing potential.  
Test must be confirmed negative within 72 h prior to drug administration. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 74 
6.4.1.2. 
Day 1; Dosing and End of Infusion (All Cycles, unless otherwise noted): 
 Administer trastuzumab deruxtecan IV infusion 90±10 min for the initial dose and, if 
no infusion-related reaction after the initial dose, infuse subsequent doses over 30±5 
min.  Record start and stop times.  Trastuzumab deruxtecan is to be administered 
every 3 wk ±2 d. 
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature, and SpO2).  More frequent examinations may be performed at the 
discretion of the investigator and if medically indicated. 
 Collect blood samples for: 
 Serum will be obtained within 15 min after the end of infusion (EOI) on Day 1: 
Cycles 1, 2, 3, 4, and 6 for PK assessments. 
 Serum will be obtained 5 h after the start of drug administration (±2 h), Cycle 1 
only. 
6.4.1.3. 
Cycle 1 - Day 8 and Day 15 (±1 d): 
 Collect blood samples for serum on Cycle 1 Day 8 (±1 d); and Day 15 (±1 d) for PK 
assessments.  
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature, and SpO2).  More frequent examinations may be performed at the 
discretion of the investigator and if medically indicated.  
6.4.2. 
Every 6 Wk (±7 d)  
 Tumor assessments, based on sites of disease identified at Screening and any 
additional newly suspected sites of PD, will be conducted every 6 wk (±7 d) from 
Cycle 1 Day 1, independent of treatment cycle.  A CT and/or MRI (spiral CT or MRI 
with ≤ 5 mm cuts) of chest, abdomen, and pelvis should be used for tumor assessment 
unless another modality of disease assessment is necessary for the lesions.  The same 
assessment modality should be used throughout the study for all assessments for each 
subject unless prior approval is obtained from the Sponsor or its designee.  
Unscheduled tumor assessments may be performed if progression is suspected.  
 A CT or MRI of the brain is mandatory for all subjects included with baseline stable 
brain metastases.  Subjects without brain metastases do not need additional brain 
scans for tumor assessment unless clinically indicated. 
Note: Imaging results will be reviewed by an independent radiologic facility. Copies of CT 
and/or MRI images should be provided after the images are taken. 
6.4.3. 
Fresh Tumor Biopsy During Treatment  
An optional fresh tumor biopsy specimen will be obtained from a subject at Day 43 from Cycle 1 
Day 1 (±7 d) if a subject agrees.  Tumor tissue will be sent to the central laboratory for 
exploratory biomarker analysis. Further details will be provided in the laboratory manual.  If the 
tumor is not taken, document the reason why the fresh tumor tissue sample is unavailable. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 75 
6.5. 
End of Treatment 
The EOT visit should be conducted within 7 d after Investigator decides to discontinue study 
drug.  The following procedures will be performed as specified in the Schedule of Events 
(Table 16.1).  However, if the EOT assessments have been performed within 40 (+7 d) of their 
last treatment, they can be considered to be the EOT data and there is no need to repeat them; 
otherwise, these assessments need to be repeated: 
 Perform a physical examination (Section 9.11), including weight.  
 Perform ophthalmologic assessment, including visual acuity testing, slit lamp 
examination, and fundoscopy.  
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature, and SpO2). 
 Perform triplicate 12-lead ECG.  ECGs will be taken in close succession, initiated 
approximately 3 minutes apart, while in a supine/semi-recumbent position. 
 Perform an ECHO or MUGA (Note: The same test must be used for the subject 
throughout the study). 
 Collect sample for ADA  
 Collect blood samples for the following tests: 
 Hematology; 
 Chemistry;  
 Troponin (local testing: preferably high-sensitivity troponin-T).  An additional 
sample should be submitted for central lab troponin-T testingIf troponin levels are 
above the upper limit of normal and below the level of myocardial infarction as 
defined by the manufacturer (CTCAE Grade 1) at baseline, no repeat testing is 
required if the troponin level is <Grade 3. 
 Blood sample for exploratory biomarkers, such as cfDNA analysis, will be collected. 
 Serum or urine sample for pregnancy testing in women of childbearing potential. 
 Tumor assessments should include all sites of disease identified at screening and any 
other locations if PD is suspected (eg, MRI of the brain if brain metastases are 
suspected) should also be imaged, per RECIST Version 1.1.  If the previous scan was 
within the last 6 wk, this assessment does not need to be performed at the EOT Visit.  
If investigator makes a clinical diagnosis that there has been progression, imaging 
examinations should be performed as promptly as possible, and effort should be made 
to obtain an image based assessment of PD. 
 A CT or MRI of the brain is mandatory for all subjects included with baseline stable 
brain metastases.  Subjects without brain metastases do not need brain scan for tumor 
assessment unless clinically indicated.  
 Assess functional status using the ECOG PS. 
 Obtain an optional fresh tumor specimen from a subject at the EOT if a subject 
agrees.  Tumor tissue will be sent to the central laboratory for an exploratory 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 76 
biomarker analysis. Further details will be provided in the laboratory manual.  If the 
tumor is not taken, document the reason why the fresh tumor tissue sample is 
unavailable. 
 Record concomitant medications and AEs. 
6.6. 
Follow-up 
6.6.1. 
40-Day Follow-up (within + 7 d) 
Forty days (within +7 d) after last study drug administration or before starting new anticancer 
treatment, whichever comes first, the following procedures will be performed as specified in the 
Schedule of Events (Table 16.1).  If EOT is > 40 d after last treatment, then the EOT assessments 
can also function as the 40-Day Follow-up visit.  
 Obtain vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, 
body temperature, and SpO2).  
 Perform a physical examination (Section 9.11), including weight.  
 Assess functional status using the ECOG PS.  
 Collect blood samples for the following tests: 
 Hematology 
 Chemistry 
 Serum or urine sample for pregnancy testing in women of childbearing potential. 
 Obtain blood samples for ADA 
For subjects with positive ADA at the 40-Day Follow-up visit, additional blood ADA 
samples may be collected every 3 mo (±14 d) up to 1 y from the last dose of study 
drug, or until the ADA becomes negative, or until the ADA titer becomes less than 
baseline (applicable when preexisting ADA is observed), or until the subject starts 
another therapy for cancer, or withdraws consent from the study, whichever occurs 
first. 
 Record concomitant medications and AEs. 
6.6.2. 
Long-Term Follow-up Visits 
After completion of the 40-Day Follow-up Visit, the Long-Term Follow-up Visits will be 
performed every 3 mo (±14 d), from the date of 40-Day Follow-up Visit, until death, withdrawal 
of consent, loss to follow-up, or study closure, whichever occurs first or until follow-up data 
collection is no longer of scientific value or otherwise needed (at the Sponsor’s discretion), to 
obtain information about subsequent treatment(s) and survival status.  
This information may be collected in a visit or via phone contact, or (as necessary for survival 
status, in the case of withdrawal of consent or loss to follow-up) from public records (eg, death 
certificates) in accordance with local laws. 
Further follow-up may be required for ongoing AEs (see Section 9.2) 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 77 
6.7. 
Additional PK assessments due to COVID-19 infection 
In case of chloroquine or hydroxychloroquine administration for SARS CoV-2 infection, 
additional PK samples should be collected at the following time points (See Table 8.2). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 78 
7. 
EFFICACY ASSESSMENTS 
7.1. 
Assessments for Efficacy Endpoint(s) 
7.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is ORR, defined as the sum of CR rate; PR rate, assessed by ICR 
based on RECIST Version 1.1.  Efficacy assessments will be based on tumor assessments to be 
performed at screening and every 6 wk while the subject remains on study drug.  
7.1.2. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints noted below that will be assessed by the investigator and/or ICR 
review will be based on RECIST version 1.1.  Secondary efficacy endpoints include: 
 DoR, defined as time from the initial response (CR or PR) until documented tumor 
progression or death from any cause, based on ICR and investigator assessment.  DoR 
is only defined for subjects who achieved confirmed CR or PR.  Censoring is the 
same as for PFS analysis and will be detailed in SAP. 
 DCR, defined as the proportion of subjects who achieved CR, PR, or SD during study 
treatment, based on ICR and investigator assessment 
 PFS, defined as the time from date of enrollment until first objective radiographic 
tumor progression or death from any cause, based on ICR and investigator 
assessment.  Detailed censoring rules will be provided in SAP. 
 ORR, defined in Section 7.1.1, based on investigator assessment 
 OS, defined as the time from date of enrollment until death from any cause (based on 
records in clinical database and public records where it is allowed by law).  Subjects 
last known to be alive are censored at the date of last contact.  
Detailed censoring rules for secondary efficacy endpoints will be specified in the SAP. 
7.1.3. 
Exploratory Efficacy Endpoints 
Exploratory efficacy endpoints include: 
 TTR, defined as the time from the date of enrollment to the date of the first 
documentation of objective response (CR or PR), based on ICR and investigator 
assessment.  TTR will be measured for responding subjects (CR or PR) only 
 Best percent change from baseline in the sum of the diameters for all target lesions 
based on ICR and investigator assessment  
 Analysis of biopsied materials for mechanisms of resistance to trastuzumab 
deruxtecan  
 Exposure-response relationships for efficacy and safety endpoints 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 79 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ASSESSMENTS 
8.1. 
Pharmacokinetic Assessment(s) 
Blood samples for PK assessments will be collected at multiple time points in the study, as 
outlined in Table 8.1. 
Table 8.1: 
Blood Sampling for Pharmacokinetic Analysis  
Cycle 
Day 
Sampling Time Point (Acceptable Range) 
Cycle 1 
Day 1 
BI (– 8 to 0 h)  
EOI: Within 15 min after EOI 
5 h after the start of drug administration (±2 h) 
 
Day 8 
7 d after the start of drug administration (±1 d) 
 
Day 15 
14 d after the start of drug administration (±1 d) 
 
(Day 22) 
If the schedule on Day 1 of the next cycle is delayed for 3 d or more, 
including if the subject cannot continue onto the next cycle, collect 
blood sample 21 d after the start of drug administration (±2 d).  If 
the next schedule is not delayed, sampling at this point is not 
necessary 
Cycle 2 
Day 1 
BI (– 8 to 0 h) 
EOI: Within 15 min after EOI 
Cycle 3 
Day 1 
BI (– 8 to 0 h) 
EOI: Within 15 min after EOI 
Cycle 4 
Day 1 
BI (– 8 to 0 h) 
EOI: Within 15 min after EOI 
Cycle 6 
Day 1 
BI (– 8 to 0 h) 
EOI: Within 15 min after EOI 
BI = before infusion; EOI = end of infusion 
Note: Obtain one blood sample collection for PK as soon as ILD/pneumonitis is suspected, if feasible. 
In case of chloroquine or hydroxychloroquine administration for COVID-19, additional PK 
samples should be collected at the following time points  
Table 8.2: 
Schedule of PK Sample Collection in Case of Chloroquine or 
Hydroxychloroquine Treatment 
Day of Chloroquine or Hydroxychloroquine 
Administration 
Sampling Time Point 
Day 1 
Prior to chloroquine or hydroxychloroquine dose   
Day 3 or 4 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 h)   
EOT with chloroquine or hydroxychloroquine 
Prior to chloroquine or hydroxychloroquine dose 
(within 4 h)  
Prior to re-initiation of trastuzumab deruxtecan 
BI (within 8 hours) 
BI = Before Infusion; EOT = End of Treatment 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 80 
At each time point, blood will be collected for trastuzumab deruxtecan, total anti-HER2 
antibody, and MAAA-1181a PK analysis.  The actual times of study drug administration and the 
exact time of blood sampling for PK analysis must be recorded on the eCRF, including those 
samples collected in case of chloroquine or hydroxychloroquine administration for SARS CoV-2  
infection.  
Details for blood sampling, processing, storage and shipment for PK samples will be provided in 
the study laboratory manual. 
Serum concentrations of trastuzumab deruxtecan, total anti-HER2 antibody and MAAA-1181a 
will be measured using validated assays at the bioanalytical laboratory. 
8.2. 
Biomarker Assessment(s) 
In this study biomarker analyses will be used to investigate the effect of trastuzumab deruxtecan 
at the molecular and cellular level as well as to determine how changes in the markers may relate 
to exposure and clinical outcomes.  The sample collection information as required should be 
recorded on the eCRF page(s) and central laboratory requisition form(s).  Detailed instructions 
for the collection, handling, and shipping of biomarker samples are outlined in the Laboratory 
Manual. 
HER2 gene mutations in tissue are planned to be analyzed in a central laboratory as exploratory 
biomarkers when tissue samples are available. 
Detailed instructions for the collection, handling, and shipping of biomarker samples are outlined 
in the study laboratory manual. 
8.2.1. 
Tumor and Blood Biomarker Assessments 
Tumor specimens will be used to assess the HER2 expression using IHC and ISH, HER2 
mutation using NGS technology or other methods.  Blood samples for exploratory biomarkers, 
such as cfDNA, are planned with intent of monitoring the antitumor impact of treatment with 
trastuzumab deruxtecan.   
8.2.2. 
Additional Biomarker Assessments 
During the study, in addition to the biomarkers specified above, other exploratory biomarker 
research may be conducted on tissue and/or soluble samples.  These studies would extend the 
search for other potential biomarkers relevant to the effects of trastuzumab deruxtecan, cancer 
and/or the resistance to the treatment.  This may include the development of ways to detect, 
monitor or treat cancer.  These additional investigations would be dependent upon clinical 
outcome, reagent and sample availability. 
If the patient agrees, the remaining biomarker samples (tumor tissue, blood, or other specimen 
obtained in the study) may be stored for up to 15 y and further analyzed to address scientific 
questions related to trastuzumab deruxtecan and/or cancer. 
8.3. 
Immunogenicity 
Blood samples for ADA analyses will be collected at the time points specified in Section 16.1.  
A blood sample will be drawn at each time point.  Instructions for the handling and shipping of 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 81 
ADA serum samples are included in a separate document (ie, laboratory manual).  The ADA 
samples will be shipped to a central laboratory for forwarding to the Sponsor-designated 
bioanalytical laboratory. 
The immunogenicity testing will be performed using validated ADA assay following tiered assay 
steps including screening, confirmatory as well as titer determination.  Samples confirmed 
positive will be analyzed with the neutralizing antibody assay.  Serum concentrations of 
trastuzumab deruxtecan and/or total anti-HER2 antibody may be measured using the same ADA 
samples as part of ADA assessment. 
For subjects with positive anti-trastuzumab deruxtecan antibodies on the blood sample drawn at 
the F/U Visit, additional serum samples will be obtained every 3 mo (± 14 d) for ADA 
measurement for up to 1 year from the last dose of trastuzumab deruxtecan, or until the subject 
has a negative ADA result or started another cancer therapy, whichever occurs first. 
8.4. 
Pharmacogenomic Analysis 
8.4.1. 
Genomic or Genetic Banking and Analysis 
A single blood sample for pharmacogenomics analysis will be collected from each subject, who 
consented to this test, predose on Cycle 1 Day 1.  Participation in this part of the study is 
optional for all subjects. 
The following procedures will be used for the long-term preservation (banking) of DNA 
specimens extracted from subjects' blood samples.  Pharmacogenomic samples may be analyzed 
for genes involved in absorption, distribution, metabolism, elimination, safety, and efficacy of 
trastuzumab deruxtecan.  Additionally, samples may be analyzed for genes involved in 
trastuzumab deruxtecan related signaling pathways, or to examine diseases or physiologic 
processes related to trastuzumab 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, as well as helping in the development of 
new drugs or improvement of existing drugs. 
Specimen shipping and handling details will be included in the study laboratory manual. 
8.4.1.1. 
Disclosure of the Results of Genomic or Genetic Analysis 
See the Main ICF for details on disclosure. 
8.4.1.2. 
Storage and Disposal of Specimens for Genomic or Genetic Banking and 
Analysis 
Samples will be retained until the genetic material has been exhausted or until the Sponsor 
instructs the genotyping contractor to destroy the sample (in accordance with laboratory 
procedures).  During the period of storage, the genetic samples 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 genetic analysis has been completed before the subject 
withdraws consent. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 82 
9. 
SAFETY EVALUATION AND REPORTING 
9.1. 
Assessment of Safety Endpoint(s) 
Safety endpoints will include SAEs, TEAEs, adverse events of special interest (AESIs), 
ECHO/MUGA findings; ophthalmologic findings, physical examination findings (including 
ECOG PS), vital sign measurements, standard clinical laboratory parameters (central laboratory; 
troponin), ADAs, and ECG parameters.  All AEs will be categorized using the Medical 
Dictionary for Regulatory Activities (MedDRA).  Adverse events and abnormal laboratory test 
results, if applicable, will be graded using CTCAE version 5.0.  Safety analyses in general will 
be descriptive and will be presented in tabular format with the appropriate summary statistics. 
9.2. 
Adverse Event Collection and Reporting 
All clinical AEs (see Section 9.4.1 for definitions) occurring after the subject signs the ICF and 
up to 40 (within + 7) d after last treatment (ie, the 40-Day Follow-up period), whether observed 
by the Investigator or reported by the subject, will be recorded on the AE eCRF page.  All SAEs 
occurring after subject signs the ICF and up to 40 (within + 7) d after last treatment will be 
recorded on the eCRF.  Medical conditions (including laboratory values/vital signs that are out of 
range) that were diagnosed or known to exist prior to Informed Consent will be recorded as part 
of medical history.  
All AEs, SAEs, and AESIs are to be reported according to the procedures in Section 9.5.  
All 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, dose reduction, require corrective 
treatment, or constitute an AE in the Investigator’s clinical judgment. 
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
subject.  Adverse events may be directly observed, reported spontaneously by the subject or by 
questioning the subject 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, in accordance with the definitions in 
Section 9.4.  The investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature.  
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. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE.  Preplanned (prior to signing the ICF) 
procedures or treatments requiring hospitalization for preexisting conditions that do not worsen 
in severity should not be reported as SAEs (see Section 9.4.2 for definitions). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 83 
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Disease progression is a study endpoint and, consequently, should not be reported as an 
AE/SAE.  However, when a subject dies from PD with no other immediate causes, “disease 
progression” should be reported as an SAE. 
Any serious, untoward event that may occur subsequent to the reporting period that the 
investigator assesses as related to study drug should also be reported and managed as an SAE. 
9.3. 
Adverse Events of Special Interest 
9.3.1. 
LVEF Decrease 
Clinical Summary: LVEF decrease in association with trastuzumab deruxtecan is considered to 
be an important potential risk based on the available pre-clinical data in association with 
trastuzumab deruxtecan is considered to be an important potential risk based on the available 
nonclinical data, literature, and available safety information for drugs of similar class.  Refer to 
the current IB for a summary of preliminary clinical trial data. 
Management Guidance: LVEF will be measured by either ECHO or MUGA scan.  All 
ECHOs/MUGAs will be evaluated by the investigator or delegated physician for monitoring 
cardiac function.   
Troponin will be measured at screening and EOT, and as needed based on subject reported 
cardiac signs or symptoms suggesting congestive heart failure, myocardial infarction, or other 
causes of cardiac myocyte necrosis.  An additional sample will be submitted for central lab 
troponin-T testing, and ECG will be performed in triplicate. If ECG is abnormal, follow 
institutional guidelines. 
ECGs will be performed and standard ECG parameters will be measured, including RR, PR, QT 
intervals, and QRS duration. All ECGs must be evaluated by Investigator or delegated physician 
for the presence of abnormalities.  Whether or not measurement is performed, date performed, 
results, and findings for each parameter is to be recorded in the eCRF. 
For broad surveillance of LVEF decrease, relevant AEs under the standardized  MedDRA 
queries (SMQs) of cardiac failure is included for enhanced data collection; additional data for 
these AEs are collected via targeted questionnaires for heart failure. 
9.3.2. 
Interstitial Lung Disease 
Clinical Summary:  Interstitial lung disease is considered an important identified risk based on a 
comprehensive cumulative review of the available safety data from the Study DS8201-A-J101 
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.  
Management Guidance:   
ILD/pneumonitis should be ruled out if a subject develops radiographic changes potentially 
consistent with ILD/pneumonitis or develops an acute onset of new or worsening pulmonary or 
other related signs/symptoms such as dyspnea, cough, or fever.  If the AE is confirmed to have 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 84 
an etiology other than ILD/pneumonitis, follow the management guidance outlined in the 
designated “Other Non-Laboratory Adverse Events” dose modification section of the study 
protocol.  
If the AE is suspected to be ILD/pneumonitis, treatment with study drug should be interrupted 
pending further evaluations. Evaluations should include high-resolution CT, pulmonologist 
consultation (infectious disease consultation as clinically indicated), blood culture and CBC 
(other blood tests could be considered as needed), bronchoscopy and bronchoalveolar lavage if 
clinically indicated and feasible should be considered, pulmonary function tests and pulse 
oximetry (SpO2), arterial blood gases if clinically indicated, and one blood sample collection for 
PK as soon as ILD/pneumonitis is suspected, if feasible. Other tests could be considered as 
needed. If the AE is confirmed to be ILD/pneumonitis, follow the management guidance 
outlined in the designated “Pulmonary Toxicity” dose modification section of the study protocol. 
All events of ILD/pneumonitis regardless of severity or seriousness will be followed until 
resolution including after study drug discontinuation. 
Additional relevant information regarding the AESI, ILD/pneumonitis for the trastuzumab 
deruxtecan clinical program is to be collected through the targeted questionnaires within the 
clinical study database, regardless of seriousness. 
For broad surveillance of ILD/pneumonitis, selected 42 Preferred Terms (PTs) [all from the ILD  
Standard MedDRA Query (SMQ)] plus 2 PTs of acute respiratory failure and respiratory failure 
are included for enhanced data collection. 
9.3.2.1. 
Interstitial Lung Disease Adjudication Committee 
An independent ILD Adjudication Committee (AC) for the trastuzumab deruxtecan program is 
responsible for reviewing all cases of potential ILD/pneumonitis.  To ensure adequate and 
relevant independent evaluation, systematic additional data collection will be conducted for all 
cases that will be brought for adjudication. This additional data collection will cover a more 
in-depth and relevant medical history (eg, smoking, radiation, chronic obstructive pulmonary 
disease, and other chronic lung conditions), diagnostic evaluation, treatment, and outcome of the 
event.  This data collection will be triggered for adverse events reported using selected 
42 Preferred Terms (all from the ILD Standard MedDRA Query [SMQ]) plus 2 PTs of acute 
respiratory failure and respiratory failure.  
9.4. 
Adverse Event 
9.4.1. 
Definition of Adverse Event 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical product 
and that does not necessarily have to have a causal relationship with this treatment.  An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product (International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use 
[ICH] E2A Guideline: Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting, Oct 1994). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 85 
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. 
9.4.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death, 
 Is life-threatening, 
 Requires inpatient hospitalization or prolongation of existing hospitalization, 
 Results in persistent or significant disability/incapacity, 
 Is a congenital anomaly/birth defect, or 
 Is an important medical event. 
Note: 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 (ICH E2A Guideline. Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting, Oct 1994).  
Medical and scientific judgment should be exercised in deciding whether expedited 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 
intervention to prevent one of the other outcomes listed in the definition above.  Examples 
include allergic bronchospasm, convulsions, and blood dyscrasias or development of drug 
dependency or drug abuse. 
Note:  
 Procedures are not AEs or SAEs, but the reason for the procedure may be an AE or 
SAE. 
 Preplanned (prior to signing the ICF) procedures or treatments requiring 
hospitalizations for preexisting conditions that do not worsen in severity are not 
SAEs. 
9.4.3. 
Severity Assessment 
All AEs will be graded (1 to 5; see below) according to the latest CTCAE version 5.0: 
 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 
Severity versus Seriousness: Severity is used to describe the intensity of a specific event while 
the event itself, however, may be of relatively minor medical significance (such as severe 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 86 
headache).  Seriousness of an event is based upon a universal and global regulatory definition for 
reporting SAEs to regulatory agencies.  For example, Grade 4 (life-threatening consequences; 
urgent intervention indicated) is assessed based on unique clinical descriptions of severity for 
each AE, and these criteria may be different from those used for the assessment of AE 
seriousness.  An AE assessed as Grade 4 may or may not be assessed as serious based on the 
seriousness criteria.  Overall, the severity of an event may be graded by the investigator as Grade 
1 or 2, but if the subject presents to the emergency facility for evaluation and is hospitalized 
overnight for observation that immediately makes the event serious based upon hospitalization 
without regard to the investigator assessment of severity. 
9.4.4. 
Causality Assessment 
The investigator should assess causal relationship between an AE and the study drug on the basis 
of his/her clinical judgment and the following definitions.  The causality assessment must be 
made based on the available information and can be updated as new information becomes 
available. 
 Related: 
 The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications). 
or 
 The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
 Not Related: 
 The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the subject’s clinical state or other factors 
(eg, disease under study, concurrent diseases, and concomitant medications).  
9.4.5. 
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 had been permanently discontinued prior to 
reaction/event, or reaction/event occurred prior to start of study drug. 
9.4.6. 
Other Action Taken for Event 
 None. 
 No treatment was required. 
 Medication required. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 87 
 Prescription and/or over-the-counter medication was required to treat the AE. 
 Hospitalization or prolongation of hospitalization required. 
 Hospitalization was required or prolonged due to the AE, whether or not 
medication was required. 
 Other. 
9.4.7. 
Adverse Event Outcome 
 Recovered/Resolved 
 The subject fully recovered from the AE with no residual effect observed. 
 Recovering/Resolving 
 The AE improved but has not fully resolved. 
 Not Recovered/Not Resolved 
 The AE itself is still present and observable. 
 Recovered/Resolved with Sequelae 
 The residual effects of the AE are still present and observable. 
 Include sequelae/residual effects. 
 Fatal 
 Fatal should be used when death is a direct outcome of the AE. 
 Unknown 
 Unknown should be used if subject is lost to follow-up before an outcome can be 
determined. 
9.5. 
Serious Adverse Events Reporting–Procedure for Investigators 
All AEs, SAEs, and AESIs will be reported in the eCRF. 
Serious events that are also efficacy endpoints (eg, PD) and/or safety endpoints will be exempted 
from SAE processing and expedited reporting.  Disease progression should not be reported as an 
AE/SAE.  However, when a subject dies from PD with no other immediate causes, “disease 
progression” should be reported as an SAE and captured on designated eCRF.  These events are 
clinically anticipated events in the target treatment population and will be periodically reviewed 
by the Daiichi Sankyo safety teams to ensure prompt identification of any clinically concerning 
safety issues. 
Any SAEs directly related to a tumor biopsy procedure should also be reported.  
The following types of events should be reported by the Investigator in electronic data capture 
(EDC) within 24 h of awareness: 
 SAEs (see Section 9.4.2 for definition) 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 88 
 All potential ILD/pneumonitis cases should be reported within 24 h; including both 
serious and non-serious potential ILD/pneumonitis cases (potential ILD/pneumonitis 
is defined by the Event Adjudication Site Manual List of Preferred Terms). 
 Hepatic events (both serious and non-serious) which meet the potential Hy’s Law 
criteria defined as an elevated (ALT or AST) ≥ 3 × ULN and an elevated TBL > 2 × 
ULN that may occur either at different time points or simultaneously during the 
study.  A targeted questionnaire is built as an eCRF to collect relevant additional 
information for these potential cases  
 Overdose, defined as the accidental or intentional administration of any dose of a 
product that is considered both excessive and medically important.  An “excessive 
and medically important” overdose includes any overdose in which either a serious 
adverse event, a non-serious adverse event, or no adverse event occurs and is 
considered by the Investigator as clinically relevant, i.e., poses an actual or potential 
risk to the subject.  
 Overdose is always serious. By definition an overdose is medically important, 
which meets the seriousness criterion of important medical event. An overdose 
can occur with or without an AE. AEs can either be serious or non-serious. 
Details of the overdose including trastuzumab deruxtecan dosage, clinical course, 
associated AEs, and outcome must be captured in the Narrative form of the eCRF 
within EDC. 
All events (serious and non-serious) must be reported with investigator’s assessment of the 
event’s seriousness, severity, and causality to the study drug.  A detailed narrative summarizing 
the course of the event, including its evaluation, treatment, and outcome should be provided.  
Specific or estimated dates of event onset, treatment, and resolution should be included when 
available.  Medical history, concomitant medications, and laboratory data that are relevant to the 
event should also be summarized in the narrative.  For fatal events, the narrative should state 
whether an autopsy was or will be performed, and include the results if available.  Source 
documents (including medical reports) will be retained at the study center and should not be 
submitted to the Sponsor for SAE reporting purposes. 
Urgent safety queries must be followed up and addressed promptly.  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.  In the event that eCRF is unavailable, report 
SAEs by faxing the paper Serious Adverse Event Report (SAVER) Form to the CRO using the 
provided fax cover sheet and the appropriate fax number provided for your country.  Once eCRF 
becomes available, please enter SAEs reported on the SAVER Form into eCRF as soon as 
possible.  Please refer to eCRF Completion Guide for additional instructions. 
See Section 14.10 for contact information for SAE reporting.  Please call the local SAE Hotline 
or your study monitor for any questions on SAE reporting. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 89 
9.6. 
Notifying Regulatory Authorities, Investigators, and Institutional 
Review Board/Ethics Committee 
The Sponsor and/or CRO will inform the Investigators, IRBs/ECs, and Regulatory Authorities of 
any suspected unexpected serious adverse reactions (SUSARs) occurring in other study centers 
or other studies of the study drug, as appropriate per local reporting requirements.  The Sponsor 
and/or CRO will comply with any additional local safety reporting requirements. 
In the United States, upon receipt of the Sponsor’s notification of SUSARs that occurred with the 
study drug, unless delegated to the Sponsor, it is the investigator’s responsibility to inform the 
IRB/EC per the Sponsor’s instruction. 
In the European Economic Area states, it is the Sponsor’s responsibility to report SUSARs to all 
ECs. 
In Japan, it is the Sponsor’s responsibility to report SUSARs to the IRB/ECs. 
9.7. 
Exposure In Utero During Clinical Studies 
The Sponsor must be notified of any female subject who becomes pregnant within 7 mo of the 
last dose of study drug or the female partner of a male subject who becomes pregnant while 
receiving or within 4.5 mo of, the last dose of the study drug.  
Although pregnancy is not technically an AE, all pregnancies must be followed to conclusion to 
determine their outcome.  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 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 subject until completion of the pregnancy and complete 
the EIU Reporting Form with complete pregnancy outcome information, including normal 
delivery and induced abortion.  The 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 a SAE (ie, postpartum complications, spontaneous 
abortion, stillbirth, neonatal death, or congenital anomaly, including that in an aborted fetus), the 
investigator should follow the procedures for reporting SAEs outlined in Section 9.5. 
9.8. 
Clinical Laboratory Evaluations 
The following clinical laboratory tests will be performed: 
1. Hematology tests 
a. Red blood cell count, hemoglobin, hematocrit, platelet count, white blood cell count, 
differential white blood cell count (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils). 
2. Blood chemistry tests 
a. Total protein, albumin, alkaline phosphatase, ALT, AST, TBL, blood urea nitrogen 
(BUN)/urea, calcium, chloride, serum creatinine, lactate dehydrogenase (LDH), 
potassium, sodium, and magnesium. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 90 
b. A coagulation test (prothrombin time and activated partial thromboplastin time) will 
be performed at screening and thereafter as needed. 
c. Creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation 
(see Section 16.2). 
3. Troponin T will be analyzed at the local and central laboratory for each sample. Local 
laboratory values will be used for treatment decisions and narratives, the central 
laboratory values will be stored within the central database.  
4. Urinalysis 
a. Protein, glucose, blood, microscopy assessment (if indicated), and specific gravity. 
In addition, the following parameters will be analyzed at the visits indicated in the Schedule 
of Events (see Section 16.1).  
5. Pregnancy test (serum or urine) for all female subjects of childbearing potential must be 
performed during the Screening Period and on Day 1 of each cycle before infusion. 
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, relevant procedures must be 
followed (see Section 9.5).  Abnormal laboratory values (CTCAE Grade 3 or 4) occurring 
during the clinical study will be followed until repeat test results return to normal (or 
baseline), stabilize, or are no longer clinically significant. 
9.9. 
Vital Signs 
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, respiratory 
rate, SpO2 and body temperature.   
9.10. 
Electrocardiograms 
Standard supine/semi-recumbent 12-lead ECGs in triplicate (taken in close succession, initiated 
approximately 3 min apart) will be performed as described in the Schedule of Events.  Standard 
ECG parameters will be measured, including RR, PR, QT intervals, and QRS duration.  All 
ECGs must be evaluated by investigator or delegated physician for the presence of abnormalities. 
9.11. 
Physical Examinations 
Physical examination findings will evaluate the following body systems/organs: general 
appearance; dermatological; head and; ears, nose, mouth, and throat; pulmonary; cardiovascular; 
abdominal; genitourinary (optional); lymphatic; musculoskeletal/extremities; and neurological.  
Weight and height will also be recorded in kilograms and centimeters, respectively. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 91 
9.12. 
Other Examinations 
9.12.1. 
Cardiac Assessments 
Either ECHO or MUGA, will be performed as described in the Schedule of Events 
(Section 16.1); LVEF will be measured. 
9.12.2. 
Pulmonary Assessments 
Computed tomography or MRI of the chest will be performed as described in Section 6.2 and 
Section 6.4.2.  Additionally, SpO2 will be measured at Screening, before administration and end 
of infusion on Day 1 of each cycle, and at the EOT and the 40-Day Follow-up Visits. For more 
details please refer to Section 6. 
An ILD AC will review all cases of (potential) ILD on an ongoing basis.  Description of the ILD 
AC is available in Section 9.3.2.1. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 92 
10. 
STATISTICAL METHODS 
10.1. 
General Statistical Considerations 
Summary statistics will be presented by cohort.  Continuous variables will be summarized by the 
number of observations, mean, standard error, median, minimum, and maximum values (as well 
as geometric means and geometric coefficient of variation for Cmax and AUC PK parameters).  
Categorical variables will be summarized using frequency counts and percentages. 
Assessment of change from baseline to posttreatment or the ratio of posttreatment to baseline 
will include only those subjects with both baseline and posttreatment measurements.  The last 
non-missing value of a variable taken before the first dose of the study drug will be used as the 
baseline value, unless otherwise specified.  In general, missing or dropout data will not be 
imputed for the purpose of data analysis, unless otherwise specified. 
Efficacy analyses will be performed on the Full Analysis Set (FAS).  In addition, select efficacy 
analyses will also be performed on the Response Evaluable Set (RES).  Safety analyses will be 
performed using the Safety Analysis Set.  Analysis of PK parameters will be based on the PK 
Analysis Set.  All other exploratory analyses will be performed based on the RES. 
Efficacy and safety interim analyses will be performed on cohorts 1 and 2 when approximately 
20 subjects in cohort 2 have had at least 18 weeks of follow up after initiation of therapy (usually 
three CT scans post baseline) or have discontinued treatment. The purpose of the interim analysis 
is to guide the future strategy for trastuzumab deruxtecan in this patient population.  
A second interim analysis will be conducted when at least 60 subjects in Cohort 2 have had at 
least 12 weeks of follow-up after initiation of therapy or discontinued treatment.  This interim 
analysis will also be performed on cohorts 1 and 2.A third interim analysis will be performed 
when at least 20 subjects in Cohort 1a have completed at least 18 weeks of follow up after 
initiation of therapy (usually three CT scans post baseline) or have discontinued treatment. This 
interim analysis will be performed on cohorts 1, 1a, and 2.   
A primary analysis will be performed when subjects in Cohort 2 have sufficient follow-up for the 
assessment of primary efficacy endpoint. This primary analysis will include all available data, 
but the results of Cohort 2 will be the focus.  A Clinical Study Report (CSR) will be based on 
this primary analysis. 
At the time of this primary analysis, the data for Cohort 1a may not be sufficiently mature.  An 
additional analysis will be performed when subjects have sufficient follow-up.  Additional 
analyses may be performed to address COVID-19 impact. 
10.2. 
Analysis Sets 
10.2.1. 
Full Analysis Set 
The FAS will include all subjects who signed an ICF and were enrolled in the study.   
10.2.2. 
Safety Analysis Set  
The Safety Analysis Set will include all enrolled subjects who received at least one dose of study 
drug. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 93 
10.2.3. 
Response Evaluable Set 
The RES will include all enrolled subjects who received at least 1 dose of study drug and had 
measurable disease at baseline per ICR. 
10.2.4. 
Pharmacokinetic Analysis Set 
The PK Analysis Set will include all enrolled subjects who received at least one dose of study 
drug and had measurable serum concentrations of trastuzumab deruxtecan. 
10.3. 
Study Population Data 
Subject disposition will be summarized for subjects in the FAS.  The total number of subjects for 
each defined analysis set will also be tabulated.  The demographic and baseline characteristics 
will be summarized descriptively for the FAS and RES.  Study drug exposure and treatment 
duration will be summarized using descriptive statistics for the FAS. 
10.4. 
Efficacy Analyses 
The primary efficacy analysis will be performed for the FAS.  All efficacy analyses will be 
performed for FAS.  In addition, select efficacy analyses will also be performed on the Response 
Evaluable Set (RES).  All CIs will be 2-sided 95% CIs, unless stated otherwise. 
10.4.1. 
Primary Efficacy Analyses 
The primary efficacy endpoint is ORR assessed by ICR.  Primary analysis of ORR will be 
summarized by cohort for FAS.  Their corresponding 2-sided 95% exact CI will be provided. 
10.4.2. 
Key Secondary Efficacy Analyses 
The secondary efficacy endpoints are: DoR, DCR, and PFS, which will be determined based on 
ICR and based on investigator assessment , as well as ORR based on investigator assessment, 
and OS will be the other secondary endpoints. 
ORR and DCR will be summarized by cohort, and their 95% exact CIs will be provided.  
For time to event endpoints (DoR, PFS, OS), Kaplan-Meier estimates of medians and their 
corresponding 95% CIs will be computed using Brookmeyer and Crowley method will be 
provided by cohort.  Kaplan-Meier estimates of survival curves will be plotted. 
10.4.3. 
Exploratory Efficacy Analyses 
Exploratory efficacy endpoints include TTR, best percent change from baseline in the sum of the 
diameters for all target lesions, analysis of biopsies for mechanisms of resistance to trastuzumab 
deruxtecan and exposure-response relationships.   
Summary statistics (n, mean, standard error, median, min, max) will be provided by cohort for 
TTR and for best percent change from baseline in the sum of the diameters for all target lesions, 
respectively. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 94 
10.4.4. 
Pharmacokinetic and Pharmacodynamic Analyses 
10.4.4.1. Pharmacokinetic Analyses 
Analysis of PK parameters (serum concentrations and PK parameters of trastuzumab deruxtecan, 
total anti-HER2 antibody, and MAAA-1181) will be based on the PK analysis set.  Descriptive 
statistics will be provided by cohort for all serum concentration data at each time point and PK 
parameter as appropriate. 
The population pharmacokinetic analysis to evaluate the effect of intrinsic and extrinsic factors 
of trastuzumab deruxtecan, and, if appropriate, total anti-HER2 antibody and MAAA-1181a will 
be characterized, including available PK data from the Phase 1 study.  After establishment of the 
pop-PK model, a pop-PK/pharmacodynamic model may be developed to evaluate the 
relationship between exposure and efficacy and toxicity.  The population PK and 
PK/pharmacodynamic modeling analyses may be reported separately from the clinical study 
report. 
10.4.4.2. Pharmacodynamic Analyses 
Not applicable. 
10.4.5. 
Biomarker Analyses 
Biomarkers will be listed and summarized by cohort using descriptive statistics. 
10.4.6. 
Immunogenicity (Anti-Drug Antibody [ADA]) Analyses 
Immunogenicity will be assessed through characterization of incidence and titer of the ADA.  
The number and percentage of subjects will be calculated for the presence or absence of 
development of ADA after the start of administration, defining subjects who are negative for 
ADA at all-time points as negative and subjects who are positive for ADA at least one time point 
post-study drug treatment as positive.  The raw values and change from baseline for ADA titers 
will be summarized by time point and cohort using descriptive statistics.  The raw values and 
change from baseline for ADA titers will be summarized by time point and cohort using 
descriptive statistics.  The treatment-emergent ADA incidence will also be calculated.  
Treatment-emergent ADA positive subjects will be defined as subjects who are ADA negative at 
baseline and become ADA positive post-treatment, or who are ADA positive at baseline and 
post-treatment, but have an increase in ADA titer from baseline to post-treatment, or those who 
have missing ADA data at baseline but become ADA positive post-treatment.  The number and 
percentage of subjects positive for neutralizing antibody (Nab) of trastuzumab deruxtecan will 
also be assessed. 
10.5. 
Safety Analyses 
Safety analysis will be performed using the Safety Analysis Set. 
Safety analyses in general will be descriptive and will be presented in tabular format with the 
appropriate summary statistics by cohort.  Listings of safety data will be provided and details 
will be specified in SAP. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 95 
10.5.1. 
Study drug exposure 
Treatment duration, total dose, dose intensity and relative dose intensity will be summarized by 
cohort using descriptive statistics.  In addition, the total number of cycles initiated will be 
summarized by cohort using descriptive statistics. 
10.5.2. 
Adverse Event Analyses 
A TEAE is defined as an AE that occurs, having been absent before the first dose of study drug, 
or has worsened in severity or seriousness after the initiating the study drug until 47 days after 
last dose of the study drug. SAEs with an onset or worsening 48 days or more after the last dose 
of study drug, if considered related to the study treatment, are also TEAEs.  
Adverse events will be coded using MedDRA and graded using CTCAE version 5.0.  The 
number and percentage of subjects reporting TEAEs will be tabulated by system organ class 
(SOC), PT, relationship to the study drug, the worst CTCAE grade and by cohort.  Similarly, the 
number and percentage of subjects reporting serious TEAEs will be tabulated by cohort, as well 
as TEAEs leading to discontinuation of the study drugs. 
A by-subject AE (including TEAE) data listing including but not limited to the verbatim terms, 
SOC, PT, CTCAE grade, and relationship to study drug will be provided.  Deaths, other SAEs, 
AESIs, and other significant AEs, including those leading to discontinuation of the study drugs, 
will be listed. 
10.5.3. 
Clinical Laboratory Evaluation Analyses 
Descriptive statistics will be provided for the clinical laboratory test results and changes from 
baseline by cohort at each scheduled time of evaluation. 
Abnormal clinical laboratory results will be graded according to CTCAE version 5.0, if 
applicable, and the grade will be presented in a by-subject data listing.  A shift table, presenting 
2-way frequency tabulation for baseline and the worst posttreatment value according to CTCAE 
grade, will be provided for clinical laboratory tests. 
All clinical laboratory test results and abnormal clinical laboratory test results deemed of clinical 
significance or of Grade 3 or 4 will be listed. 
10.5.4. 
Vital Sign Analyses 
Descriptive statistics will be provided by cohort for vital sign measurements and changes from 
baseline by scheduled time of evaluation.  The baseline value is defined as the last non-missing 
value before the initial administration of study treatment. 
10.5.5. 
Electrocardiogram Analyses 
Descriptive statistics will be provided by cohort for ECG parameters and changes from baseline 
by scheduled time of evaluation.  In addition, the number and percentage of subjects with ECG 
interval values meeting the criteria will be tabulated (QTc ≤450 ms, >450 to ≤480 ms, >480 ms 
to ≤500 ms, and >500 ms).  Maximum change from baseline will be tabulated (≤30 ms, >30 to 
≤60 ms, >60 ms).  The QT intervals will be corrected for heart rate by Fridericia’s formula 
(QTcF).  ECG data will also be listed. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 96 
10.5.6. 
Other Safety Analysis 
Concomitant medications will be coded using the World Health Organization drug dictionary 
(most recent version).  Number and percentage of subjects taking concomitant medications will 
be summarized.  Concomitant medications will also be listed. 
All other safety endpoints (eg, physical examination findings including ECOG PS, 
ECHO/MUGA, and ophthalmologic findings) will be listed. 
10.5.7. 
Other Analyses - 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. 
10.6. 
Interim Analyses 
Efficacy and safety interim analyses will be performed on Cohorts 1 and 2, when approximately 
20 subjects in cohort 2 have had at least 18 weeks of follow -up after initiation of therapy 
(usually three CT scans post baseline) or have discontinued treatment.   
A second interim analysis will be conducted when at least 60 subjects in Cohort 2 have had at 
least 12 weeks of follow-up after initiation of therapy or discontinued treatment. Safety data 
related to adverse events will be summarized with descriptive statistics by each cohort. This 
interim analysis will also be performed on cohorts 1 and 2. 
A third interim analysis will be performed when approximately 20 subjects in cohort 1a have had 
at least 18 weeks of follow-up after initiation of therapy (usually three CT scans post baseline) or 
have discontinued treatment. This interim analysis will be performed on cohorts 1, 1a, and 2. 
For each cohort, the primary efficacy endpoint of ORR will be summarized using descriptive 
statistics including 2-sided exact 95% CI (Clopper-Pearson).  Other efficacy endpoints based on 
response rates will be summarized by cohort using the same methodology as the primary efficacy 
endpoint. For time to event endpoint PFS, Kaplan-Meier estimates of medians and their 
corresponding 95% CIs using Brookmeyer and Crowley method will be provided by cohort. 
Safety data related to adverse events will be summarized with descriptive statistics by each 
cohort.  
In addition, PK endpoints of trastuzumab deruxtecan and MAAA-1181a, Cmax, Tmax, AUClast, 
and AUC0-21d for each cohort may be summarized using descriptive statistics. The relationship 
between trastuzumab deruxtecan or MAAA-1181 exposure and efficacy or safety may be 
explored. 
The results of any interim efficacy or PK analysis, if performed, will not be used to change the 
conduct of the study. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 97 
10.7. 
Sample Size Determination 
There will be approximately 40 subjects in Cohort 1, approximately 40 subjects in Cohort 1a (to 
be enrolled after protocol V6.0), and approximately 90 subjects in Cohort 2, of which 50 will be 
enrolled following Protocol Amendment Version 5.0. Thus, in all the total number of subjects on 
the study will be approximately 170. 
A sample size of 40 response evaluable subjects each in Cohorts 1 and 1a is required so that the 
average distance from the limits of the respective 95% CIs to the observed ORR is 
approximately 0.14, assuming the expected ORR is 0.3. 
A sample size of 90 subjects in Cohort 2 ensures that the average distance from the limits of a 
95% CI to the observed ORR is approximately 0.09, assuming the expected ORR is 0.3. With 
this sample size, the probability of the lower bound of the 95% CI exceeding 0.3 is more than 
49% when the true ORR is 0.4 and the probability increases to more than 96% when the true 
ORR is 0.5. The operating characteristics for a few other scenarios are included in the following 
table. 
Table 10.1: 
Operating Characteristics for Single Arm Expansion Design with 90 Subjects 
True ORR 
 
Observed ORR 
95% confidence 
interval (CI) 
Probability of lower confidence limit 
exceeding 30% under the true ORR 
30% 
30% (27 out of 90) 
(20.79%,  40.57%) 
2.50% 
40% 
40% (36 out of 90) 
(29.81%,  50.87%) 
49.06% 
50% 
50% (45 out of 90) 
(39.27%,  60.73%) 
96.67% 
60% 
60% (54 out of 90) 
(49.13%,  70.19%) 
99.99% 
70% 
70% (63 out of 90) 
(59.43%,  79.21%) 
100.00% 
ORR = Overall Response Rate 
The upper 95% confidence limit of the ORR for the current standard of care (SOC) Docetaxel 
was observed to be under 0.2 or 20% 33. The threshold of 0.3 or 30% was decided by 
benchmarking against this estimate of the upper limit of 20% and allowing a further increment of 
10% to account for the sparseness of the available data. 
10.8. 
Statistical Analysis Process 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other clinical study 
information such as subject disposition, demographic and baseline characteristics, study drug 
exposure, and prior and concomitant medications.  The SAP will also include a description of 
how missing, unusable, or spurious data will be addressed. 
To preserve the integrity of the statistical analysis and clinical study conclusions, the SAP will be 
finalized prior to database lock. 
Sample size is calculated using EAST software (Cytel, MA 02139), and the open-source R 
software.  All statistical analyses will be performed using SAS® version 9.3 or higher (SAS 
Institute Inc., Cary, NC 27513). 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 98 
11. 
DATA INTEGRITY AND QUALITY ASSURANCE 
The investigator/investigational site will permit study related monitoring, audits, IRB/EC review 
and regulatory inspections by providing direct access to source data/documents.  Direct access 
includes permission to examine, analyze, verify, and reproduce any records and reports that are 
important to the evaluation of a clinical study. 
11.1. 
Monitoring and Inspections 
The Sponsor, 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 Good Clinical Practices (GCP) and local regulations on the conduct 
of clinical research will be accomplished through a combination of onsite visits by the monitor 
and review of study data remotely.  The frequency of the monitoring visit will vary based on the 
activity at each study site.  The monitor is responsible for inspecting the eCRFs and ensuring 
completeness of the study essential documents.  The monitor should have access to subject 
medical records and other study-related records needed to verify the entries on the eCRFs.  
Detailed information is provided in the monitoring plan. 
The monitor will communicate deviations from the protocol, SOPs, GCP and applicable 
regulations to the investigator and will ensure that appropriate action (s) designed to prevent 
recurrence of the detected deviations is taken and documented. 
The investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits are addressed to the satisfaction of the Sponsor and 
documented. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study site 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. 
11.2. 
Data Collection 
All relevant observations and data related to the study, as per the study protocol, will be recorded 
on eCRF pages.  A representative of Daiichi Sankyo or their designee will provide instruction for 
completing the eCRF.  Adequate and accurate case records should be maintained, including the 
evaluation of inclusion and exclusion criteria, medical history, physical examinations, clinical 
assessments, a record of clinical safety laboratory sample collection drug administration, AEs, 
and final evaluation  
The eCRF should be kept current to enable the monitor to review the subject’s status throughout 
the course of the study.  The information should be entered into the eCRF within 5 d of the visit 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 99 
and should be completed, reviewed, and signed off by the investigator within 2 wk of the last 
subject visit.  Query resolution should be completed within 48 h. 
An eCRF must be completed for each subject who signs an ICF and undergoes any screening 
procedures. For subjects who are screened but not registered, minimal data will be recorded on 
the eCRF, including demography, subject status, and AEs.  All study related data for these 
subjects will be maintained in the medical records at the site. 
The investigator will sign and date the indicated places on the eCRF via the EDC system’s 
electronic signature.  These signatures will indicate that the investigator inspected or reviewed 
the data on the eCRF, the data queries, and the site notifications, and agrees with the content. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
11.3. 
Data Management 
Each subject will be identified in the database by a unique subject identifier as defined by the 
Sponsor. 
To ensure the quality of clinical data across all subjects and study sites, a Clinical Data 
Management review will be performed on subject data according to specifications given to 
Sponsor or Designee.  Data will be vetted both electronically and manually for eCRFs and the 
data will be electronically vetted by programmed data rules within the application.  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 laboratory will be reconciled to the clinical 
database. 
Serious AEs in the clinical database will be reconciled with the safety database. 
All AEs and medical histories will be coded using MedDRA.   
All concomitant medications and prior cancer therapies will be coded using the World Health 
Organization Drug Reference List Dictionary. 
11.4. 
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 make entries and/or corrections on 
eCRFs will be included on the Signature List. 
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, IRB/EC 
correspondence and approvals, approved and signed ICFs, Investigator’s Agreement, clinical 
supplies receipts, distribution and return records), and other sponsor correspondence pertaining 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 100 
to the study must be kept in appropriate study files at the study site (Trial Master File [TMF]).  
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 the institution 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 further store such records. 
11.5. 
Record Keeping 
The investigator and study staff are responsible for maintaining a comprehensive and centralized 
filing system, Trial Master File (TMF) 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 copies of 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 IRB/EC and the Sponsor. 
 Records related to the study drug(s) including acknowledgment of receipt at study 
site, accountability records and final reconciliation and applicable correspondence. 
In addition, all original source documents supporting entries in the eCRFs must be maintained 
and be readily available. 
All study related essential documentation will be retained by the investigator until at least 3 y 
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 3 y 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 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. 
Subject's 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. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 101 
12. 
FINANCING AND INSURANCE 
12.1. 
Finances 
Prior to starting the study, the investigator and/or institution will sign a clinical study agreement 
with the Sponsor or the CRO.  This agreement will include the financial information agreed upon 
by the parties. 
12.2. 
Reimbursement, Indemnity, and Insurance 
The Sponsor provides insurance for study subjects to make available compensation in case of 
study-related injury. 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on terms 
agreed upon by the parties. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 102 
13. 
PUBLICATION AND PUBLIC DISCLOSURE OF CLINICAL 
TRIAL INFORMATION 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 103 
14. 
ETHICS AND STUDY ADMINISTRATIVE INFORMATION 
14.1. 
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 ICH consolidated Guideline E6 for GCP 
(CPMP/ICH/135/95), and applicable regulatory requirement(s) including the following: 
 United States Food and Drug Administration GCP Regulations: Code of Federal 
Regulations Title 21, parts 11, 50, 54, 56 and 312 as appropriate and/or; 
 Japanese Ministry of Health, Labor and Welfare Ordinance No. 28 of 27 March, 1997 
and/or; 
 Directive 2001/20/EC of the European Parliament and of the Council on the 
approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of GCP in the conduct of clinical trials on 
medicinal product for human use; 
 Other applicable local regulations. 
14.2. 
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. 
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 identifier 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(ies), and the 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. 
14.3. 
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 satisfactory answers 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. 
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 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 104 
have their origin in the Declaration of Helsinki.  The ICF and any revision(s) should be approved 
by the IRB/EC 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 and time (if applicable) that informed consent was given 
should be recorded on the eCRF. 
14.4. 
Regulatory Compliance 
The study protocol, subject information and ICF, the IB, any subject written instructions to be 
given to the subject, available safety information, subject recruitment procedures (eg, 
advertisements), information about payments and compensation available to the subjects, and 
documentation evidencing the investigator’s qualifications should be submitted to the EC or IRB 
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. 
The investigator and/or the Sponsor must submit and, where necessary, obtain approval from the 
EC or IRB for all subsequent protocol amendments and changes to the ICF.  The investigator 
should notify the EC or IRB 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. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group or representative 
to whom this responsibility has been delegated will ensure all legal aspects are covered, and 
approval from the appropriate regulatory bodies obtained, prior to study initiation.  If changes to 
the initial protocol and other relevant study documents are made, this representative will also 
ensure that any revised documents required for submission are submitted to regulatory 
authorities and implementation of these changes are made after approval by the relevant 
regulatory bodies, as needed. 
In the event of any prohibition or restriction imposed (eg, clinical hold) by an applicable 
Regulatory Authority(ies) in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the investigational 
drug, the Sponsor should be informed immediately.   
In addition, the investigator will inform the Sponsor immediately 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. 
14.5. 
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 IRBs/ECs. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 105 
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 of all intended or unintended deviations to the protocol (eg, inclusion/exclusion 
criteria, dosing, missed study visits) on an expedited basis. 
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 drug, and had at least one 
administration of study drug, data should be collected for safety purposes. 
If applicable, the investigator should notify the IRB/EC of deviations from the protocol in 
accordance with local procedures. 
14.6. 
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, 
IRBs/ECs, 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 IRB/EC.  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. 
14.7. 
Protocol Amendments 
Any amendments to the study protocol that seem to be appropriate as the study progresses will 
be communicated to the investigator by Daiichi Sankyo or the CRO.  Also, the Sponsor will 
ensure the timely submission of amendments to regulatory authorities. 
A global protocol amendment will affect study conduct at all study sites in all regions of the 
world.  Such amendments will be incorporated into a revised protocol document.  Changes made 
by such amendments will be documented in a Summary of Changes document.  These protocol 
amendments will undergo the same review and approval process as the original protocol.   
A local protocol amendment will affect study conduct at a particular study site(s) and/or in a 
particular region/country.  The Sponsor approval of local amendments will be clearly 
documented. 
A protocol amendment may be implemented after it has been approved by the IRB/EC and by 
regulatory authorities where appropriate, unless immediate implementation of the change is 
necessary for subject safety. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 106 
14.8. 
Study Termination 
The Sponsor has the right to terminate the study at any time and study termination may also be 
requested by (a) competent authority(ies). 
14.9. 
Data Monitoring Committee  
Not applicable. 
14.10. 
Address List 
A list of key study personnel (including personnel at the Sponsor, CRO, laboratories, and other 
vendors) and their contact information (address, telephone, fax, email) will be kept on file and 
regularly updated as necessary. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 107 
15. 
REFERENCES 
1. Jemal A, Bray F, Center MM, et al. Global Cancer Statistics. CA Cancer J Clin 
2011;61(2):69–90. 
2. NCCN Clinical Practice Guidelines in Oncology. Non-small cell lung cancer. v.2.2014. 
www.nccn.org. 
3. Kern JA, Slebos RJ, Top B, et al. C-erbB-2 expression and codon K-ras mutations both 
predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest. 
1994; 93(2):516-20. 
4. Harpole DH Jr, Marks JR, Richards WG, et al. Localized adenocarcinoma of the lung: 
oncogene expression of erbB-2 and p53 in 150 patients. Clin Cancer Res. 1995; 1(6):659-
64. 
5. Shi D, He G, Cao S, Pan W, Zhang HZ, et al. Overexpression of the c-erbB-2/neu-
encoded p185 protein in primary lung cancer. Mol Carcinog. 1992; 5(3):213-8. 
6. Scheurle D, Jahanzeb M, Aronsohn RS, et al. HER-2/neu expression in archival non-
small cell lung carcinomas using FDA-approved Hercep test. Anticancer Res. 2000: 
20(3B):2091–6. 
7. Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: 
epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013; 
31(16):1997–2003. 
8. Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and 
molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung 
adenocarcinomas. Clin Cancer Res. 2012; 18(18):4910–8. 
9. Li C, Sun Y, Fang R, et al. Lung adenocarcinomas with HER2-activating mutations are 
associated with distinct clinical features and HER2/EGFR copy number gains. J Thorac 
Oncol. 2012;7(1):85–9. 
10. Tomizawa K, Suda K, Onozato R, et al. Prognostic and predictive implications of 
HER2/ERBB2/neu gene mutations in lung cancers. Lung Cancer. 2011; 74(1):139–44. 
11. Shigematsu H, Takahashi T, Nomura M, et al. Somatic mutations of the HER2 kinase 
domain in lung adenocarcinomas. Cancer Res. 2005; 65(5):1642–6. 
12. Yokoyama T, Kondo M, Goto Y, et al. EGFR point mutation in non-small cell lung 
cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci. 
2006; 97(8):753–9. 
13. Stinchcombe T, Stahel RA, Bubendorf L, et al. Efficacy, safety, and biomarker results of 
trastuzumab emtansine (T-DM1) in patients (pts) with previously treated HER2-
overexpressing locally advanced or metastatic non-small cell lung cancer (mNSCLC). J 
Clin Oncol. 2017; 35(15 Suppl):abstract 8509. 
14. Li BT, Shen R, Buonocore D, et al. Ado-trastuzumab emtansine in patients with HER2 
mutant lung cancers: Results from a phase II basket trial. J Clin Oncol. 2017; 35(15 
Suppl):abstract 8510. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 108 
15. Abou-Alfa GK, Letourneau R, Harker G, et al. Randomized phase III study of exatecan 
and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic 
cancer. J. Clin Oncol. 2006; 24(27):4441-7. 
16. Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-8951f) versus 
gemcitabine (Gem) in chemotherapy- naïve patients with advanced pancreatic cancer 
(APC). J Clin Oncol. 2004; 22(14 Suppl):abstract 4005. 
17. De Jager R, Cheverton P, Tamanoi K, et al. DX-8951f: summary of phase I clinical trials. 
Ann N Y Acad Sci. 2000; 922:260-73. 
18. Ogitani Y, Aida T, Hagihara K, et al. Trastuzumab deruxtecan, a novel HER2-targeting 
ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor 
efficacy with differentiation from T-DM1. Clin Cancer Res. 2016; 22(20):5097-108. 
19. Archer SG, Eliopoulos A, Spandidos D, et al. Expression of ras p21, p53 and c-erbB-2 in 
advanced breast cancer and response to first line hormonal therapy. Br J Cancer. 1995; 
72(5):1259-66. 
20. Ross JS, Slodkowska EA, Symmans WF, et al. The HER-2 receptor and breast cancer: 
ten years of targeted anti-HER-2 therapy and personalized medicine. Oncologist. 2009; 
14(4):320-68. 
21. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric 
cancer: results from a validation study. Histopathology. 2008; 52(7):797-805.  
22. Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel 
therapeutic target. Ann Oncol. 2008; 19(9):1523-9. 
23. Yoshizawa A, Sumiyoshi S, Sonobe M, et al. HER2 status in lung adenocarcinoma: a 
comparison of immunohistochemistry, fluorescence in situ hybridization (FISH), dual-
ISH, and gene mutations. Lung Cancer. 2014; 85(3):373-8. 
24. Harder J, Ihorst G, Heinemann V, et al. Multicentre phase II trial of trastuzumab and 
capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer. Br J 
Cancer. 2012; 106(6):1033-8. 
25. Blok EJ, Kuppen PJ, van Leeuwen JE, et al. Cytoplasmic overexpression of HER2: a key 
factor in colorectal cancer. Clin Med Insights Oncol. 2013; 7:41-51. 
26. Verri E, Guglielmini P, Puntoni M, et al. HER2/neu oncoprotein overexpression in 
epithelial ovarian cancer: evaluation of its prevalence and prognostic significance. 
Clinical study. Oncology. 2005; 68(2-3):154-61. 
27. Clamon G, Herndon J, Kern J, et al. Lack of trastuzumab activity in nonsmall cell lung 
carcinoma with overexpression of erb-B2: 39810: a phase II trial of Cancer and 
Leukemia Group B. Cancer. 2005; 103(8):1670-5. 
28. Kris MG, Camidge DR, Giaccone G, et al. Targeting HER2 aberrations as actionable 
drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor 
dacomitinib in patients with HER2-mutant or amplified tumors. Ann Oncol. 2015; 
26(7):1421-7.  


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 109 
29. Hyman DM, Piha-Paul SA, Rodón J, et al. Neratinib for ERBB2 mutant, HER2 non-
amplified, metastatic breast cancer: Preliminary analysis from a multicenter, open-label, 
multi-histology phase II basket trial. Cancer Res. 2016; 76(4 Suppl):abstract PD5-05. 
30. Gandhi L, Besse B, Mazieres J, et al. Neratinib ± temsirolimus in HER2-mutant lung 
cancers: an international, randomized phase II study. J Thorac Oncol. 2017; 12(1 
Suppl):abstract MA04.02. 
31. Lai W-CV, Lebas L, Milia J, et al. Afatinib in patients with metastatic HER2-mutant lung 
cancers: an international multicenter study. J Clin Oncol. 2017; 35(15 suppl):abstract 
9071.  
32. Tsurutani J, Park H, Doi T, et al. Updated Results of Phase 1 Study of DS-8201a in 
HER2-Expressing or –Mutated Advanced Non-Small-Cell Lung Cancer. J Thorac Oncol. 
2018; 13 (10), supplement: S324 
33. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non–Small-Cell Lung Cancer N Engl J Med. 2015; 373:1627-1639 
34. Trastuzumab Deruxtecan Global Investigator’s Brochure Version 6.0, September 09, 
2019 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 110 
16. 
APPENDICES 
16.1. 
Appendix 1: Schedule of Events 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 111 
Table 16.1: 
Schedule of Events 
Visit/Cycle 
Tissue 
Screen 
(Cohort 1, 
Cohort 1a) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and  
subsequent  
cycles Day 1 
EOTa  
 
F/Ub  
 
Long-
Term 
Q3M 
F/U  
(±14D) 
Day 1 
Day 8 
Day 
15 
Day 
22 
Day 1 
Day 1 
 
 
BI 
EOI (±1 D) 
(±1 D) 
(±2 D) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Informed consent 
X 
(Cohort 1, 
Cohort1a) 
X 
 
 
 
 
 
 
 
 
 
 
Tumor tissue 
sample for tissue 
screenings 
X 
(Cohort 1, 
Cohort 1a) 
 
 
 
 
 
 
 
 
 
 
 
Tumor tissue 
sample for HER2 
status 
 
X 
 
 
 
 
 
 
 
 
 
 
Fresh tumor 
biopsy 
 
Xc 
Xd 
 
 
Administer 
trastuzumab 
deruxtecan  
 
 
X 
 
 
 
                  X 
X 
X 
 
 
 
Medical history/ 
Demographic 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
Xe 
Xf 
X 
X 
X 
 
Xf 
X 
Xf 
X 
Xf 
X  
X 
X 
 
Physical 
examination 
 
Xe 
Xf 
 
 
 
 
Xf 
 
Xf 
 
Xf 
 
X 
X 
 
SpO2 
 
Xe 
Xf 
X 
X 
X 
 
Xf 
X 
Xf 
X 
Xf 
X 
X 
X 
 
Height 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight, ECOG PS 
 
Xe 
Xf 
 
 
 
 
Xf 
 
Xf 
 
Xf 
 
X 
X 
 
Clinical laboratory 
tests (Hematology, 
Chemistry) 
 
Xe 
Xf 
 
X 
X 
 
Xf 
 
Xf 
 
Xf 
 
X 
X 
 
Coagulation 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Troponing 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 112 
Visit/Cycle 
Tissue 
Screen 
(Cohort 1, 
Cohort 1a) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and  
subsequent  
cycles Day 1 
EOTa  
 
F/Ub  
 
Long-
Term 
Q3M 
F/U  
(±14D) 
Day 1 
Day 8 
Day 
15 
Day 
22 
Day 1 
Day 1 
 
 
BI 
EOI (±1 D) 
(±1 D) 
(±2 D) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
cfDNA 
blood samples 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Pharmacogenomic 
blood sample 
 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK blood samplev 
 
 
Xi 
Xj,k 
X 
X 
Xl 
Xi 
Xj 
Xi 
Xj 
Xi 
Xj 
 
 
 
PK Sampling for 
CQ/HCQ 
Administration 
 
 
If subject provides consent, samples should be collected. 
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 trastuzumab deruxtecan  resumption, after the CQ/HCQ washout periodw, (within 8h BI of 
trastuzumab deruxtecan). 
 
 
 
ADA 
Blood Sample 
 
 
Xm 
 
 
 
 
Xm 
 
 
 
Xm 
 
X 
X 
Xn 
HIV antibody test 
(as required by 
local regulation) 
 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/ / C 
serology 
 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 
testingx 
 
 
X 
 
 
 
 
 
 
 
 
Xy 
 
 
 
 
ECHO or MUGA 
(LVEF) 
 
Xo 
 
 
 
 
 
 
 
 
 
Xo,p 
 
X 
 
 
12-lead ECG 
in triplicater 
 
Xe 
X 
 
 
 
 
Xq 
 
Xq 
 
Xq 
 
X 
 
 
Pregnancy test 
 
Xu 
Xf,u 
 
 
 
 
Xu 
 
Xu 
 
Xu 
 
X 
X 
 
Ophthalmologic 
assessmentt 
 
Xo,t 
 
 
 
 
 
Xt 
 
 
 
Xt 
 
Xt 
 
 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 113 
Visit/Cycle 
Tissue 
Screen 
(Cohort 1, 
Cohort 1a) 
SCR 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 and  
subsequent  
cycles Day 1 
EOTa  
 
F/Ub  
 
Long-
Term 
Q3M 
F/U  
(±14D) 
Day 1 
Day 8 
Day 
15 
Day 
22 
Day 1 
Day 1 
 
 
BI 
EOI (±1 D) 
(±1 D) 
(±2 D) 
BI 
EOI 
BI 
EOI 
BI 
EOI 
Urinalysis 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
assessmento 
 
X 
Every 6 wk (±7 d) until PD or starting new anticancer treatment regardless of Post-treatment Follow-up period 
 
Pulmonary 
imagingo 
 
X 
Every 6 wk (±7 d) until PD or starting new anticancer treatment regardless of Post-treatment Follow-up period 
 
Concomitant 
medications 
 
X 
 
AEs 
 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ADA = anti-drug antibody; AE = adverse event; BI = before infusion; cfDNA = cell-free deoxyribonucleic acid; COVID-19 = Coronavirus disease 19; CTCAE = 
Common Terminology Criteria for Adverse Events; D = day; ECG = electrocardiogram; EOI = end of infusion; EOT = end of treatment; F/U = follow-up; HCQ 
= hydroxychloroquine; HIV = human immunodeficiency virus; LVEF = left ventricular ejection fraction, MUGA = multigated acquisition; PD = progressive 
disease; PK = pharmacokinetic; SCR = screening; SpO2 = peripheral oxygen saturation 
 
a The date Investigator decides to discontinue study treatment (within + 7 d). 
b 40 d (+7 d) after the last study drug administration or before starting new anticancer treatment, whichever comes first. 
c For all Cohort 1, Cohort 1a and Cohort 2, fresh tumor biopsy must be obtained after discontinuation of the most recent treatment regimen and before treatment 
with trastuzumab deruxtecan.  The detailed procedures for preparing and submitting tumor tissue samples will be provided in the laboratory manual.  There is 
no need to perform fresh tumor biopsy if a subject already has an adequate tumor tissue sample that was taken after the completion of the most recent treatment 
regimen and available to be submitted. 
d An optional tumor rebiopsy will be taken on Day 43 from Cycle 1 Day 1 (±7 d) and at the EOT if a patient agrees. 
e Within 14 d before enrollment. 
f Within 72 h of infusion 
g Collect blood samples for troponin (local testing: preferably high-sensitivity troponin-T) at screening, EOT, and if at any time a subject reports signs or 
symptoms suggesting congestive heart failure, myocardial infarction, or other causes of myocyte necrosis.  An additional sample should be submitted for 
central lab troponin-T testing, and perform ECG in triplicate. If ECG is abnormal, follow institutional guidelines. If troponin levels are above the upper limit of 
normal and below the level of myocardial infarction as defined by the manufacturer (CTCAE Grade 1) at baseline, no repeat testing is required if the troponin 
level is not Grade 3. 
h Participation in this part of the study is optional for all subjects. 
i Within -8 h BI on Day 1 of each cycle until Cycle 4 and then at Cycle 6 (ie, Cycle 1, 2, 3, 4, 6). 
j Within 15 min after EOI on Day 1 of each cycle until Cycle 4 (eg, Cycle 1, 2, 3 and 4) and then at Day 1 of Cycle 6. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 114 
k Cycle 1 Day 1 only, 5 h (±2 h) after the start of drug administration. 
l If treatment of next cycle is delayed for 3 d or more, or subject is discontinued, collect PK blood on this day (±2 d). 
m Within -8 h BI on Day 1 in Cycles 1, 2 and 4, and then every 4 cycles.  If subject provides consent and once protocol version 7.0 is applied, leftover samples 
after ADA testing would be used for future central laboratory analysis for COVID-19 testing at Cycles 1, 4 and every 4 cycles thereafter. 
n For subjects with positive ADA at F/U visit, additional blood ADA samples may be collected every 3 mo (±14 d) up to 1 y from the last dose of study drug, or 
until the ADA becomes negative, or until ADA titer becomes less than baseline (applicable when preexisting ADA was observed), or until the subject starts 
another therapy for cancer, or withdraws consent from the study, whichever occurs first. 
o Within 28 d before enrollment. 
p ECHO or MUGA scan assessments will be performed at Screening and every 4 cycles (-7 d) starting with Cycle 5 (ie, Cycle 5, 9, 13…). If the planned date of 
study drug administration is delayed after examination of ECHO or MUGA, and there are no abnormal findings on the examination, it is up to the investigator’s 
judgment as to whether ECHO or MUGA need to be repeated. 
q Day 1, before infusion at all cycles. 
r ECGs will be taken in close succession, approximately 3 minutes apart, while in a supine/semi-recumbent position. ECGs should be performed before PK 
blood draws 
s For cohort 1 and Cohort 1a: HER2 IHC 2+ or 3+ status must be determined by central laboratory from an archival tumor tissue sample. 
t Ophthalmologic assessment, including visual acuity testing, slit lamp examination, and fundoscopy on Day 1: Cycles 2, 6, 10, 14, etc (-7 d) and EOT. If the 
planned date of study drug administration is delayed after examination of ophthalmologic assessments, and there are no abnormal findings on the examination, 
it is up to the investigator’s judgment as to whether ophthalmologic assessments need to be repeated. 
u Within 72 h before enrollment and study drug administration.  
v One blood sample collection for PK analysis as soon as ILD /pneumonitis is suspected, if feasible. 
w A washout period of more than 14 days is required before restarting trastuzumab deruxtecan 
x If subject provides consent and once protocol version 7.0 is applied, leftover samples after ADA testing would be used for future central laboratory analysis for 
COVID-19 testing at Cycles 1, 4 and every 4 cycles thereafter .  For subjects with suspected or confirmed COVID-19, follow the dose modifications in 
Section 16.7   
y Starting at C4, D1 and every 4 cycles thereafter to align with ADA blood sample collections.   
For suspected interstitial lung disease (ILD) /pneumonitis , treatment with study drug should be interrupted pending evaluation.  
Evaluations should include: 
 High resolution computed tomography (CT)  
 Pulmonologist consultation (Infectious Disease consultation as clinically indicated) 
 Blood culture and CBC. Other blood tests could be considered as needed 
 Consider bronchoscopy and bronchoalveolar lavage if clinically indicated and feasible 
 Pulmonary function tests and pulse oximetry (SpO2) 
 Arterial blood gases if clinically indicated  
 One blood sample collection for pharmacokinetic (PK) analyses as soon as ILD /pneumonitis is suspected, if feasible. 
Other tests could be considered as needed. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 115 
16.2. 
Appendix 2: Cockcroft-Gault Equation 
The estimated creatinine clearance rate (CrCl; mL/min) will be calculated using the 
Cockcroft-Gault equation based on actual weight: 
Conventional – serum creatinine in mg/dL: 
Male: 
CrCl (mL/min) = 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140


 
Female: 
CrCl (mL/min) = 
72
 
 
mg/dL)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140


  0.85 
International System of Units (SI) – serum creatinine in μmol/L: 
Male: 
CrCl (mL/min) = 
 
Female: 
CrCl (mL/min) = 
0.0113
 x 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140



  0.85 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-
41. 
0.0113
 x 
72
 
 
mol/L)
(in 
 
creatinine
 
serum
kg)
(in 
 weight 
 
years)]
(in 
 
age
 - 
[140





Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 116 
16.3. 
Appendix 3: New York Heart Association (NYHA) 
Table 16.2: 
New York Heart Association Functional Classification 
Functional Capacity  
Objective Assessment  
Class I. Patients 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. 
Class II. Patients 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. 
Class III. Patients 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. 
Class IV. Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart failure or 
the 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, Inc. Classification of Functional Capacity and Objective Assessment. 
Available from: 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-of-
Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp 
16.4. 
Appendix 4: Eastern Cooperative Oncology Group (ECOG) 
Performance Status  
Table 16.3: 
Eastern Cooperative Oncology Group Performance Status Scale 
GRADE 
DESCRIPTION 
0 
Fully active, able to carry on all predisease 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 house work, 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 h 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking h 
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;5:649-655. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 117 
16.5. 
Appendix 5: Response Evaluation Criteria in Solid Tumors, 
Version 1.1 
16.5.1. 
Measurability of Tumor at Baseline 
16.5.1.1. Definitions 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows: 
16.5.1.1.1. 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 short axis when assessed by CT scan 
(CT scan slice thickness recommended to be no greater than 5 mm).  At baseline (ie, 
screening for this study) and in follow-up (ie, all measurements past screening for this 
study), 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.  
16.5.1.1.2. 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, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not measurable by 
reproducible imaging techniques. 
16.5.1.1.3. Special Considerations Regarding Lesion Measurability 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment. 
16.5.1.1.3.1. Bone Lesions 
 Bone scan, positron emission tomography (PET) scan or plain films are not 
considered adequate imaging techniques to measure bone lesions.  However, these 
techniques can be used to confirm the presence or disappearance of bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross-sectional imaging techniques such as CT 
or MRI can be considered as measurable lesions if the soft tissue component meets 
the definition of measurability described above. 
 Blastic bone lesions are non-measurable. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 118 
16.5.1.1.3.2. 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.  
16.5.1.1.3.3. 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. 
16.5.1.2. Specifications by Methods of Measurements 
16.5.1.2.1. 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 28 d before enrollment. 
16.5.1.2.2. 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 performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical exam. 
Computed tomography, 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.  Magnetic resonance imaging is also acceptable in certain situations 
(eg, for body scans). 
16.5.2. 
Tumor Response Evaluation 
16.5.2.1. 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. 
16.5.2.2. Baseline Documentation of “Target” and “Non-target” Lesions 
When more than one measurable lesion is present at baseline, all lesions up to a maximum of 
five lesions total (representative of all involved organs) should be identified as target lesions and 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 119 
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. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum.  The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline.  Measurements are not required and 
these lesions should be followed as “present,” “absent,” or in rare cases “unequivocal 
progression.”  In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”). 
16.5.2.3. Response Criteria 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
16.5.2.3.1. Evaluation of Target Lesions 
Complete response (CR): Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 120 
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 (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
16.5.2.3.2. 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 less likely 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 retroperitoneum; however, if a lymph node is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm 
should be assigned in this circumstance as well).  This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness).  The 
measurement of these lesions is potentially non-reproducible; therefore, providing this default 
value will prevent false responses or progressions based upon measurement error.  To reiterate, 
however, if the radiologist is able to provide an actual measure, 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.” 
16.5.2.3.3. Evaluation of Non-target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions.  While some non-target lesions may actually be measurable, they 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 121 
need not be measured and instead should be assessed only qualitatively at the time points 
specified in the protocol. 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (< 10 mm short axis). 
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).  
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
16.5.2.3.4. 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. 
When the subject has only non-measurable disease: The same general concepts apply here as 
noted above; however, in this instance, there is no measurable disease assessment to factor into 
the interpretation of an increase in non-measurable disease burden.  Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-
measurable) a useful test that can be applied when assessing subjects for unequivocal 
progression is to consider if the increase in overall disease burden based on the change in 
non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease (ie, an increase in tumor burden representing an additional 
73% increase in “volume” [which is equivalent to a 20% increase diameter in a measurable 
lesion]).  If “unequivocal progression” is seen, the subject should be considered to have had 
overall PD at that point.  While it would be ideal to have objective criteria to apply to 
non-measurable disease, the very nature of that disease makes it impossible to do so; therefore, 
the increase must be substantial. 
16.5.2.3.5.  
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 preexisting lesions).  This is particularly 
important when the subject’s baseline lesions show PR or CR.  For example, necrosis of a liver 
lesion may be reported on a CT scan report as a “new” cystic lesion, which it is not. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 122 
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 brain 
ordered 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. 
16.5.2.4. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug until the 
EOT. 
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. 
16.5.2.4.1. Time Point Response 
It is assumed that at each protocol-specified time point, a response assessment occurs.  
Table 16.4 provides a summary of the overall response status calculation at each time point for 
subjects who have measurable disease at baseline. 
When subjects have non-measurable (therefore non-target) disease only, see Table 16.4. 
Table 16.4: 
Overall 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 
SD 
Non-PD or not all evaluated 
No  
SD 
Not all Evaluated 
Non-PD  
No 
NE 
PD   
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable disease  
16.5.2.4.2. Missing Assessments and Not Evaluable Designation 
When no imaging/measurement is performed at all at a particular timepoint, the subject is not 
evaluable (NE) at that timepoint.  If only a subset of lesion measurements are made at an 
assessment, usually the case is also considered NE at that timepoint, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response.  This would be most likely to happen in the case of PD.  For 
example, if a subject had a baseline sum of 50 mm with three measured lesions and at follow-up 
only two lesions were assessed, but those gave a sum of 80 mm, the subject will have achieved 
PD status, regardless of the contribution of the missing lesion. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 123 
16.5.2.4.3. Best Overall Response: All Time Points 
The best overall response is determined once all the data for the subject is known. 
Best response is defined as the lesser of the two best responses across two consecutive scans 
(eg, a subject who has PR at first assessment, SD at second assessment, and PD on last 
assessment; this would report as a best overall response of SD).  When SD is believed to be best 
response, it must also meet the protocol specified minimum time from baseline, 6 wk (±7 d).  If 
the minimum time is not met when SD is otherwise the best time point response, the subject’s 
best response depends on the subsequent assessments.  For example, a subject who has SD at 
first assessment, PD at second and does not meet minimum duration for SD, will have a best 
response of PD.  The same subject lost to follow-up after the first SD assessment would be 
considered NE. 
16.5.2.4.4. 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 may 
not have a total sum of “zero” on the eCRF. 
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  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 therapy.  The objective response status of 
such subjects is to be determined by evaluation of target and non-target disease. 
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. 
The convention to be followed when assessing response or progression will be to assign a single 
date to evaluations performed within that time point.  The date of response (CR, PR, SD, or NE) 
will be recorded as the date of the last radiographic evaluation included in the series for that 
assessment.  The date of progression (PD) will be recorded as the date of the earliest 
radiographic evaluation included in the series for that assessment. 
16.5.2.5. Frequency of Tumor Re-evaluation 
In this study, tumor measurement will be conducted every 6 wk (±7 d) while the subject remains 
on study until progression of disease, withdrawal of consent, death, or loss to follow-up.  Scan 
dates should not be adjusted or rescheduled due to dose interruption of any type. 
Baseline tumor assessments must be performed within 28 d before enrollment. 
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. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 124 
The radiographic evaluation must include CT or MRI scanning of chest, abdomen, and pelvis at 
screening period.  A CT or MRI of the brain is mandatory for all subjects included with baseline 
stable brain metastases.  Any additional suspected sites of disease should also be imaged.  Every 
effort should be made to use the same assessment modality for all assessments for each subject.  
Follow-up evaluations should include all sites of disease identified at screening and any other 
locations if PD is suspected (eg, CT or MRI of the brain if brain metastases are suspected) 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. 
16.6. 
Appendix 6: Relevant HER2 Mutations 
Table 16.5: 
List of HER2 Mutations 
HER2 mutations 
Glu770 Ala771insAlaTyrValMet 
Ala771 Tyr772insTyrValMetAla  
Gly776delinsLeuCys    
Gly776Ser    
Gly776Cys   
Gly776delinsValCys   
Gly776Val    
Gly776Val777insLeu   
Val777Leu  
Val777Met  
Val777 Gly778insCysGly 
Gly778 Ser779insLeuProSer 
Val777 Gly778insGly  
Gly776 Val777insValGlySer 
Val777 Gly778insGlySerPro 
Ser310Pro   
Ser310Tyr  
Ser310Phe  
Arg678Gln  
Thr733Ile  
Leu755Met  
Leu755Pro  
Leu755Ser  
Leu755Trp  
Asp769Asn  
Asp769His  
Asp769Tyr  
Source: Information extracted from Thermo Fisher’s analytical validation summary report 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 125 
16.7. 
Appendix 7: Instructions Related to Coronavirus disease 2019 
(COVID-19) 
Due to the potential impact of COVID-19, 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 trastuzumab 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 infection 
If COVID-19 is suspected, interrupt trastuzumab deruxtecan and rule out COVID-19 as per local 
guidance. 
 If COVID-19 is ruled out, follow dose modification and management guidance as 
outlined in Section 5.4   
 If COVID-19 is confirmed or is still suspected after evaluation follow dose 
modification as outlined in Table 16.6 below and manage COVID-19 per local 
guidance until recovery from COVID-19.  COVID-19 recovery is defined as no 
signs/symptoms of COVID-19, at least 1 negative real-time reverse transcription 
polymerase chain reaction (RT-PCR)* test result, and nearly or completely resolved 
chest CT findings. 
Table 16.6: 
COVID-19 Dose Modification Criteria 
COVID-19 Worst Toxicity CTCAE Version 5.0 
Grade (unless otherwise specified) 
Schedule Modification for trastuzumab 
deruxtecan 
Grade 1 
Resume study drug at the same dosea 
Grade 2 
Resume study drug at the same dose if chest CT 
findings are completely resolveda 
Reduce by 1 dose level if chest CT findings are 
nearly resolved 
Grade 3 
Reduce by 1 dose level if chest CT findings are 
completely resolved 
Discontinue study drug if chest CT findings are 
not completely resolved 
Grade 4 
Discontinue study drug 
COVID-19 = Coronavirus disease 2019; CT = computed tomography 
a Closely monitor signs/symptoms after resuming trastuzumab 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. 
In addition to the recommendations outlined in Table 16.6 , Investigators may consider dose 
modifications of the study drug according to the subject’s condition and after discussion with the 
study Medical Monitor or designee. 
If an event is suspected to be drug-related ILD/pneumonitis, manage per protocol 
ILD/pneumonitis management guideline Table 5.5. 


Protocol DS8201-A-U204 
Version 7.0, 14 July2020 
 
Proprietary and Confidential 
Page 126 
* If PCR testing is not available, the subject must not have any sign/symptoms for at least 
2 weeks, in addition to meeting the requirement for chest CT imaging. 
Prior and Concomitant Medications - Prohibited Therapies/Products 
 Chloroquine or hydroxychloroquine; 
 Concomitant treatment is not allowed during the study treatment (Section 5.6). 
 If treatment is absolutely required for COVID-19 infection trastuzumab 
deruxtecan must be interrupted. 
 If administered, then a washout period of more than 14 days is required before 
resumption of trastuzumab 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, at the time points specified 
in the Schedule of Events Table 16.1.The chloroquine or hydroxychloroquine administration 
time and the exact time of blood sample collection for PK analysis must be recorded on the 
eCRF. 
COVID-19 Assessment(s) 
All confirmed or suspected COVID-19 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, the participant must not have any signs or symptoms of COVID 19 
infection for at least 2 weeks and nearly or completely resolved chest CT findings. 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, 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.