Clinical trial NCT04581824
Conditions: Lung Cancer, Non-Small Cell
Keywords: Non small cell lung cancer Dostarlimab Pembrolizumab Pemetrexed Carboplatin Cisplatin
Sponsor: GlaxoSmithKline
Start date: 2020-11-19; Completion date: 2024-09-10
Enrollment: 243 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
NSCLC comprises of approximately 84 percent (%) of all lung cancers and is often diagnosed at advanced stage due to poor prognosis. Dostarlimab is an immunoglobulin G (IgG)4 kappa humanized monoclonal antibody (mAb) that binds with high affinity to programmed cell death protein 1 (PD 1), resulting in inhibition of binding to programmed death ligand 1 (PD L1) and programmed death ligand 2 (PD L2). This study aims to compare the efficacy and safety PD-1 inhibitors dostarlimab and pembrolizumab, when administered in combination with chemotherapy (pemetrexed, cisplatin and carboplatin), in participants with non-squamous NSCLC without a known sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or receptor tyrosine kinase-1 (ROS-1) mutation, BRAF V600E mutation, or other genomic aberration for which an approved targeted therapy is available. A total of approximately 240 participants will be enrolled in the study for a period of 5 years.

Detailed description:

Arms: arm 1: Participants will receive dostarlimab on Day 1 of every 21 Day cycle followed by pemetrexed, and then followed by cisplatin or carboplatin (Cycles 1 to 4 only) as per investigator decision. arm 2: Participants will receive pembrolizumab on Day 1 of every 21 Day cycle followed by pemetrexed, and then followed by cisplatin or carboplatin (Cycles 1 to 4 only) as per investigator decision.
Interventions: intervention 1: Dostarlimab intervention 2: Pembrolizumab intervention 3: Chemotherapy
Intervention descriptions: intervention 1: Dostarlimab will be administered through a 30 minute infusion at a dose of 500 milligrams (mg) intravenously (IV) every 3 weeks (Q3W) up to a maximum of 35 cycles (each cycle of 21 days). intervention 2: Pembrolizumab will be administered through a 30 minute infusion at a dose of 200 mg Q3W up to a maximum of 35 cycles (each cycle of 21 days). intervention 3: Pemetrexed will be administered at 500 milligram per meter square (mg/m\^2 ) IV through a 10 minute IV infusion Q3W, up to a maximum of 35 cycles (each cycle of 21 days).

Cisplatin will be administered at 75 mg/m\^2 through a 30 minute IV infusion Q3W for 4 cycles (each cycle of 21 days) as per investigator decision.

Carboplatin will also be administered at area under the concentration time curve 5 milligram/milliliters/minute (mg/mL/min) (maximum dose: 750 mg) through a 15 to 60 minute IV infusion Q3W for 4 cycles (each cycle of 21 days) as per investigator decision.

Protocol documents:
Prot_004.pdf: 
RPS-CLIN-050714 
 
CONFIDENTIAL 
GSK group of companies 
 
Clinical Study Protocol 213403 Version 05 
Page 1 of 166 
 
A RANDOMIZED, PHASE 2, DOUBLE-BLIND STUDY TO 
EVALUATE THE EFFICACY OF DOSTARLIMAB PLUS 
CHEMOTHERAPY VERSUS PEMBROLIZUMAB PLUS 
CHEMOTHERAPY IN METASTATIC NON-SQUAMOUS 
NON-SMALL CELL LUNG CANCER 
Brief Title: 
Efficacy Comparison of Dostarlimab Plus 
Chemotherapy vs Pembrolizumab Plus Chemotherapy 
in Participants with Metastatic Non-squamous 
Non-small Cell Lung Cancer 
Protocol Number: 
213403 Amendment 5 
Compound Name: 
Dostarlimab (GSK4057190) 
Study Phase: 
Phase 2 
Sponsor Name and Legal 
Registered Address:  
GSK Research & Development Limited 
980 Great West Road 
Brentford 
Middlesex, TW8 9GS 
UK 
SPONSOR SIGNATORY: 
Neda Stjepanovic, 
Medical Director 
Approval Date: 
14 February 2023 
Medical Monitor Name and 
Contact Information: 
Can be found in the Study Reference Manual. 
Regulatory Agency 
Identification Numbers: 
IND Number 150997 
EudraCT Number 2020-002327-11 
 
 
Version of Protocol: 
05 
 
 
 
Copyright 2023 the GSK group of companies. All rights reserved. Unauthorized copying 
or use of this information is prohibited. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 2 of 166 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Table 1: 
Document History 
Document 
Date 
DNG Number 
Sponsor 
Amendment 5 (Version 05) 
14 February 2023 
RPS-CLIN-050714 
GSK 
Amendment 4 (Version 04) 
30 November 2021 
TMF-14193704 
GSK 
Amendment 3 (Version 03) 
17 June 2021 
TMF-12053714 
GSK 
Amendment 2 (Version 02) 
10 September 2020 
2020N447469_02 
GSK 
Amendment 1 DEU-1 
(Version 01 DEU-1) 
07 January 2021 
2020N447469_01 
DEU-1 
GSK 
Amendment 1 (Version 01) 
24 July 2020 
2020N447469_00 
GSK 
Original Protocol (Version 
00) 
18 June 2020 
2020N436839_00 
GSK 
Abbreviations: DNG=document number generator; TMF=trial master file. 
 
Amendment 5 (14 February 2023) 
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 neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 05  
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 3 of 166 
 
Summary of Changes for the Amendment 05  
Table 2: 
Summary of Changes for Amendment 05 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 8.3.3 Supplementary 
Analyses 
Added 2 supplementary 
analyses at DCO2 and 
DCO3.  
Section 8.4.3 Primary Efficacy 
Analyses   
Added supplementary 
analysis of ORR 
approximately15 months 
after the last subject was 
randomized. 
Appendix 4: Committees 
Structure   
Clarified that blinded 
independent central review 
(BICR) will be utilized for 
review of radiological 
images and assessment of 
tumor response and 
progression. 
Appendix 
4: 
Data 
Quality 
Assurance   
Added involvement of 
central reading mechanism 
as content part of the 
Monitoring Plan. 
Appendix 
4: 
Data 
Quality 
Assurance   
Added a statement 
specifying the duration of 
documents storage (i.e., 
radiographic images) at 
external body. 
Appendix 4: Source Documents   
Added a statement 
regarding documents which 
may be shared with external 
third parties contracted by 
GSK.  
Appendix 11: Amendment 4 
Added protocol amendment 
04 summary. 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 4 of 166 
 
TABLE OF CONTENTS 
1. 
PROTOCOL SUMMARY ................................................................ 11 
1.1. 
Synopsis ............................................................................................ 11 
1.2. 
Schema .............................................................................................. 18 
1.3. 
Schedule of Activities ....................................................................... 18 
2. 
INTRODUCTION ............................................................................ 33 
2.1. 
Study Rationale ................................................................................. 33 
2.2. 
Background ....................................................................................... 33 
2.2.1. 
Lung Cancer ...................................................................................... 33 
2.2.2. 
Programmed Cell Death, Immune Evasion, and Immunotherapy .... 34 
2.2.3. 
Overview of PD-1 Inhibitors ............................................................ 35 
2.2.4. 
PD-1 Inhibitors in Combination with Chemotherapy ....................... 36 
2.2.5. 
Dostarlimab ....................................................................................... 38 
2.2.6. 
Pembrolizumab ................................................................................. 41 
2.3. 
Benefit/Risk Assessment .................................................................. 41 
2.3.1. 
Risk Assessment ............................................................................... 42 
2.3.2. 
Benefit Assessment ........................................................................... 43 
2.3.3. 
Overall Benefit/Risk Conclusion ...................................................... 43 
3. 
OBJECTIVES AND ENDPOINTS .................................................. 44 
4. 
STUDY DESIGN ............................................................................. 47 
4.1. 
Overall Design .................................................................................. 47 
4.2. 
Scientific Rationale for Study Design .............................................. 50 
4.3. 
Justification for Dose ........................................................................ 50 
4.4. 
End of Study Definition .................................................................... 50 
5. 
SELECTION OF STUDY POPULATION AND WITHDRAWAL 
CRITERIA ........................................................................................ 51 
5.1. 
Inclusion Criteria .............................................................................. 51 
5.2. 
Exclusion Criteria ............................................................................. 53 
5.3. 
Lifestyle and/or Dietary Considerations ........................................... 56 
5.4. 
Screen Failures .................................................................................. 56 
5.5. 
Criteria for Temporarily Delaying .................................................... 56 
5.6. 
Withdrawal/Stopping Criteria ........................................................... 56 
5.6.1. 
Liver Chemistry Stopping Criteria ................................................... 58 
5.6.2. 
QTc Stopping Criteria ....................................................................... 59 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 5 of 166 
 
5.7. 
Lost to Follow-up ............................................................................. 59 
5.8. 
Participant and Study Completion .................................................... 60 
6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY ...... 61 
6.1. 
Study Treatments Administered ....................................................... 61 
6.1.1. 
Dostarlimab ....................................................................................... 62 
6.1.2. 
Pembrolizumab ................................................................................. 62 
6.1.3. 
Chemotherapy (Pemetrexed, Cisplatin, and Carboplatin) ................ 62 
6.1.4. 
Administration .................................................................................. 63 
6.2. 
Preparation/Handling/Storage/Accountability .................................. 63 
6.3. 
Measures to Minimize Bias .............................................................. 64 
6.3.1. 
Method of Treatment Assignment: Randomization ......................... 64 
6.3.2. 
Blinding ............................................................................................ 64 
6.4. 
Planned Dose Adjustments ............................................................... 65 
6.4.1. 
Dose Levels and Dose Adjustment ................................................... 65 
6.4.2. 
Guidelines for Events of Special Interest ......................................... 67 
6.5. 
Participant-specific Dose Adjustments ............................................. 78 
6.6. 
Study Treatment Compliance ........................................................... 78 
6.7. 
Treatment of Overdose ..................................................................... 78 
6.7.1. 
Protocol-defined Overdose ............................................................... 78 
6.8. 
Treatment After the End of the Study ............................................... 78 
6.9. 
Concomitant Medications and Non-drug Therapies ......................... 79 
6.9.1. 
Prohibited Medications and Non-drug Therapies ............................. 79 
7. 
STUDY ASSESSMENTS AND PROCEDURES ............................ 80 
7.1. 
General Guidelines ........................................................................... 80 
7.1.1. 
General Guidance for Treatment Continuity when Participants are 
Unable to Come into the Clinic ........................................................ 80 
7.2. 
Screening and Critical Baseline Assessments .................................. 82 
7.2.1. 
Baseline Assessments at Screening .................................................. 82 
7.2.2. 
Baseline Tumor Assessment (Documentation of Target and 
Non-target Lesions) .......................................................................... 82 
7.2.3. 
Determination of PD-L1 Status Prior to Randomization .................. 83 
7.3. 
Efficacy ............................................................................................. 84 
7.3.1. 
Post-baseline Imaging and Tumor Assessment ................................ 84 
7.4. 
Safety ................................................................................................ 86 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 6 of 166 
 
7.4.1. 
Physical Examinations ...................................................................... 86 
7.4.2. 
ECOG Performance Status ............................................................... 86 
7.4.3. 
Vital Signs ........................................................................................ 86 
7.4.4. 
Pulse Oximetry ................................................................................. 86 
7.4.5. 
Electrocardiograms ........................................................................... 86 
7.4.6. 
Clinical Safety Laboratory Assessments .......................................... 87 
7.4.7. 
Pregnancy Testing ............................................................................ 88 
7.5. 
AEs, SAEs, and Other Safety Reporting .......................................... 88 
7.5.1. 
Time Period and Frequency for Collecting AE and SAE Information
 .......................................................................................................... 88 
7.5.2. 
Method of Detecting AEs and SAEs ................................................ 89 
7.5.3. 
Follow-up of AEs and SAEs ............................................................. 89 
7.5.4. 
Regulatory Reporting Requirements for SAEs ................................. 90 
7.5.5. 
Pregnancy ......................................................................................... 90 
7.5.6. 
Cardiovascular and Death Events ..................................................... 91 
7.5.7. 
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as SAEs ........................................................................... 91 
8. 
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .. 97 
8.1. 
Hypothesis ........................................................................................ 97 
8.2. 
Sample Size Considerations ............................................................. 97 
8.3. 
Data Analysis Considerations ........................................................... 97 
8.3.1. 
Analysis Populations ........................................................................ 97 
8.3.2. 
Interim Analysis ................................................................................ 98 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 7 of 166 
 
8.3.3. 
Supplementary Analyses .................................................................. 98 
8.4. 
Key Elements of Analysis Plan ........................................................ 98 
8.4.1. 
Participant Disposition ...................................................................... 99 
8.4.2. 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications ................................................................. 99 
8.4.3. 
Primary Efficacy Analyses ............................................................... 99 
8.4.4. 
Secondary Efficacy Analyses ........................................................... 99 
8.4.6. 
Secondary Safety Analyses ............................................................. 100 
9. 
REFERENCES ............................................................................... 104 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 8 of 166 
 
LIST OF TABLES  
Table 1: 
Document History ............................................................................... 2 
Table 2: 
Summary of Changes for Amendment 04 .......................................... 3 
Table 3: 
Objectives and Endpoints for Study 213403 .................................... 12 
Table 4: 
Schedule of Activities for Study 213403 .......................................... 19 
Table 5: 
Risk Assessment ............................................................................... 42 
Table 6: 
Objectives and Endpoints for Study 213403 .................................... 44 
Table 7: 
Adequate Baseline Organ Function Inclusion Criteria ..................... 52 
Table 8: 
Bundle Branch Block QTc Discontinuation Criteria ........................ 59 
Table 9: 
Study Treatments for Study 213403 ................................................. 61 
Table 10: Dose Modifications for Chemotherapies Used in Study 213403 ..... 66 
Table 11: Recommended Dose Modifications for Hematological Chemotherapy 
Toxicities .......................................................................................... 66 
Table 12: Recommended Dose Modifications for Non‑hematological 
Chemotherapy Toxicities .................................................................. 67 
Table 13: Dose Modification Guidelines for PD-1 Inhibitor-related AEs ........ 68 
Table 14: Infusion Reaction Treatment Guidelines .......................................... 77 
Table 15: Critical Data Collection and Safety Precautions .............................. 82 
Table 16: Collecting and Reporting AEs, Pregnancy, and Survival ................. 89 
Table 17: Evaluation of Overall Response for Participants with Measurable 
Disease at Baseline ......................................................................... 114 
Table 18: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grading ........................................................................................... 117 
Table 19: Protocol‑required Safety Laboratory Tests ..................................... 119 
Table 20: Female Contraceptives Allowed During the Study ........................ 128 
Table 21: Liver Chemistry Increased Monitoring Criteria ............................. 131 
Table 22: Liver Chemistry Stopping Criteria ................................................. 131 
Table 23: Required Actions and Follow-up Assessments Following ANY Liver 
Stopping Event ................................................................................ 133 
Table 24: Abbreviations and Specialist Terms ............................................... 145 
Table 25: Summary of Changes for Amendment 1 ........................................ 149 
Table 26: Summary of Changes for Amendment 1 DEU-1 ............................ 150 
Table 27: Summary of Changes from Amendment 1 DEU-1 (07 January 2021) 
to Amendment 3 (17 June 2021) .................................................... 151 
Table 28: Summary of Changes for Amendment 02 ...................................... 157 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 9 of 166 
 
Table 29: Summary of Changes for Amendment 03 ...................................... 158 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 10 of 166 
 
LIST OF FIGURES  
Figure 1:  Schema for Study 213403 ................................................................. 18 
Figure 2: 
Liver Chemistry Stopping and Increased Monitoring Algorithm ..... 58 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 11 of 166 
 
1. 
PROTOCOL SUMMARY  
1.1. 
Synopsis  
Protocol Title  
A Randomized, Phase 2, Double-blind Study to Evaluate the Efficacy of Dostarlimab 
Plus Chemotherapy versus Pembrolizumab Plus Chemotherapy in Metastatic 
Non-Squamous Non-Small Cell Lung Cancer  
Brief Title  
Efficacy Comparison of Dostarlimab Plus Chemotherapy vs Pembrolizumab Plus 
Chemotherapy in Participants with Metastatic Non-squamous Non-small Cell Lung 
Cancer 
Rationale  
The ongoing Phase 1/2 dose escalation and cohort expansion study (Study 4010-01-001 
[GARNET; GSK Study 213346]), which is evaluating dostarlimab as monotherapy, has 
shown promising preliminary efficacy data in 67 participants with previously treated 
advanced non-small cell lung cancer (NSCLC); 18 out of 67 participants with NSCLC 
have achieved a confirmed partial response (PR) (26.9% objective response rate [ORR] 
by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), which is comparable 
to the reported efficacy of other programmed cell death protein 1 (PD-1) inhibitors in this 
setting. This response in participants with NSCLC in the GARNET study was observed 
even with negative enrichment by tumor proportion score (TPS). 
Indirect comparison of the preliminary efficacy and safety profile of dostarlimab 
monotherapy from the GARNET study and the data of pembrolizumab monotherapy in 
second-line NSCLC (Herbst, Baas et al. 2016) indicates that the 2 PD-1 inhibitors may 
produce similar anti-tumor activity with comparable safety profiles. This study will 
provide a direct comparison of the efficacy, safety, and tolerability of dostarlimab versus 
pembrolizumab, both in combination with platinum-based chemotherapy.  
The design of the proposed similarity study relies, in part, on the estimated treatment 
effect of pembrolizumab plus chemotherapy from 3 adequate and well-controlled studies 
(KEYNOTE studies) where said regimen was shown to be superior to chemotherapy 
alone (Langer, Gadgeel et al. 2016, Gandhi, Rodríguez-Abreu et al. 2018, Paz-Ares, Luft 
et al. 2018). The robustness of these studies in design and conduct help to provide a 
reliable estimate of pembrolizumab’s effect. The proposed study follows KEYNOTE 
studies with respect to important study design features, including patient population and 
dosing of reference products.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 12 of 166 
 
Objectives and Endpoints  
Table 3: 
Objectives and Endpoints for Study 213403 
Objectives 
Endpoints 
Primary 
 
To compare the ORR of PD-1 inhibitor 
dostarlimab vs pembrolizumab administered 
in combination with chemotherapy as 
evaluated using RECIST v1.1 based on BICR 
in participants with metastatic non-squamous 
NSCLC, without a known EGFR, ALK, 
ROS-1, or BRAF V600E mutation or other 
genomic aberration for which an approved 
targeted therapy is available, who have 
received no prior treatment of metastatic 
disease 
 
The primary efficacy endpoint ORR will be 
evaluated by RECIST v1.1 based on BICR 
and will be defined as the proportion of 
participants with BOR of CR or PR in the 
analysis population. 
Secondary 
 
To evaluate the following measures of clinical 
benefit of PD-1 inhibitor administered in 
combination with chemotherapy:  
 
OS 
 
PFS evaluated using RECIST v1.1 based 
on Investigator assessment 
 
 
OS will be defined as the time from the date 
of randomization to the date of death by any 
cause. 
 
PFS will be evaluated using RECIST v1.1 
based on Investigator assessment and will be 
defined as the time from the date of 
randomization to the date of PD or death by 
any cause, whichever occurs first. 
 
To evaluate the safety of PD-1 inhibitor in 
combination with chemotherapy 
 
Assess the incidence of TEAEs, SAEs, irAEs, 
TEAEs leading to death, and AEs leading to 
discontinuation occurring while participants 
are on treatment or up to 90 days after the last 
dose of study treatment. Clinical laboratory 
parameters (hematology, chemistry, thyroid 
function, urinalysis), vital signs, ECOG 
performance status, ECG parameters, physical 
examinations, and usage of concomitant 
medications will be collected. 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 13 of 166 
 
Table 3: 
Objectives and Endpoints for Study 213403 (Continued) 
Objectives 
Endpoints 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 14 of 166 
 
Table 3: 
Objectives and Endpoints for Study 213403 (Continued) 
Objectives 
Endpoints 
 
Abbreviations: 
; ALK=anaplastic lymphoma kinase; 
BICR=blinded independent central review; 
; BRAF= proto-oncogene B-raf; 
 
 CR=complete response; 
; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor 
receptor; 
 
 
 EOT=End-of-Treatment; 
 
 irAE=immune-related adverse event; 
 
; NSCLC=non-small cell lung cancer; ORR=objective response rate; OS=overall survival; 
PD=progressive disease; PD-1=programmed cell death protein 1; 
 
PFS=progression-free survival;
 
 PR=partial response; 
 
 RECIST=Response Evaluation Criteria in Solid Tumors; ROS-1=receptor tyrosine kinase-1; 
SAE=serious adverse event; TEAE=treatment-emergent adverse event; 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 15 of 166 
 
Overall Design  
This is a randomized, Phase 2, double-blind, 2-arm study to compare the efficacy and 
safety of PD-1 inhibitors dostarlimab and pembrolizumab, when administered in 
combination with chemotherapy, in male and female participants 18 years and older with 
non-squamous NSCLC without a known sensitizing epidermal growth factor receptor 
(EGFR), anaplastic lymphoma kinase (ALK), receptor tyrosine kinase-1 (ROS-1), or 
proto-oncogene B-raf (BRAF) V600E mutation or other genomic aberration for which an 
approved targeted therapy is available who have not received previous systemic 
anticancer therapy for metastatic disease.  
The study consists of a Screening Period (Day-28 to Day-1) for completion of all 
Screening assessments and subsequent randomization, a Treatment Period, an 
End-of-Treatment (EOT) Visit (within 7 days of the decision to discontinue treatment for 
any reason), a Safety Follow-up Period with a visit at 30 (+7) and 90 (+7) days after the 
last dose of study treatment, and a Post-treatment Follow-up Period with assessments 
occurring 180 days after the last dose of study treatment and every 90 (±14) days 
thereafter, continuing until death, withdrawal of consent, or the end of study data 
collection. During the Treatment Period, clinic visits will occur every 3 weeks (Q3W). 
Any serious adverse events (SAEs) assessed as related to study participation should be 
reported from the signing of informed consent form, with all AEs and SAEs reported 
from the start of study treatment, and according to the time points specified in the 
schedule of activities (SoA) (Table 4) and Section 7.5.1. 
To be eligible for the study, participants must have documented PD-L1 status by the 
22C3 pharmDx assay (Agilent/Dako). If no prior PD-L1 result is available at the time of 
Screening, the participant can be tested locally using the aforementioned method, or 
central PD-L1 testing can be completed (refer to the Laboratory Manual for 
country-specific details of central assessment). For participants requiring PD-L1 testing 
at the time of study entry, an archival formalin-fixed paraffin-embedded (FFPE) tumor 
tissue specimen, which may have been collected at any time prior to Screening, can be 
submitted for analysis within 28 days of the participant’s first dose. Specimens used to 
confirm diagnosis or collected after the participant has been diagnosed with metastatic 
disease will be preferred for determination of PD-L1 status. Both tissue block and freshly 
cut (within 6 months) slides (10 to 15) are acceptable. If no archival FFPE tumor tissue is 
available, a fresh tumor tissue biopsy should be obtained and tested within 28 days of the 
participant’s first dose. Biopsies obtained prior to receipt of adjuvant/neoadjuvant 
chemotherapy will be permitted if a fresh biopsy is not feasible. As the results of baseline 
PD-L1 status assessment will be used as a stratification factor in this study, results must 
be provided prior to randomization. Participants who do not have documented PD-L1 
status and cannot provide archived or fresh tissue sample for PD-L1 testing will not be 
eligible for the study. 
Within 35 days prior to the first dose, participants must have a baseline tumor assessment 
of the chest and abdomen (including the entire liver and both adrenal glands). Other 
regions should be imaged as clinically indicated (e.g., pelvis, brain, etc). This assessment 
should be conducted by intravenous (IV) contrast-enhanced computed tomography (CT) 
or magnetic resonance imaging (MRI) scan. MRI should be used for abdominal (and 
pelvic) imaging if CT contrast is contraindicated, and, preferably, for IV 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 16 of 166 
 
contrast-enhanced imaging of the brain. The same imaging technique should be used in a 
participant throughout the study. The CT component of positron emission tomography 
(PET)/CT may be used according to RECIST v1.1 guidelines, with full radiation dose 
diagnostic CT and IV CT contrast, and as clinically indicated. At each post-baseline 
assessment, evaluations of the sites of the disease identified by these scans are required. 
Following informed consent and completion of all Screening assessments, all participants 
who meet the eligibility criteria will be randomized 1:1 to receive chemotherapy in 
combination with either dostarlimab or pembrolizumab. Randomization will be 
completed in a blinded manner using an interactive web response system. Dostarlimab 
and pembrolizumab must be dispensed in a blinded manner. Details of blinding will be 
documented in site-specific blinding plans. The dosing regimen is described in 
Section 6.1.4. Randomization will be stratified by the following 2 factors: 
 PD-L1 status of the tumor (TPS <1% vs 1% to 49% vs ≥50%) 
 Smoking status (never vs former/current) 
To support continued tumor assessment while on study, serial imaging will then be 
performed at 6 weeks (42 [±7] days) and again at 12 weeks (84 [±7] days) from the 
randomization date. Following the 12-week scan, imaging will be performed every 9 
weeks (Q9W) (every 63 [±7] days), or more frequently, if clinically indicated. After 48 
weeks, participants who remain on treatment will have imaging performed every 12 
weeks (Q12W) (every 84 [±7] days). Imaging should continue to be performed until 
discontinuation of study treatment due to disease progression with clinical instability, 
start of subsequent anticancer treatment, withdrawal of informed consent, or death, 
whichever comes first. Imaging must be performed on a calendar schedule and should not 
be affected by dose interruptions/delays. All radiographic images/scans at the specified 
time points, as well as any unscheduled images/scans, will be collected and stored 
centrally for blinded independent central review (BICR), potential future evaluation, and 
archiving. Digital copies of all Digital Imaging and Communications in Medicine 
(DICOM)-formatted scans must be maintained at the Investigative site. 
Following the initial radiologic assessment of progressive disease (PD), clinically stable 
participants should continue study treatment and a follow-up scan should be performed at 
least 4 weeks and no longer than 8 weeks later. The follow-up scan will provide 
additional information to the Investigator for participant management and further 
treatment decisions. Further guidance for the assessment of scans acquired after RECIST 
v1.1-defined PD are provided in Appendix 1. For participants who are not clinically 
stable (clinically progressing) at the initial radiologic assessment of PD, study treatment 
will be discontinued and a follow-up scan is not required. Following the initial radiologic 
assessment of complete response (CR) or PR, a confirmatory follow-up scan should be 
performed at least 4 weeks later. 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 17 of 166 
 
Biomedical Research  
Brief Summary  
The purpose of this study is to compare the efficacy and safety of dostarlimab in 
combination with chemotherapy to the efficacy and safety of pembrolizumab in 
combination with chemotherapy in participants with non-squamous NSCLC who have 
not received previous systemic anticancer therapy for metastatic disease. Study details 
include the following: 
 Study duration: 5 years 
 Treatment duration: Up to 35 cycles total 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 18 of 166 
 
 Visit frequency: Q3W (cycles are 21 [±3] days) 
Number of Participants  
Approximately 240 participants will be randomly assigned to 2 study treatments, such 
that approximately 120 evaluable participants in each of the 2 arms complete the study.  
Treatment Groups and Duration  
Participants will be randomized in a 1:1 ratio into the dostarlimab plus chemotherapy arm 
or the pembrolizumab plus chemotherapy arm. Prior to randomization, Investigators will 
select, based on their clinical judgment, cisplatin or carboplatin as the chemotherapy to 
be administered. Randomization will be stratified by PD-L1 status of the tumor (TPS 
<1% versus 1% to 49% versus ≥50%) and smoking status (never vs former/current). A 
PD-L1 result obtained prior to Screening is allowed.  
The study will last approximately 5 years. 
Safety Data Monitoring  
To safeguard the interest and safety of the participants in the study, a safety 
monitoring/review panel will be used to conduct review of incoming data to monitor 
emerging safety signals. 
1.2. 
Schema  
The schema for Study 213403 is presented in Figure 1. 
Figure 1:  
Schema for Study 213403 
 
Abbreviations: 1L=first-line; NSCLC=non-small cell lung cancer. 
Note: Both arms will be stratified by PD-L1 status (TPS <1% vs 1% to 49% vs ≥50%) and smoking status 
(never vs former/current). 
1.3. 
Schedule of Activities  
Schedules of activities for Study 213403 are provided in Table 4. Each treatment cycle is 
3 weeks (21 [±3] days).


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 19 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
review 
X 
 
 
 
 
 
Clinical status should be rechecked 
before randomization and/or first dose 
of study treatment. 
Demographics 
X 
 
 
 
 
 
 
Medical, surgical, cancer, 
smoking, and medication 
history 
X 
 
 
 
 
 
 
Current medical conditions 
and medications 
X 
 
 
 
 
 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 20 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Tumor assessment 
The baseline tumor assessment will be completed within 35 days prior to the first dose of study 
treatment. To support continued tumor assessment while on study, serial imaging will then be 
performed at 6 weeks (42 [±7] days) and again at 12 weeks (84 [±7] days) from the 
randomization date. Following the 12 week scan, imaging will be performed Q9W (every 63 
[±7] days), or more frequently, if clinically indicated. After 48 weeks, participants who remain 
on treatment will have imaging performed Q12W (every 84 [±7] days). Imaging should 
continue to be performed until discontinuation of study treatment due to disease progression 
with clinical instability, start of subsequent anticancer treatment, withdrawal of informed 
consent, or death, whichever comes first. Imaging must be performed on a calendar schedule 
and should not be affected by dose interruptions/delays. All radiographic images/scans at the 
specified time points, as well as any unscheduled images/scans, will be collected and stored 
centrally for BICR, potential future evaluation, and archiving. Digital copies of all DICOM 
formatted scans must be maintained at the Investigative site. 
If a participant had a tumor assessment 
of the clinically indicated areas within 
the 35 days before dosing on C1/D1 but 
prior to signing the main ICF, an 
additional CT/MRI scan for study 
screening is not required. CT/MRI 
scans completed during Screening prior 
to signing the main ICF must have been 
performed and available for submission 
per the image acquisition guidelines. 
If EOT occurs between the scheduled 
radiologic disease assessments, the 
scans do not need to be repeated at EOT 
if fewer than 5 weeks have passed since 
the time of the previous disease 
assessment that did not document PD. 
For more details on tumor assessment, 
see Section 7.2.2, Section 7.3.1, and 
Appendix 1 (RECIST). 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 21 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
PD-L1 status 
X 
 
 
 
 
 
Required for randomization; may 
require tumor tissue submission or 
collection (see Section 7.2.3.). 
 
 
 
 
 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 22 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Evaluate genomic 
aberration 
X 
 
 
 
 
 
Participant is required to have 
histologically or cytologically 
confirmed metastatic non squamous 
NSCLC with documented absence of a 
sensitizing EGFR, ALK, ROS 1, or 
BRAF V600E mutation or other 
genomic aberration for which an 
approved targeted therapy is available 
(Inclusion Criteria 2, Section 5.1). An 
assessment at Screening is only required 
if prior documentation is not available. 
Optional blood sample for 
genetic testing 
X 
 
 
 
 
 
Sample may be obtained after 
randomization during first cycle if not 
collected at screening.  
Randomization 
X 
 
 
 
 
Randomization could be completed any 
time during the Screening Period once 
eligibility criteria have been confirmed. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 23 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
ECOG performance status 
X 
X 
X 
X 
X 
 
See Appendix 2. 
CBC 
X 
X 
X 
X 
X 
 
If Screening assessments were 
performed within 72 hours of D1, repeat 
testing is not required. 
See Appendix 3 for analytes. 
Serum chemistry 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
 
Every 6 cycles 
starting at C6D1 
 
 
 
See Appendix 3 for analytes. 
Thyroid panel 
X 
 
Q6W starting at 
C2D1 
X 
X 
 
Collect sample at 90-day Safety FUP 
Visit only if assessment is clinically 
indicated. 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 24 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Highly sensitive urine or 
serum pregnancy test 
(WOCBP only) 
X 
X 
X 
Monthly for at least 180 days after the last dose 
of study treatment (Note: duration of 
contraceptive use after last dose of chemotherapy 
must be consistent with local requirements and 
local approved product labels; however, the 
minimum duration is 180 days after last dose of 
chemotherapy) 
A highly sensitive pregnancy test (urine 
or serum, as required by local 
regulations) is required within 72 hours 
before study treatment administration. 
At Screening, if a urine test cannot be 
confirmed as negative (e.g., an 
ambiguous result), a serum pregnancy 
test is required. In such cases, the 
participant must be excluded from 
participation if the serum pregnancy 
result is positive. See Section 5.1, 
Section 7.4.7, and Appendix 3. 
HIV, hepatitis B, and 
hepatitis C screening 
X 
 
 
 
 
 
If a participant was tested within 3 
months prior to the first dose of study 
treatment, testing at Screening is not 
required. See Appendix 3. 
Full physical examination, 
including height 
X 
 
 
X 
 
 
Height will be measured at Screening 
only. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 25 of 166 
 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Vital signs and weight 
X 
X 
X 
X 
X 
 
 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 26 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Pulse oximetry 
X 
X 
X 
X 
X* 
 
*At the 30-day Safety Follow-up Visit, 
only 
 
Performed using local standard 
procedures; to be completed prior to 
dosing when performed during the 
Treatment Period. 
12-lead ECG 
X 
X 
 
X 
 
 
 
AE monitoring 
Collection of AEs begins after first treatment. AEs are required to be collected from the first 
treatment through 30 days after cessation of study treatment. However, SAEs are required to be 
captured through 90 days after cessation of study treatment (or to a minimum of 30 days 
post-treatment if the participant starts alternate anticancer therapy), and any pregnancies that 
occur while participant is on the study are to be captured. SAEs assessed as related to study 
participation and AESIs of any causality should be collected from the time informed consent 
was signed until study closeout. Monitoring of AEs after 90 days may be done via telephone 
assessment (Section 7.5.1). 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 27 of 166 
 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
 
 
 
 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 28 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date.1        
Immunotherapy 
administered 
 
X 
X 
 
 
 
Immunotherapy (500-mg 30- [-5 to 
+15] minute IV infusion of dostarlimab 
[Arm 1] or 200-mg 30- [-5 to +15] 
minute IV infusion of pembrolizumab 
[Arm 2]) will be administered for up to 
35 cycles total (approximately 24 
months). 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 29 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date1        
Pemetrexed treatment 
administered 
 
X 
X 
 
 
 
500 mg/m2 pemetrexed will be 
administered via 10-minute IV infusion, 
following immunotherapy 
administration. Pre-treatment for 
pemetrexed (folic acid, vitamin B12, 
and glucocorticoids) must be 
administered according to the product 
label and local guidelines. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 30 of 166 
 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date1        
Platinum chemotherapy 
treatment administered 
 
X 
X 
 
 
 
Platinum chemotherapy will be 
administered for the first 4 cycles only, 
following pemetrexed administration. If 
selected by the Investigator, cisplatin 
(75 mg/m2) will be given via IV 
infusion (approximately 30 minutes 
after pemetrexed infusion). If selected 
by the Investigator, carboplatin (AUC 
5 mg/mL/min via IV infusion) 
immediately following the pemetrexed 
infusion. Chemotherapeutic agents 
should be administered according to 
local practice and local approved 
product labels. For participants 
receiving cisplatin, pre- and 
post-treatment hydration procedures 
must be administered according to local 
practice and labels. 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 31 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date1        
Concomitant 
medications/procedures 
 
Recorded from the first dose of study treatment through Safety 
FUP 
 
Any subsequent anticancer treatment 
started during the study should also be 
collected. 
Symptom-directed physical 
examination 
 
X 
X 
 
X 
 
 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 32 of 166 
 
Table 4: 
Schedule of Activities for Study 213403 (Continued) 
Visit/Cycle: 
Screening 
Treatment Period 
EOT 
Safety 
FUP 
Post-treatment 
FUP 
Notes 
C1 
Subsequent 
Cycles 
Day: 
Procedure: 
Up to 28 
days 
before D1 
D1 
Cn, D1 (±3) 
Within 7 
days after 
last dose (or 
decision to 
discontinue) 
30 (+7) 
and 90 
(+7) days 
after last 
dose 
180 days after 
last dose, then 
every 90 
(±14) days 
Treatment cycles are 21 days long with 
dosing scheduled on D1 of each cycle.  
All assessments should be done prior to 
drug administration and within 72 h 
prior to 1st dose of study drugs 
administrated in that cycle, unless 
otherwise specified. Visits starting at 
Cycle 2 can be performed ±3 days of 
the scheduled date1        
Survival, AESIs, and 
study-drug related SAEs 
 
 
 
 
 
X 
Participant will be followed until study 
closeout for survival status, AESIs 
(regardless of causality), and study-drug 
related SAEs. 
Abbreviations: AE=adverse event; AESI=AE of special interest, AUC=area under the concentration-time curve; BICR=blinded independent central review; C=Cycle; 
Cn=Cycle subsequent to Cycle 1, i.e., C2, C3, C4, etc; CBC=complete blood count; CT=computed tomography; 
 
D=day; DICOM=Digital Imaging and Communications in Medicine; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
 
 
EOT=End-of-Treatment;
; FFPE=formalin-fixed paraffin-embedded; FUP=follow-up; 
ICF=informed consent form; IV=intravenous; MRI=magnetic resonance imaging; n=number of subsequent;
 
; Q12W=every 12 weeks; Q6W=every 6 
weeks; Q9W=every 9 weeks; RECIST=Response Evaluation Criteria in Solid Tumors; SAE=serious adverse event; WOCBP=woman of childbearing potential. 
.1 Standard-of-care tests/procedures, including laboratory assessments, ECG, physical examination, vital signs, height, weight, and ECOG performance status 
performed before the participant signs the ICF can be used as part of the Screening assessments, as long as the tests/procedures are performed within the 28‑day 
Screening Period. 
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 33 of 166 
 
2. 
INTRODUCTION  
2.1. 
Study Rationale  
The ongoing Phase 1/2 dose escalation and cohort expansion study (Study 4010-01-001 
[GARNET; GSK Study 213346]), which is evaluating dostarlimab as monotherapy, has 
shown promising preliminary efficacy data in 67 participants with previously treated 
advanced NSCLC; 18 out of 67 participants with NSCLC have achieved a confirmed PR 
(26.9% ORR by RECIST v1.1) which is comparable to the reported efficacy of other 
PD-1 inhibitors in this setting. This response in participants with NSCLC in the 
GARNET study was observed even with negative enrichment by TPS. 
Although there are limited clinical data with dostarlimab in combination with 
chemotherapy agents, a number of clinical studies have been exploring the value of 
immune checkpoint inhibitors in combination with chemotherapy agents. The 
combination has been well tolerated and has shown encouraging antitumor activity in 
patients with previously untreated, metastatic NSCLC (Langer, Gadgeel et al. 2016, 
Gandhi, Rodríguez-Abreu et al. 2018, Papadimitrakopoulou, Cobo et al. 2018, Paz-Ares, 
Luft et al. 2018, Socinski, Jotte et al. 2018, West, McCleod et al. 2019). 
The efficacy of pembrolizumab in combination with pemetrexed and platinum 
chemotherapy was investigated in patients with untreated metastatic non-squamous 
NSCLC (without EGFR or ALK mutations) in the KEYNOTE-189 study. The study 
demonstrated a significant improvement in OS and PFS for pembrolizumab administered 
in combination with pemetrexed and platinum chemotherapy compared with placebo and 
chemotherapy alone (Gandhi, Rodríguez-Abreu et al. 2018, KEYTRUDA Prescribing 
Information 2020, KEYTRUDA Summary of Product Characteristics 2020). 
In the pivotal study KEYNOTE-407, pembrolizumab was studied in combination with 
carboplatin-paclitaxel (or nab-paclitaxel) in first-line metastatic squamous NSCLC. Data 
from the study demonstrated that adding pembrolizumab to carboplatin-paclitaxel (or 
nab-paclitaxel) significantly improved the median OS, regardless of PD-L1 tumor 
expression in patients with metastatic squamous NSCLC (Paz-Ares, Luft et al. 2018). 
Indirect comparison of the preliminary efficacy and safety profile of dostarlimab 
monotherapy from the GARNET study and the data of pembrolizumab monotherapy in 
second-line NSCLC (Herbst, Baas et al. 2016) indicates that the 2 PD-1 inhibitors may 
produce similar anti-tumor activity with comparable safety profiles. This study will 
provide a direct comparison of the efficacy, safety, and tolerability of dostarlimab versus 
pembrolizumab, both in combination with platinum-based chemotherapy. 
2.2. 
Background  
2.2.1. 
Lung Cancer  
Lung cancer is the most common cause of cancer mortality globally and the second most 
common cancer in both men and women. About 13% of all new cancers in the United 
States (US) are lung cancer . Most recent lung and bronchus cancer incidence rates in the 
US from the Surveillance, Epidemiology, and End Results program estimate an incidence 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 34 of 166 
 
rate of 54.9 per 100,000 from 2016 data . The 2 major forms of lung cancer 
are NSCLC and small cell lung cancer. NSCLC is a heterogeneous disease that consists 
of adenocarcinoma, large cell carcinoma, and squamous cell carcinoma, and comprises 
approximately 84% of all lung cancers . The average age of diagnosis is approximately 
70 years old. Despite advances in early detection and standard treatment, NSCLC is often 
diagnosed at an advanced stage, has poor prognosis, and is the leading cause of cancer 
deaths worldwide . In the US, the 5 year OS rate of all stages of NSCLC is approximately 
19%, with advanced patients (Stage IIIB/IV) having a 5 year OS rate of <5% . 
Platinum-based doublet chemotherapy, maintenance chemotherapy, and anti-angiogenic 
agents in combination with chemotherapy have contributed to improved patient outcomes 
in advanced NSCLC . Until recently, for most patients with NSCLC without targetable 
oncogene drivers, first-line platinum-based chemotherapy was the only standard 
treatment approach . However, recent understanding of the interactions between the 
immune system and tumor growth has led to the development of a new class of 
immunotherapies, which have now moved to the frontline setting for NSCLC treatment.  
Approval of pembrolizumab monotherapy in the US and European Union (EU) in 2016 
and 2017, respectively, as the first-line treatment approach for patients with NSCLC 
whose tumors demonstrate high expression of PD-L1 (TPS ≥50%) led to a change in the 
lung cancer management paradigm (Reck, Rodriguez-Abreu et al. 2016, Spiess, Dhillon 
et al. 2016, Herzberg, Campo et al. 2017, KEYTRUDA Summary of Product 
Characteristics 2020). Following this approval, it was shown that the addition of 
pembrolizumab to standard pemetrexed and platinum-based chemotherapy resulted in 
significantly longer OS and PFS than chemotherapy alone in patients with previously 
untreated metastatic non-squamous NSCLC (without EGFR or ALK mutations) . 
Similarly, in patients with previously untreated metastatic squamous NSCLC, the 
addition of pembrolizumab to standard carboplatin and either paclitaxel or nab-paclitaxel 
also resulted in significantly longer OS and PFS than chemotherapy alone. Based on 
these results, pembrolizumab is now approved in combination with chemotherapy as 
first-line treatment of patients with metastatic non-squamous (with no EGFR or ALK 
genomic tumor aberrations) and squamous NSCLC in the US and EU (Spiess, Dhillon et 
al. 2016, Paz-Ares, Luft et al. 2018, KEYTRUDA Summary of Product Characteristics 
2020). Most recently, pembrolizumab monotherapy was approved in the US for use in 
previously untreated advanced or metastatic NSCLC patients with PD-L1 expression 
(TPS 1%; patients with EGFR or ALK genomic tumor aberrations should have disease 
progression on an approved therapy prior to receiving pembrolizumab monotherapy) 
(Mok, Wu et al. 2019). 
2.2.2. 
Programmed Cell Death, Immune Evasion, and Immunotherapy  
Programmed cell death protein 1 (PD-1) is a cell surface receptor on activated T cells 
(Ishida, Agata et al. 1992). PD-1 is part of a complex system of receptors and ligands that 
are involved in controlling T cell activation. PD-1 has 2 known ligands, PD-L1 (B7-H1) 
and programmed death-ligand 2 (PD-L2) (B7-DC). The PD-1/PD-L1 checkpoint serves 
as a negative regulator of T cells to help control local inflammatory responses and 
maintain self-tolerance. PD-L1 is constitutively expressed on a subset of macrophages 
but is also expressed by tumor cells . In the tumor microenvironment, PD-L1 expressed 
on tumor cells binds to PD-1 on activated T cells. This results in T-cell inhibition that 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 35 of 166 
 
prevents the T cell from killing the tumor cells, a process called immune evasion . This 
observation is the basis of the hypothesis that the PD-1/PD-L1 signaling pathway may be 
exploited to regain the antitumor immune response. Nonclinical models in which PD-1 
signaling was blocked or deficient (i.e., PD-1 knockout mice) demonstrate improved 
immune-mediated tumor control (Blank, Brown et al. 2004, Zhang, Gajewski et al. 2009). 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced 
in a variety of cell types . PD-L1 is expressed at low levels on various nonhematopoietic 
tissues, most notably on the vascular endothelium, whereas PD-L2 protein is 
predominantly expressed on antigen-presenting cells found in lymphoid tissue or chronic 
inflammatory environments . The binding of PD-1 ligands to PD-1 inhibits T cell 
activation triggered through the T cell receptor. PD-L2 is thought to control immune T 
cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T cell 
function in peripheral tissues. Although healthy organs express little (if any) PD-L1, a 
variety of cancers were shown to express abundant levels (Karim, Jordanova et al. 2009, 
Taube, Anders et al. 2012) which, via its interaction with the receptor, plays a critical role 
in immune evasion by tumors . As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic treatment in cancer . 
2.2.3. 
Overview of PD-1 Inhibitors  
The recognition of tumors by the immune system has been appreciated for multiple 
decades and provides an impetus to utilize the immune system to control tumor growth. 
Studies have reported the presence of tumor-infiltrating lymphocytes as a positive 
prognostic feature in multiple tumors, supporting a role for the immune system in 
limiting tumor growth. Despite evidence of immune reactivity, tumors are able to grow in 
the presence of an immune system, suggesting a suboptimal immune response (Zhang, 
Conejo-Garcia et al. 2003, Pages, Berger et al. 2005, Fridman, Pages et al. 2012). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control (Pedoeem, Azoulay-Alfaguter et al. 2014). The normal function of PD-1, 
expressed on the cell surface of activated T cells under healthy conditions, is to 
down-modulate unwanted or excessive immune responses, including autoimmune 
reactions. PD-1 (encoded by the gene PDCD1) is an immunoglobulin superfamily 
member related to cluster of differentiation (CD) 28 and cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4), which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands. PD-1 is expressed on 
activated lymphocytes, including peripheral CD4+ and CD8+, T cells, B cells, regulatory 
T cells, and natural killer cells . Expression has also been shown during thymic 
development on CD4/CD8 (double-negative) T cells, as well as subsets of macrophages 
and dendritic cells (Nishimura, Agata et al. 1996, Huang, Venet et al. 2009, Pena-Cruz, 
McDonough et al. 2010). 
The first-in-human report of inhibition of the PD-1/PD-L1 pathway was in 2010. 
Antitumor activity was observed in patients with various solid tumors upon 
administration of nivolumab, an anti-PD-1 antibody (Brahmer, Drake et al. 2010). The 
broad spectrum of cancers amenable to PD-1 blockade supports the development of an 
antibody that targets PD-1 as a single agent, and in combination with other therapeutic 
agents. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 36 of 166 
 
Multiple clinical studies in patients with melanoma, renal cell carcinoma, NSCLC, and 
other cancer types have generated positive data with 2 different antibodies targeting 
PD-1, nivolumab and pembrolizumab, demonstrating improved response rates and 
survival (Borghaei, Paz-Ares et al. 2015, Motzer, Escudier et al. 2015, Robert, Long et al. 
2015, Robert, Schachter et al. 2015, Weber, D'Angelo et al. 2015). Based on the clinical 
activity and manageable safety profile reported in these pioneering studies, nivolumab 
and pembrolizumab both have received approval from the US Food and Drug 
Administration and European Medicines Agency in a number of indications (refer to 
approved prescribing information). 
2.2.4. 
PD-1 Inhibitors in Combination with Chemotherapy  
There is accumulating evidence that, in addition to direct cytostatic and cytotoxic effects, 
the mechanisms of action of conventional chemotherapies may also involve activation of 
tumor-targeted immune responses, including increasing the immunogenicity of cancer 
cells and reducing immunosuppression of tumors (Kroemer, Galluzzi et al. 2013, Hato, 
Khong et al. 2014). In nonclinical models, platinum-based agents have been shown to 
modulate T cell activation by several potential mechanisms, including down-regulation of 
PD-L2, increased adenosine triphosphate, and increased high mobility group protein box 
1 release from dying cells (Senovilla, Vitale et al. 2012). Several immunostimulatory 
effects of paclitaxel on the immune system have also been reported; among these are the 
induction of endoplasmic reticulum stress, which can lead to calreticulin exposure and 
dendritic cell stimulation (Senovilla, Vitale et al. 2012), depletion of myeloid-derived 
suppressor cells (Sevko, Michels et al. 2013, Liechtenstein, Perez-Janices et al. 2014), 
and boosting of T cell priming (Pfannenstiel, Lam et al. 2010). These data suggest that 
chemotherapy agents may modulate the tumor microenvironment, an effect that could be 
enhanced by the addition of immune checkpoint inhibitors, such as those targeting PD-1. 
The ongoing Phase 1/2 dose escalation and cohort expansion study (Study 4010-01-001 
[GARNET; GSK Study 213346]), which is evaluating dostarlimab as monotherapy, has 
shown promising preliminary efficacy data in 67 participants with previously treated 
advanced NSCLC; 18 out of 67 NSCLC patients have achieved a confirmed PR (26.9% 
ORR by RECIST v1.1), which is comparable to the reported efficacy of other PD-1 
inhibitors in this setting. This response participants with NSCLC in the GARNET study 
was observed even with negative enrichment by TPS. 
Although there are limited clinical data with dostarlimab in combination with 
chemotherapy agents, a number of clinical studies have been exploring the value of 
immune checkpoint inhibitors in combination with chemotherapy agents. The 
combination has been well tolerated and has shown encouraging antitumor activity in 
patients with previously untreated, metastatic NSCLC (Langer, Gadgeel et al. 2016, 
Gandhi, Rodríguez-Abreu et al. 2018, Papadimitrakopoulou, Cobo et al. 2018, Paz-Ares, 
Luft et al. 2018, Socinski, Jotte et al. 2018, West, McCleod et al. 2019). 
The efficacy of pembrolizumab in combination with pemetrexed and platinum 
chemotherapy was investigated in patients with untreated metastatic non-squamous 
NSCLC (without EGFR or ALK mutations) in the KEYNOTE-189 study. The study 
demonstrated a significant improvement in OS and PFS for pembrolizumab administered 
in combination with pemetrexed and platinum chemotherapy compared with placebo and 
chemotherapy alone. After a median follow-up of 10.5 months, the estimated OS rate at 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 37 of 166 
 
12 months was 69.2% (95% CI, 64.1% to 73.8%) in the pembrolizumab-chemotherapy 
combination arm versus 49.4% (95% CI, 42.1% to 56.2%) in the placebo-chemotherapy 
arm (hazard ratio [HR] for death, 0.49; 95% CI, 0.38 to 0.64; p<0.001). The median OS 
was not reached in the pembrolizumab-chemotherapy arm. Median PFS was 8.8 months 
(95% CI, 7.6 months to 9.2 months) in the pembrolizumab-chemotherapy arm and 4.9 
months (95% CI, 4.7 months to 5.5 months) in the placebo-chemotherapy arm (HR for 
disease progression or death, 0.52; 95% CI, 0.43 to 0.64; p<0.001). The response rate as 
assessed by BICR was 47.6% (95% CI, 42.6% to 52.5%) in the 
pembrolizumab-chemotherapy arm and 18.9% (95% CI, 13.8% to 25.0%) in the 
placebo-chemotherapy arm (p<0.001). Adverse reactions leading to discontinuation of 
pembrolizumab occurred in 20% of patients. The most common AEs (≥1%) leading to 
discontinuation were pneumonitis (3%) and acute kidney injury (2%). Adverse reactions 
leading to the interruption of pembrolizumab occurred in 53% of patients; the most 
common adverse reactions or laboratory abnormalities leading to interruption of 
pembrolizumab (≥2%) were neutropenia (13%), asthenia/fatigue (7%), anemia (7%), 
thrombocytopenia (5%), diarrhea (4%), pneumonia (4%), increased blood creatinine 
(3%), dyspnea (2%), febrile neutropenia (2%), upper respiratory tract infection (2%), 
increased alanine aminotransferase (ALT) (2%), and pyrexia (2%). AEs leading to death 
were 6.7% in pembrolizumab-chemotherapy arm versus 5.9% in placebo 
placebo-chemotherapy arm; 3 immune-mediated AEs (all pneumonitis) led to death in the 
pembrolizumab-chemotherapy arm . Pembrolizumab in combination with platinum and 
pemetrexed has since been approved in the US and EU for the treatment of metastatic, 
first-line, non-squamous NSCLC (Spiess, Dhillon et al. 2016, KEYTRUDA Prescribing 
Information 2020, KEYTRUDA Summary of Product Characteristics 2020). 
In the pivotal study KEYNOTE-407, pembrolizumab was studied in combination with 
carboplatin-paclitaxel (or nab-paclitaxel) in first-line metastatic squamous NSCLC (Paz-
Ares, Luft et al. 2018). Data from the study demonstrated that adding pembrolizumab to 
carboplatin-paclitaxel (or nab-paclitaxel) significantly improved median OS regardless of 
PD-L1 tumor expression in patients with metastatic squamous NSCLC. The median OS 
was 15.9 months (95% CI, 13.2 month to not evaluable) for the 
pembrolizumab-chemotherapy arm versus 11.3 months (95% CI, 9.5 months to 14.8 
months) for the placebo-chemotherapy arm (HR, 0.64; 95% CI, 0.49 to 0.85; p<.001). 
Consistent with OS, pembrolizumab-chemotherapy had significantly improved median 
PFS over chemotherapy alone. The median PFS was 6.4 months (95% CI, 6.2 months to 
8.3 months) for the pembrolizumab-chemotherapy arm compared with 4.8 months (95% 
CI, 4.3 months to 5.7 months) for the placebo-chemotherapy arm (HR, 0.56; 95% CI, 
0.45 to 0.70; p<.001). The response rate, as assessed by means of BICR, was 57.9% 
(95% CI, 51.9% to 63.8%) in the pembrolizumab-chemotherapy arm and 38.4% (95% CI, 
32.7% to 44.4%) in the placebo-chemotherapy arm. The frequency of AEs was mostly 
similar between the pembrolizumab-chemotherapy and placebo-chemotherapy arms, both 
for overall events (98.2% vs 97.9%) and Grades 3 to 5 events (69.8% vs 68.2%). The 
most common AEs in both arms included anemia, alopecia, neutropenia, nausea, and 
thrombocytopenia, with cytopenias comprising the majority of Grade 3 to 5 AEs in each 
arm. Immune-mediated AEs and infusion reactions did occur more frequently with the 
addition of pembrolizumab to chemotherapy, compared with both overall (28.8% vs 
8.6%) and for Grades 3 to 5 AEs (10.8% vs 3.2%). The most common immune-mediated 
AEs (incidence ≥5%) associated with the pembrolizumab regimen included 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 38 of 166 
 
hypothyroidism (7.9%), hyperthyroidism (7.2%), and pneumonitis (6.5%). AEs leading 
to death were 8.3% in the pembrolizumab-chemotherapy arm vs 6.4% in the 
chemotherapy arm; 1 patient in each arm died from an immune-mediated AE 
(pneumonitis). Importantly, no new safety signals were identified, and the safety profile 
of pembrolizumab in combination with chemotherapy was consistent with that previously 
observed in lung cancer with pembrolizumab monotherapy. Pembrolizumab and 
carboplatin-paclitaxel (or nab-paclitaxel) combination treatment has since been approved 
in the US and EU for the treatment of metastatic first-line squamous NSCLC . 
2.2.5. 
Dostarlimab  
Dostarlimab (also known as TSR-042) is an immunoglobulin G (IgG)4-kappa humanized 
monoclonal antibody (mAb) that binds with high affinity to PD-1, resulting in inhibition 
of binding to PD-L1 and PD-L2. This antibody was generated based on a proprietary 
platform that utilizes affinity maturation to select antibodies with desired functional 
characteristics. The functional antagonist activity of dostarlimab was confirmed in a 
mixed lymphocyte reaction assay demonstrating enhanced interleukin-2 production upon 
addition of dostarlimab.  
The overall immunogenicity risk for dostarlimab is low. The dostarlimab high purity drug 
product and route of administration decrease the risk for induction of immune responses. 
The current clinical data are consistent with this assessment; post-dostarlimab antibody 
responses to date have been low in incidence and with no apparent impact on PK, safety, 
or efficacy. 
The dostarlimab development program includes several ongoing studies of dostarlimab as 
monotherapy and in combination with chemotherapy and other immuno-oncology agents 
across multiple tumor types.  
Monotherapy 
 Study 4010-01-001 (GARNET; GSK Study 213346) (Investigational New Drug 
[IND] 126472), is a Phase 1/2 dose escalation and cohort expansion (multicenter, 
open-label, first-in-human) study of dostarlimab as monotherapy in participants with 
advanced solid tumors, including NSCLC. 
Combination Therapy 
 Study 3000-01-002 (IOLite; GSK Study 213351) (IND 126472), is a multi-arm Phase 
1 study of dostarlimab in various combinations with niraparib, cobolimab, 
bevacizumab and chemotherapies, including carboplatin, paclitaxel, and pemetrexed 
in advanced solid tumors, including NSCLC. 
 Study 4020-01-001 (AMBER; GSK Study 213348) (IND 129161), is a Phase 1 study 
of dostarlimab and TSR-022/cobolimab (anti-T-cell immunoglobulin and 
mucin-domain containing-3 [TIM-3]) combination therapy in advanced solid tumors. 
 Study 4040-01-001 (CITRINO; GSK Study 213349) (IND 134547), is a Phase 1 
study of dostarlimab and TSR-033 (anti-lymphocyte-activation gene 3 [LAG-3]) 
combination therapy in advanced solid tumors.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 39 of 166 
 
 Study 3000-02-001 (JASPER; GSK Study 213352) (IND 134426), is a Phase 2 
multi-arm study of dostarlimab in combination with niraparib in participants with 
NSCLC. 
 Study 3000-03-005 (FIRST; GSK Study 213350) (IND 126472), is a Phase 3, 
randomized, double-blind study comparing platinum-based therapy with dostarlimab 
and niraparib versus standard-of-care platinum-based therapy as first-line treatment of 
ovarian cancer 
 Study 3000-02-005 (OPAL; GSK Study 213357) (IND 100996), is a Phase 2 
multi-cohort study to evaluate the safety and efficacy of novel treatment combination 
in participants with recurrent ovarian cancer. 
 Study 3000-02-006 (MOONSTONE; GSK Study 213353) (IND 100996), is a Phase 2 
single-arm study of niraparib in combination with dostarlimab to evaluate the efficacy 
and safety in participants with advanced, relapsed, high-grade ovarian cancer who 
have platinum-resistant disease or for whom further platinum therapy is not 
appropriate. 
 Study 4010-03-001 (RUBY; GSK Study 213361) (IND 126472), is a Phase 3, 
randomized, double-blind study comparing dostarlimab in combination with 
platinum-based therapy versus standard-of-care platinum-based therapy efficacy in 
participants with recurrent and primary advanced EC. 
Study 4010-01-001 (GARNET; GSK 213346) is the most relevant study with respect to 
this protocol and is discussed in more detail in the following section. Additional 
information on the clinical development program is contained within the dostarlimab 
Investigator’s Brochure (IB). 
2.2.5.1. 
Efficacy of Dostarlimab in NSCLC  
Study 4010-01-001 (GARNET; GSK Study 213346), titled “A Phase 1 Dose Escalation 
and Cohort Expansion Study of TSR-042, an anti-PD-1 Monoclonal Antibody, in Patients 
with Advanced Solid Tumors,” is a multicenter, open-label, first-in-human, Phase 1/2 
study evaluating dostarlimab in participants with advanced solid tumors whose disease 
has progressed following treatment with available therapies, with dose escalation and 
fixed-dose safety evaluation phases in participants with advanced solid tumors and a dose 
expansion phase in specific tumor types, including NSCLC. 
Preliminary clinical data from the GARNET study’s NSCLC cohort show that 
dostarlimab monotherapy (500 mg Q3W for first 4 cycles and 1,000 mg every 6 weeks 
[Q6W] for all subsequent cycles) provides clinical benefits to participants with NSCLC. 
As of 08 July 2019, 67 participants with previously treated NSCLC were treated and had 
follow-up of 12 weeks or longer. Eighteen out of 67 participants with NSCLC have 
achieved a confirmed CR or PR (26.9% ORR by RECIST v1.1). Among these responders 
7/18 (38.9%) were still in response. Activity was observed across all PD-L1 TPS 
categories, and encouraging activity was observed despite the fact that vast majority 
(90%) of participants with available PD-L1 status had a TPS <50%. As 01 March 2020, 
there are 7 participants still on treatment, 5 of which are responders. 
In summary, in immuno-oncology-naïve participants with previously treated advanced 
NSCLC, the efficacy of dostarlimab was comparable to the reported efficacy of other 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 40 of 166 
 
PD-1 inhibitors in similar NSCLC populations despite negative enrichment by TPS 
(Borghaei, Paz-Ares et al. 2015, Brahmer, Reckamp et al. 2015, Herbst, Baas et al. 2016). 
2.2.5.2. 
Safety of Dostarlimab  
Available data suggest that dostarlimab has a comparable safety profile to other PD1 
inhibitors, including pembrolizumab. Dostarlimab is being investigated in multiple 
ongoing studies, including the GARNET study, with approximately 1,000 participants 
enrolled across different disease types, both in monotherapy and in combination with 
other therapies. Dostarlimab has demonstrated an acceptable safety profile with 
manageable toxicity. The observed AEs were in line with those expected in patients with 
recurrent or advanced solid tumors and were consistent with reported safety profiles of 
mAbs blocking the PD-L1 interactions, including pembrolizumab . Detailed information 
about the safety of dostarlimab is included in the IB. 
Dostarlimab in NSCLC 
As of the data cutoff date of 01 March 2020, 67 participants with NSCLC had been 
treated with dostarlimab monotherapy in the GARNET study. Within this population, all 
participants experienced treatment-emergent adverse events (TEAEs) (100%) and 55% 
(n=37) experienced any Grade ≥3 TEAEs. The rate of serious adverse events (SAEs) was 
43.3% (n=29) and the rate of TEAEs leading to dostarlimab discontinuation was 10.4% 
(n=7). However, the rates of dostarlimab-related Grade ≥3 TEAEs was 13.4% (n=9) and 
dostarlimab-related SAEs (7.5%; n=5) were slightly lower than the overall rates. The rate 
of discontinuation due to dostarlimab-related TEAEs was low (10.4%; n=7) and there 
were no dostarlimab-related TEAEs leading to death. 
In the NSCLC group, 43.3% (n=29) of participants experienced any immune-related 
adverse event (irAE) and 7.5% (n=5) experienced Grade ≥3 irAEs that were determined 
to be related to dostarlimab. All of the dostarlimab-related Grade ≥3 irAEs occurred in 
1.5% of participants. Neither Grade ≥3 pneumonitis and or colitis occurred in any 
participants in this group. 
Dostarlimab as Monotherapy 
As of the data cutoff date of 01 March 2020, all of the 515 participants enrolled in 
GARNET who had received at least 1 dose of dostarlimab are included in the Safety 
Population. Dostarlimab was generally safe with manageable toxicity. The majority of 
participants reporting TEAEs did not experience serious TEAEs and did not experience 
TEAEs requiring treatment discontinuation. TEAEs reported in >20% of participants 
were anemia, fatigue, nausea, and diarrhea. Grade ≥3 TEAEs were reported in 50.3% of 
the Safety Population. Immune-related TEAEs (Grade ≥2 based on a predefined list) 
were reported in 34.8% of participants, and immune-related TEAEs related to 
dostarlimab were reported in 22.7% of the Safety Population. Serious immune-related 
TEAEs were reported in 5.0% of participants. TEAEs leading to death were reported in 
2.7% of participants. No deaths resulting from TEAEs that were assessed as related to 
dostarlimab were reported. 
Dostarlimab as Combination Therapy 
As of the IB data cutoff date of 21 January 2020, the population of participants who 
received dostarlimab with chemotherapy was 27 participants, as compared to 535 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 41 of 166 
 
participants who received monotherapy. Those participants received dostarlimab in 
combination with a variety of chemotherapy regimens, including, but not limited to: 
carboplatin, paclitaxel, and bevacizumab; FOLFIRI and bevacizumab; and FOLFOX and 
bevacizumab. Rates of any TEAE were similar between the 2 groups. Rates of any Grade 
≥3 TEAEs and any SAEs were higher with combination therapy. However, rates of 
dostarlimab-related Grade ≥3 TEAEs were similar between the groups and 
dostarlimab-related SAEs were slightly lower in the combination group. Rates of 
discontinuation due to dostarlimab-related TEAEs were low in both groups. Rates of 
irAEs were also similar in the combination therapy and monotherapy therapy groups.  
For further safety information, refer to the current version of the IB. 
2.2.6. 
Pembrolizumab  
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2 ligands. Based on 
nonclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  
2.2.6.1. 
Pembrolizumab in NSCLC  
Pembrolizumab (KEYTRUDA®) is approved in the US and EU for multiple NSCLC 
indications . As described in Section 2.2.4, the safety of pembrolizumab in combination 
with chemotherapy was determined in patients with advanced non-squamous NSCLC 
who had documented disease progression following treatment with platinum-based 
chemotherapy in the KEYNOTE-189 study.  
For more details, refer to the approved prescribing information for pembrolizumab.  
2.3. 
Benefit/Risk Assessment  
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of dostarlimab may be found in the IB. More detailed 
information regarding the expected benefits and risks of pembrolizumab can be found in 
local approved product labels (KEYTRUDA Prescribing Information 2020, KEYTRUDA 
Summary of Product Characteristics 2020). 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 42 of 166 
 
2.3.1. 
Risk Assessment  
Table 5: 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Dostarlimab and Pembrolizumab 
IRRs 
IRRs are a risk for all 
PD-(L)1 inhibitors.  
Infusion-related reactions, 
which may be severe, have 
been reported in association 
with dostarlimab and 
pembrolizumab. 
Participants will be closely 
monitored for signs of IRR.  
For severe (Grade 3) or 
life-threatening (Grade 4) 
IRRs associated with 
dostarlimab, infusion should 
be stopped, and treatment 
should be permanently 
discontinued. 
Management of IRRs is 
provided in Table 14. 
irAEs 
irAEs, which may be severe 
or fatal, can occur in patients 
treated with monoclonal 
antibodies directed against 
immune checkpoints, 
including pembrolizumab and 
dostarlimab. While irAEs 
(e.g., diarrhea/colitis, 
pneumonitis, nephritis, 
hypophysitis, adrenalitis, 
thyroiditis, severe skin 
reactions, uveitis, 
myocarditis, and 
hepatotoxicity) usually occur 
during treatment, symptoms 
can also manifest after 
discontinuation of treatment. 
irAEs may occur in any organ 
or tissue and may affect more 
than one body system 
simultaneously. 
Participants with the 
following medical history are 
ineligible for this study: 
 
Toxicity (Grade 3) 
related to prior 
immunotherapy leading 
to study treatment 
discontinuation  
 
Active autoimmune 
disease  
 
Severe hypersensitivity to 
another mAb 
Established management 
algorithms for irAEs: refer to 
Section 6.4.2.1 for further 
details on the identification, 
evaluation, and management 
of toxicities, including 
cumulative effects, with a 
potential immune etiology. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 43 of 166 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Participants exposed to 
ionizing radiation as a 
consequence of participation 
in this study. Some of the 
radiation exposure required 
by the study is additional to 
routine clinical care. 
The ionizing radiation 
exposure arises due to the 
inclusion in the study of CT 
scans.  
The risk arising from the 
additional radiation burden is 
considered justified by the 
benefit of the clinical 
information to be obtained, 
which is critical to the study 
and cannot readily be 
obtained another way. The 
effective dose of radiation for 
these procedures is 
approximately 20 mSv per 
combined CT examination of 
the Chest and Abdomen. For 
comparison, the average 
global yearly background 
radiation dose is 2.4 mSv. 
The study has been designed 
to keep the radiation dose as 
low as reasonably practicable 
(ALARP) whilst obtaining 
images of sufficient quality to 
meet the objectives. 
Abbreviations: AE=adverse event; irAE=immune-related adverse event; IRR=infusion-related reaction; 
mAb=monoclonal antibody; PD-(L)1=programmed cell death protein 1/(programmed death-ligand 1). 
2.3.2. 
Benefit Assessment  
Preliminary clinical data from Study 4010-01-001 (GARNET; GSK Study 213346) show 
that dostarlimab monotherapy provides clinical benefits to participants with NSCLC. As 
of the 08 July 2019 data cutoff, 67 participants with NSCLC were treated and had 
follow-up of 12 weeks or longer. Eighteen out of 67 participants with NSCLC have 
achieved a confirmed CR or PR (26.9% ORR by RECIST v1.1. Among these responders, 
7 out of 18 (38.9%) were still in response. Activity was observed across all PD-L1 TPS 
categories, and encouraging activity was observed despite the fact that the vast majority 
(90%) of participants with available PD-L1 status had a TPS <50%. 
In summary, in participants with previously treated advanced NSCLC, the efficacy of 
dostarlimab was comparable to the reported efficacy of other PD-1 inhibitors in similar 
NSCLC populations despite negative enrichment by TPS (Borghaei, Paz-Ares et al. 2015, 
Herbst, Baas et al. 2016, Borghaei, Langer et al. 2019). 
2.3.3. 
Overall Benefit/Risk Conclusion  
Considering the measures taken to minimize risk to participants taking part in this study, 
the potential risks identified in association with dostarlimab are justified by the 
anticipated benefits that may be afforded to participants with NSCLC. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 44 of 166 
 
3. 
OBJECTIVES AND ENDPOINTS  
Table 6: 
Objectives and Endpoints for Study 213403 
Objectives 
Endpoints 
Primary 
 
To compare the ORR of PD-1 inhibitor 
dostarlimab vs pembrolizumab administered 
in combination with chemotherapy as 
evaluated using RECIST v1.1 based on BICR 
in participants with metastatic non-squamous 
NSCLC, without a known EGFR, ALK, 
ROS-1, or BRAF V600E mutation or other 
genomic aberration for which a targeted 
therapy is available, who have received no 
prior treatment of metastatic disease 
 
The primary efficacy endpoint ORR will be 
evaluated by RECIST v1.1 based on BICR 
and will be defined as the proportion of 
participants with BOR of CR or PR in the 
analysis population. 
Secondary 
 
To evaluate the following measures of clinical 
benefit of PD-1 inhibitor administered in 
combination with chemotherapy:  
 
OS 
 
PFS evaluated using RECIST v1.1 based 
on Investigator assessment 
 
 
OS will be defined as the time from the date 
of randomization to the date of death by any 
cause. 
 
PFS will be evaluated using RECIST v1.1 
based on Investigator assessment and will be 
defined as the time from the date of 
randomization to the date of PD or death by 
any cause, whichever occurs first. 
 
To evaluate the safety of PD-1 inhibitor in 
combination with chemotherapy 
 
Assess the incidence of TEAEs, SAEs, irAEs, 
TEAEs leading to death, and AEs leading to 
discontinuation occurring while participants 
are on treatment or up to 90 days after the last 
dose of study treatment. Clinical laboratory 
parameters (hematology, chemistry, thyroid 
function, urinalysis), vital signs, ECOG 
performance status, ECG parameters, physical 
examinations, and usage of concomitant 
medications will be collected. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 45 of 166 
 
Table 6: 
Objectives and Endpoints for Study 213403 (Continued) 
Objectives 
Endpoints 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 46 of 166 
 
Table 6: 
Objectives and Endpoints for Study 213403 (Continued) 
Objectives 
Endpoints 
Abbreviations: 
; ALK=anaplastic lymphoma kinase; 
BICR=blinded independent central review; 
; BRAF=proto-oncogene B-raf; 
 
 CR=complete response; 
; 
ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EGFR=epidermal growth factor 
receptor; 
 
 EOT=End-of-Treatment; 
 
 irAE=immune-related adverse event; 
 
; NSCLC=non-small cell lung cancer; ORR=objective response rate; OS=overall survival; 
PD=progressive disease; PD-1=programmed cell death protein 1; 
; 
PFS=progression-free survival;
 
 PR=partial response; 
 
 RECIST=Response Evaluation Criteria in Solid Tumors; ROS-1=receptor tyrosine kinase-1; 
SAE=serious adverse event; TEAE=treatment-emergent adverse event; 
 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 47 of 166 
 
4. 
STUDY DESIGN  
4.1. 
Overall Design  
This is a randomized, Phase 2, double-blind, 2-arm study to compare the efficacy and 
safety of PD-1 inhibitors dostarlimab and pembrolizumab, when administered in 
combination with chemotherapy, in male and female participants 18 years and older with 
non-squamous NSCLC without a known sensitizing EGFR, ALK, ROS-1, or BRAF 
V600E mutation or other genomic aberration for which an approved targeted therapy is 
available who have not received previous systemic anticancer therapy for metastatic 
disease.  
The study consists of a Screening Period (Day -28 to Day -1) for completion of all 
Screening assessments and subsequent randomization, a Treatment Period, an EOT Visit 
(within 7 days of the decision to discontinue treatment for any reason), a Safety 
Follow-up Period with a visit at 30 (+7) and 90 (+7) days after the last dose of study 
treatment, and a Post-treatment Follow-up Period with assessments occurring 180 days 
after the last dose of study treatment and every 90 (±14) days thereafter, continuing until 
death, withdrawal of consent, or the end of study data collection. During the Treatment 
Period, clinic visits will occur Q3W. Collection of AEs begins from the start of study 
treatment and according to the time points specified in the SoA (Table 4) and 
Section 7.5.1. Any SAEs assessed as related to study participation (e.g., study treatment, 
protocol-mandated procedures, invasive tests, or change in existing therapy) or related to 
a GSK product will be recorded from the time a participant consents to participate in the 
study. 
To be eligible for the study, participants must have documented PD-L1 status by the 
22C3 pharmDx assay (Agilent/Dako). If no prior PD-L1 result is available at the time of 
Screening, the participant can be tested locally using the aforementioned method, or 
central PD-L1 testing can be completed (refer to the Laboratory Manual for 
country-specific details of central assessment). For participants requiring PD-L1 testing 
at the time of study entry, an archival FFPE tumor tissue specimen, which may have been 
collected at any time prior to Screening, can be submitted for analysis within 28 days of 
the participant’s first dose. Specimens used to confirm diagnosis or collected after the 
participant has been diagnosed with metastatic disease will be preferred for determination 
of PD-L1 status. Both tissue block and freshly cut (within 6 months) slides (10 to 15) are 
acceptable. If no archival FFPE tumor tissue is available, a fresh tumor tissue biopsy 
should be obtained and tested within 28 days of the participant’s first dose. Biopsies 
obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if a 
fresh biopsy is not feasible. As the results of baseline PD-L1 status assessment will be 
used as a stratification factor in this study, results must be provided prior to 
randomization. Participants who do not have documented PD-L1 status and cannot 
provide archived or fresh tissue sample for PD-L1 testing will not be eligible for the 
study. 
Within 35 days prior to the first dose, participants must have a baseline tumor assessment 
of the chest and abdomen (including the entire liver and both adrenal glands). Other 
regions should be imaged as clinically indicated (e.g., pelvis, brain, etc). This assessment 
should be conducted by IV contrast-enhanced computed tomography (CT) or magnetic 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 48 of 166 
 
resonance imaging (MRI) scan. MRI should be used for abdominal (and pelvic) imaging 
if CT contrast is contraindicated, and, preferably, for IV contrast-enhanced imaging of 
the brain. The same imaging technique should be used in a participant throughout the 
study. The CT component of positron emission tomography (PET)/CT may be used 
according to RECIST v1.1 guidelines, with full radiation dose diagnostic CT and IV CT 
contrast, and as clinically indicated. At each post-baseline assessment, evaluations of the 
sites of the disease identified by these scans are required. 
Following informed consent and completion of all Screening assessments, all participants 
who meet the eligibility criteria will be randomized 1:1 to receive chemotherapy in 
combination with either dostarlimab or pembrolizumab. Randomization will be 
completed in a blinded manner using an interactive web response system. Dostarlimab 
and pembrolizumab must be dispensed in a blinded manner. Details of blinding will be 
documented in site-specific blinding plans. The dosing regimen is described in 
Section 6.1.4. Randomization will be stratified by the following 2 factors: 
 PD-L1 status of the tumor (TPS <1% vs 1% to 49% vs ≥50%) 
 Smoking status (never vs former/current) 
To support continued tumor assessment while on study, serial imaging will then be 
performed at 6 weeks (42 [±7] days) and again at 12 weeks (84 [±7] days) from the 
randomization date. Following the 12-week scan, imaging will be performed Q9W (every 
63 [±7] days), or more frequently, if clinically indicated. After 48 weeks, participants 
who remain on treatment will have imaging performed Q12W (every 84 [±7] days). 
Imaging should continue to be performed until discontinuation of study treatment due to 
disease progression with clinical instability, start of subsequent anticancer treatment, 
withdrawal of informed consent, or death, whichever comes first. Imaging must be 
performed on a calendar schedule and should not be affected by dose 
interruptions/delays. All radiographic images/scans at the specified time points, as well as 
any unscheduled images/scans, will be collected and stored centrally for BICR, potential 
future evaluation, and archiving. Digital copies of all DICOM-formatted scans must be 
maintained at the Investigative site as source documents. 
Following the initial radiologic assessment of progressive disease (PD), clinically stable 
participants should continue study treatment and a follow-up scan should be performed at 
least 4 weeks and no longer than 8 weeks later. The follow-up scan will provide 
additional information to the Investigator for participant management and further 
treatment decisions. Further guidance for the assessment of scans acquired after RECIST 
v1.1-defined PD are provided in Appendix 1. For participants who are not clinically 
stable (clinically progressing) at the initial radiologic assessment of PD, study treatment 
will be discontinued and a follow-up scan is not required. Following the initial radiologic 
assessment of CR or PR, a confirmatory follow-up scan should be performed at least 4 
weeks later. 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 49 of 166 
 
Biomedical Research  
Number of Participants  
Approximately 240 participants will be randomly assigned to 2 study treatments, such 
that approximately 120 evaluable participants in each of the 2 arms complete the study.  
Treatment Groups and Duration  
Participants will be randomized in a 1:1 ratio into the dostarlimab plus chemotherapy arm 
or the pembrolizumab plus chemotherapy arm. Prior to randomization, Investigators will 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 50 of 166 
 
select, based on their clinical judgment, cisplatin or carboplatin as the chemotherapy to 
be administered. Randomization will be stratified by PD-L1 status of the tumor (TPS 
<1% versus 1% to 49% versus ≥50%) and smoking status (never vs former/current). A 
PD-L1 result obtained prior to Screening is allowed.  
The study will last approximately 5 years. 
4.2. 
Scientific Rationale for Study Design  
The design of the proposed similarity study relies, in part, on the estimated treatment 
effect of pembrolizumab plus chemotherapy from 3 adequate and well-controlled studies 
(KEYNOTE studies) where said regimen was shown to be superior to chemotherapy 
alone (Langer, Gadgeel et al. 2016, Gandhi, Rodríguez-Abreu et al. 2018, Paz-Ares, Luft 
et al. 2018). The robustness of these studies in design and conduct help provide a reliable 
estimate of pembrolizumab’s effect. The proposed study follows KEYNOTE studies with 
respect to important study design features, including patient population and dosing of 
reference products.  
4.3. 
Justification for Dose  
As determined in the Phase 1/2 Study 4010-01-001 (GARNET; GSK Study 213346), the 
recommended clinical dose of dostarlimab deemed safe and effective is 500 mg Q3W for 
4 cycles, followed by 1,000 mg Q6W. To allow for comparison between the 2 arms of 
this study, dostarlimab dosing will remain at 500 mg Q3W dosing for all cycles (up to 35 
total) to align with Q3W dosing of the comparator regimen. 
Additional dose justification information for dostarlimab can be found in the IB. 
4.4. 
End of Study Definition  
The end of the study is defined as 5 years after the first participant received the first dose 
of study treatment. 
A participant is considered to have completed the study if he/she has completed all 
phases of the study including the last visit or meets the criteria in Section 5.8. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 51 of 166 
 
5. 
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria  
Participants are eligible to be included in the study only if all of the following criteria 
apply: 
1. Participant must be ≥18 years old, must be able to understand the study 
procedures, and agrees to participate in the study by providing written informed 
consent (as described in Appendix 4), which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol. 
2. Participant has histologically- or cytologically-confirmed metastatic 
non-squamous NSCLC with documented absence of a sensitizing EGFR, ALK, 
ROS-1, or BRAF V600E mutation or other genomic aberration for which an 
approved targeted therapy is available. Mixed tumors will be categorized by the 
predominant cell type; if the tumor has predominantly squamous cell histology or 
if small cell elements are present, the participant is ineligible. 
3. Participants must have measurable disease, i.e., presenting with at least 1 
measurable lesion per RECIST v1.1 as determined by the local site 
Investigator/radiology assessment. Measurable lesions situated in a previously 
irradiated area may be considered target lesions if progression has been 
demonstrated in such lesions and if there are other target lesions. If there is only 1 
target lesion that was previously irradiated, the participant is not eligible. See 
Appendix 1 for the definition of a measurable lesion. 
4. Participant has documented PD-L1 status by the 22C3 pharmDx assay 
(Agilent/Dako). If no prior PD-L1 result is available at the time of Screening, the 
participant can be tested locally using the stated method, or central PD-L1 testing 
can be completed. Results are needed for stratification and must be available prior 
to randomization. 
5. Participant has an Eastern Cooperative Oncology Group (ECOG) performance 
status score of 0 or 1. 
6. Participant has a life expectancy of at least 3 months.  
7. Participant has adequate organ function as defined in Table 7. (Note: A complete 
blood count test should be obtained without transfusion or receipt of 
colony-stimulating factors within 2 weeks of obtaining the sample.) 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 52 of 166 
 
Table 7: 
Adequate Baseline Organ Function Inclusion Criteria 
System 
Laboratory Values 
Notes 
Hematologic 
 ANC 
≥1.5×109/L 
 
 Hemoglobin 
≥9 g/dL  
 
 Platelets 
≥100×109/L 
 
Hepatic 
 ALT 
See Exclusion Criterion 5. 
 Bilirubin  
Renal 
 Serum creatinine 
 (OR creatinine clearance) 
≤1.5×ULN 
(OR ≥50 mL/min) 
Creatinine clearance calculated 
by the Cockcroft-Gault formula 
(or measured using 24-hour 
creatinine clearance) for 
participants with creatinine levels 
>1.5×institutional ULN 
Abbreviations: ALT=alanine aminotransferase; ANC=absolute neutrophil count; ULN=upper limit of 
normal. 
8. Participant has recovered to Grade ≤1 from any prior treatment-related toxicities 
at the time of randomization. A participant with Grade 2 alopecia is an exception 
to this criterion and may qualify for this study. 
9. Contraceptive use by male and female participants should be consistent with local 
regulations regarding the methods of contraception for those participating in 
clinical studies. 
a. Male participants are eligible to participate if they agree to the following 
during the Treatment Period and for at least 180 days after the last dose of 
study treatment. (Note: duration of contraceptive use after last dose of 
chemotherapy must be consistent with local requirements and local approved 
product labels; however, the minimum duration is 180 days after last dose of 
chemotherapy) 
 Refrain from donating sperm 
PLUS, either:  
 Be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent.  
OR 
 Must agree to use contraception/barrier as follows: 
 Agree to use a male condom (and should also be advised of the benefit for 
a female partner to use a highly effective method of contraception, as a 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 53 of 166 
 
condom may break or leak) when having sexual intercourse with a woman 
of childbearing potential (WOCBP) who is not currently pregnant. 
 Agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
b. A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and 1 of the following conditions applies: 
 Is a woman of non-childbearing potential (WONCBP), as defined in 
Appendix 5. 
OR 
 Is a WOCBP, as defined in Appendix 5, using a contraceptive method that is 
highly effective (with a failure rate of <1% per year and, preferably, with low 
user dependency, as described in Appendix 5) during the Treatment Period 
and for at least 180 days after the last dose of study treatment and agrees not 
to donate eggs (ova or oocytes) for the purpose of reproduction during this 
period. (Note: duration of contraceptive use after last dose of chemotherapy 
may be longer than 180 days in order to comply with local requirements and 
local approved product labels). Contraceptive use should be consistent with 
local regulations regarding the methods of contraception for those 
participating in clinical studies. The Investigator should evaluate the potential 
for contraceptive method failure (e.g., noncompliance and recently initiated) 
in relationship to the first dose of study treatment. 
 A WOCBP must have a negative highly sensitive pregnancy test (urine or 
serum, as required by local guidelines) within 72 hours before the first 
dose of study treatment. If a urine test cannot be confirmed as negative 
(e.g., an ambiguous result), a serum pregnancy test is required. In such 
cases, the participant must be excluded from participation if the serum 
pregnancy result is positive. 
Note: Additional requirements for pregnancy testing during and after study 
treatment are located in Section 7.4.7. 
Note: The Investigator is responsible for review of medical history, menstrual 
history, and recent sexual activity to decrease the risk for inclusion of a 
woman with an early undetected pregnancy 
5.2. 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
1. Participant has received prior systemic therapy for the treatment of metastatic 
NSCLC. Participants who have received neoadjuvant or adjuvant chemotherapy 
are eligible if the neoadjuvant/adjuvant therapy was completed at least 12 months 
prior to the development of metastatic disease. 
2. Participant has received prior therapy with a PD-(L)1 or PD-L2 inhibitor, a 
CTLA-4 inhibitor, a TIM-3 inhibitor, or any other immunotherapy agent (e.g., 
OX40) for the treatment of cancer.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 54 of 166 
 
3. Participant has received radiation to the lung that is >30 Gy within 6 months of 
the first dose of study treatment. 
4. Participant has completed palliative radiotherapy within 7 days of the first dose of 
study treatment. 
5. Participant is ineligible if any of the following hepatic characteristics are present: 
a. ALT >2.5×upper limit of normal (ULN) without liver metastases/tumor 
infiltration 
b. ALT >5×ULN with liver metastases/tumor infiltration  
c. Bilirubin >1.5×ULN (isolated bilirubin >1.5×ULN is acceptable if bilirubin is 
fractionated and direct bilirubin is <35%) 
d. Current active liver or biliary disease (with the exception of Gilbert’s 
syndrome or asymptomatic gallstones, liver metastases, or otherwise stable 
chronic liver disease per Investigator assessment) 
Note: Stable chronic liver disease should generally be defined by the absence 
of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or 
gastric varices, persistent jaundice, or cirrhosis 
6. Participant has a corrected QT interval (QTc) >450 msec (or QTc >480 msec for 
participants with bundle branch block). 
Notes: 
 The QTc is the QT interval corrected for heart rate according to Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read. 
 The specific formula that will be used to determine eligibility and 
discontinuation for an individual participant should be determined prior to 
initiation of the study. In other words, several different formulae cannot be 
used to calculate the QTc for an individual participant and then the lowest 
QTc value used to include or discontinue the participant from the study. 
 For purposes of data analysis, QTcB, QTcF, another QT correction formula, 
or a composite of available values of QTc will be used as specified in the 
Reporting and Analysis Plan (RAP). 
7. Participant has had major surgery within 3 weeks of the first dose of study 
treatment or has not adequately recovered from any AEs (Grade ≤1) and/or 
complications from any major surgery. Surgical implantation of a port catheter is 
not exclusionary. 
8. Participant has an additional malignancy or a history of prior malignancy, with 
the exception of adequately treated basal or squamous skin cancer, cervical 
carcinoma in situ, superficial bladder cancer without evidence of disease, other in 
situ cancers, or had a malignancy treated with curative intent and with no 
evidence of disease recurrence for 5 years since the initiation of that therapy.  
9. Participant has known active brain metastases and/or leptomeningeal metastases. 
Participants who have received prior therapy for their brain metastases and have 
radiographically stable central nervous system disease may participate, provided 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 55 of 166 
 
they are neurologically stable for at least 2 weeks before study entry and must be 
off corticosteroids within 3 days prior to the first dose of study treatment. Stable 
brain metastases by this definition should be established prior to the first dose of 
study treatment. Participants with known untreated, asymptomatic brain 
metastases (i.e., no neurological symptoms, no requirements for corticosteroids, 
no or minimal surrounding edema, and no lesions >1.5 cm) may participate, but 
will require regular imaging of the brain as a site of disease. 
10. Participant has tested positive for the presence of hepatitis B surface antigen or 
has a positive hepatitis C antibody test result at Screening, or within 3 months 
prior to first dose of study treatment.  
11. Participant has an active infection requiring systemic therapy within 1 week prior 
to the anticipated first dose of study treatment. 
12. Participant has known HIV (positive for HIV-1 or HIV-2 antibodies). 
13. Participant has active autoimmune disease that required systemic treatment in the 
past 2 years, is immunocompromised in the opinion of the Investigator, or is 
receiving systemic immunosuppressive treatment. (Note: Participants with 
splenectomy are allowed.) Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc) is not considered a form of systemic treatment. 
14. Participant has received systemic steroid therapy within 3 days prior to the first 
dose of the study treatment or is receiving any other form of immunosuppressive 
medication. Replacement therapy is not considered a form of systemic therapy. 
Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is 
allowed. 
15. Participant has symptomatic ascites or pleural effusion. A participant who is 
clinically stable following treatment of these conditions (including therapeutic 
thoraco- or paracentesis) is eligible. 
16. Participant has current interstitial lung disease, current pneumonitis, or a history 
of pneumonitis that required the use of oral or IV glucocorticoids to assist with 
management. Lymphangitic spread of the NSCLC is not exclusionary.  
17. Participant has a history or current evidence of any medical condition, therapy, or 
laboratory abnormality that might confound the study results, interfere with their 
participation for the full duration of the study treatment, or indicate it is not in the 
best interest of the participant to participate, in the opinion of the Investigator.  
18. Participant has clinically active diverticulitis, intra-abdominal abscess, 
gastrointestinal obstruction, or peritoneal carcinomatosis. 
19. Participant has pre-existing peripheral neuropathy that is Grade ≥2 by National 
Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) v5.0 criteria. 
20. Participant has received a live vaccine within 30 days of the first dose of study 
treatment. Seasonal flu vaccines that do not contain live virus are permitted.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 56 of 166 
 
21. Participant does not meet requirements per local prescribing guidelines for 
receiving treatment with either pemetrexed and cisplatin or carboplatin. 
22. Participant has sensitivity to any of the study treatments, or components thereof, 
or a history of drug or other allergy that, in the opinion of the Investigator or GSK 
Medical Monitor, contraindicates their participation.  
23. Participant is unable to interrupt aspirin or other nonsteroidal anti-inflammatory 
drugs (NSAIDs), other than an aspirin dose ≤1.3 g per day, for a 5-day period 
(8-day period for long-acting agents, such as piroxicam). 
5.3. 
Lifestyle and/or Dietary Considerations  
There are no identified lifestyle and/or dietary considerations or restrictions for this 
study. 
5.4. 
Screen Failures  
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently randomized into the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, any protocol deviations 
and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. 
5.5. 
Criteria for Temporarily Delaying  
Planned dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons not related to study treatment (e.g., elective surgery, unrelated medical 
events, participant vacation, or holidays). Participants should be placed back on study 
treatment within 3 weeks of the scheduled interruption, unless otherwise discussed with 
the Sponsor. The reason for interruption or discontinuation of treatment should be 
recorded in the electronic case report form (eCRF). 
5.6. 
Withdrawal/Stopping Criteria  
Participants will receive study treatment until any of the following occurs: 
 Progressive disease (PD) according to RECIST v1.1 AND* the participant is 
clinically unstable, defined as follows: 
 Worsening of performance status 
 Clinically relevant increase in disease-related symptoms 
 Requirement for intensified management of disease-related symptoms 
(e.g., analgesics, radiation, palliative care) 
*Note: PD according to RECIST v1.1 alone is NOT a reason to discontinue study 
treatment. Clinically stable participants with RECIST v1.1-defined PD should 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 57 of 166 
 
continue study treatment and a follow-up scan should be performed at least 4 weeks 
and no longer than 8 weeks later. The follow-up scan will provide additional 
information to the Investigator for participant management and further treatment 
decisions. Further guidance for the assessment of scans acquired after RECIST 
v1.1-defined PD are provided in Appendix 1. 
 Unacceptable toxicity or other adverse event, that cannot be managed by dose 
modification (including meeting stopping criteria for liver chemistry defined in 
Section 5.6.1) 
 Death 
 Request of the participant or proxy (withdrawal of consent by subject or proxy) 
 Participant is lost to follow-up  
 Participant has received PD-1 inhibitor treatment for a maximum of 35 cycles total 
(approximately 24 months) 
 It is in the best interest of the participant as judged by the Investigator and/or Sponsor 
 Participant becomes pregnant 
In addition, study treatment may be permanently discontinued for any of the following 
reasons: 
 Deviation(s) from the protocol 
 Study is closed or terminated 
The primary reason study treatment was permanently discontinued must be documented 
in the participant’s medical records and eCRF.  
All participants who permanently discontinue study treatment without disease 
progression will be followed for progression according to the protocol schedule until any 
of the following occurs: 
 Initiation of new anti-cancer therapy 
 Disease progression 
 Death 
All participants who permanently discontinue study treatment will be followed for 
survival and new anti-cancer therapy, including radiotherapy. If participants are unable or 
unwilling to attend clinic visits during Follow-up, contact to assess survival may be made 
via another form of communication (e.g., phone, email, etc.). 
If the participant voluntarily discontinues from treatment due to toxicity, ‘adverse event 
(AE)’ will be recorded as the primary reason for permanent discontinuation on the eCRF.  
Once a participant has permanently discontinued from study treatment, the participant 
will not be allowed to be retreated.  
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 58 of 166 
 
All participants who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in the SoA 
(Table 4).  
5.6.1. 
Liver Chemistry Stopping Criteria  
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure participant safety and evaluate liver event etiology. 
Discontinuation of study treatment for abnormal liver tests is required when the following 
occurs: 
 A participant meets one of the conditions outlined in the Liver Chemistry Stopping 
and Increased Monitoring Algorithm (Figure 2) 
OR 
 In the presence of abnormal liver chemistry not meeting protocol-specified stopping 
rules, if the Investigator believes that it is in the best interest of the participant. 
Figure 2: 
Liver Chemistry Stopping and Increased Monitoring Algorithm 
 
Abbreviations: ALT=alanine aminotransferase; INR=international normalized ratio; SAE=serious adverse 
event; ULN=upper limit of normal. 
*INR value not applicable to participants on anticoagulants. 
Liver safety required actions and follow-up assessments can be found in Appendix 6. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 59 of 166 
 
5.6.1.1. 
Restart/Rechallenge After Liver Stopping Criteria Met  
If participant meets liver chemistry stopping criteria, do not restart/rechallenge 
participant with study treatment unless all of the following occurs: 
 GSK Medical Governance approval is granted 
AND 
 Ethics and/or IRB approval is obtained, if required 
AND 
 Separate consent for intervention restart/rechallenge is signed by the participant 
Note: If study treatment was interrupted for suspected drug-induced liver injury, the 
participant should be informed of the risk of death, liver transplantation, hospitalization, 
and jaundice and re-consented before resumption of dosing. 
 Refer to Appendix 7 for details on the restart/rechallenge process. 
 If GSK Medical Governance approval to restart/rechallenge participant with study 
treatment is not granted, then the participant must permanently discontinue study 
treatment and may continue in the study for protocol-specified follow-up 
assessments. 
5.6.2. 
QTc Stopping Criteria  
If a participant meets the following QTc criteria, they must be discontinued from the 
study. 
 QTc >500msec  
OR 
 Change from baseline of QTc >60 msec 
For participants with underlying bundle branch block, follow the discontinuation 
criteria in Table 8. 
Table 8: 
Bundle Branch Block QTc Discontinuation Criteria 
Baseline QTc with Bundle Branch Block 
Discontinuation QTc with Bundle Branch 
Block 
<450 msec 
>500 msec 
450 to 480 msec 
≥530 msec 
5.7. 
Lost to Follow-up  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
 The site must attempt to contact the participant, reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 60 of 166 
 
schedule, and ascertain whether or not the participant wishes to and/or should 
continue in the study. 
 Before a participant is deemed lost to follow-up, the Investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record. 
 Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
 Site personnel, or an independent third party, will attempt to collect the vital status of 
the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get study treatment. Public sources may be searched for 
vital status information. If vital status is determined as deceased, this will be 
documented, and the participant will not be considered lost to follow-up. Sponsor 
personnel will not be involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are outlined in Appendix 4. 
5.8. 
Participant and Study Completion  
A participant will be considered to have completed the study as per the end of study 
definition in Section 4.4, if the participant dies during the Treatment or Follow-up Period, 
withdraws from the study, or completes the last study related visit or contact, whichever 
is sooner. If a participant dies, document the cause of death in the eCRF. A participant 
will be considered to have withdrawn from the study if the participant has not died and is 
lost to follow up, has withdrawn consent, at the Investigator’s discretion is no longer 
being followed, or if the study is closed/terminated. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 61 of 166 
 
6. 
STUDY TREATMENTS AND CONCOMITANT THERAPY  
Study treatment is defined as any investigational treatment(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according 
to the study protocol. 
Study treatments to be administered in this study are summarized in Table 9 and 
Section 6.1.1, Section 6.1.2, and Section 6.1.3. For further details, refer to the Pharmacy 
Manual (dostarlimab) or to the product labels. 
6.1. 
Study Treatments Administered  
Table 9: 
Study Treatments for Study 213403 
Arm Name 
Dostarlimab 
Pembrolizumab 
Chemotherapy Standard of Care (BOTH 
Arms) 
Treatment 
name 
Dostarlimab 
Pembrolizumab 
Pemetrexed 
Cisplatin 
Carboplatin 
Type 
Biologic 
Biologic 
Drug 
Drug 
Drug 
Dose 
formulation 
Solution 
Solution 
Solution 
Solution 
Solution 
Unit dose 
strength 
500 mg Q3W 
200 mg  
Q3W 
500 mg/m2 
Q3W 
75 mg/m2 
Q3W for 
4 cycles 
AUC 5 
mg/mL/min 
Q3W for 
4 cycles 
Route of 
administration 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
IV infusion 
Use 
Experimental 
Comparator 
Background 
intervention 
Background 
intervention 
Background 
intervention 
Sourcing 
Provided 
centrally by 
the Sponsor 
May be provided 
centrally by the 
Sponsor or 
locally by the 
study site 
May be 
provided 
centrally by 
the Sponsor 
or locally by 
the study site 
May be 
provided 
centrally by 
the Sponsor 
or locally by 
the study site 
May be 
provided 
centrally by 
the Sponsor 
or locally by 
the study site 
Packaging and 
labeling 
Study 
treatment will 
be provided in 
a single-use 
vial. Each vial 
will be labeled 
as required per 
country 
requirements. 
Study treatment 
will be provided 
in a single-use 
vial. Each vial 
will be labeled 
as required per 
country 
requirements. 
Study 
treatment will 
be labeled as 
required per 
country 
requirements 
Study 
treatment will 
be labeled as 
required per 
country 
requirements 
Study 
treatment will 
be labeled as 
required per 
country 
requirements 
Abbreviations: AUC=area under the concentration-time curve; ICF=informed consent form; Q3W=every 
3 weeks; SRM=study reference manual. 
Note: These formulation details are current at the time of protocol finalization and may be updated in other 
documents (e.g., SRM and/or ICF) without requiring protocol amendment. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 62 of 166 
 
6.1.1. 
Dostarlimab  
Dostarlimab for IV infusion will be supplied by the Sponsor as a solution of 500 mg at a 
concentration of 50 mg/mL in a single-use vial. 
Dostarlimab will be administered through a 30-minute infusion at a dose of 500 mg IV 
Q3W up to a maximum of 35 cycles total (approximately 24 months).  
Sites should make every effort to target the infusion timing to be as close to 30 minutes 
as possible. Given the variability of infusion pumps from site to site, however, a window 
between-5 and +15 minutes is permitted.  
6.1.2. 
Pembrolizumab  
Pembrolizumab for injection may be supplied by the Sponsor as a solution of 100 mg/4 
mL (25 mg/mL) in a single-use vial or may be obtained locally as a commercially 
available dosage formulation with reimbursement by the Sponsor. 
Pembrolizumab will be administered through a 30-minute infusion at a dose of 200 mg 
Q3W up to a maximum of 35 cycles total (approximately 24 months).  
Sites should make every effort to target the infusion timing to be as close to 30 minutes 
as possible. Given the variability of infusion pumps from site to site, however, a window 
between-5 and +15 minutes is permitted. 
6.1.3. 
Chemotherapy (Pemetrexed, Cisplatin, and Carboplatin)  
Pemetrexed, cisplatin, and carboplatin may be supplied by the Sponsor or may be 
obtained locally as a commercially available dosage formulation for infusion, with 
reimbursement by the Sponsor. 
Pemetrexed will be administered at 500 mg/m2 IV through an IV infusion Q3W, up to a 
maximum of 35 cycles total (approximately 24 months). Pre-treatment for pemetrexed 
(folic acid, vitamin B12, and glucocorticoids) must be administered according to local 
guidelines and product label. 
Platinum chemotherapy will be administered for the first 4 cycles only, following 
pemetrexed administration. Chemotherapeutic agents should be administered according 
to local practice and local approved product labels.  
If selected by the Investigator, cisplatin (75 mg/m2) will be given via IV infusion 
(approximately 30 minutes after pemetrexed infusion) for the first 4 cycles. For 
participants receiving cisplatin, pre- and post-treatment hydration procedures must be 
administered according to local practice and labels. 
If selected by the Investigator, carboplatin (area under the concentration-time curve 
5 mg/mL/min) will be given via IV infusion immediately following the pemetrexed 
infusion for the first 4 cycles.  
Anti-emetics and hydration may be prescribed per institutional guidance. Refer to local 
prescribing guidelines for additional information on the dose and instructions for 
administration of pemetrexed, cisplatin, and carboplatin.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 63 of 166 
 
6.1.4. 
Administration  
PD-1 inhibitor (dostarlimab or pembrolizumab) and chemotherapy will be administered 
at the study site on Day 1 of every 21-day cycle beginning with Cycle 1. After Cycle 1, 
treatment for subsequent cycles may be administered within a ±3-day window of the 
scheduled dosing day. Both PD-1 inhibitor and chemotherapy should be given on the 
same day of the window.  
The order of administration is: PD-1 inhibitor (dostarlimab or pembrolizumab) first, 
immediately followed by pemetrexed, and then followed by cisplatin or carboplatin 
(Cycles 1 to 4 only). Cisplatin (if selected by the Investigator), should be administered 
approximately 30 minutes after pemetrexed. Carboplatin (if selected by the Investigator) 
should be administered immediately following pemetrexed. 
6.2. 
Preparation/Handling/Storage/Accountability  
Preparation  
The Pharmacy Manual contains specific instructions for the preparation of study 
treatment and administration of the infusion solution. During the Treatment Period, 
dostarlimab and pembrolizumab will be prepared by an unblinded pharmacist or designee 
and dispensed in a blinded manner to the study staff for administration to participants. 
Handling and Storage (Including Disposal)  
1. The Investigator or designee must confirm appropriate temperature conditions 
have been maintained during transit for all study treatment received. Any 
discrepancies must be reported and resolved before use of the study treatment. 
2. Only participants enrolled in the study may receive study treatment, and only 
authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions, 
with access limited to the Investigator and authorized site staff. 
3. Precaution will be taken to avoid direct contact with the study treatment. A Safety 
Data Sheet describing occupational hazards and recommended handling 
precautions will be provided to the Investigator. In the case of unintentional 
occupational exposure, notify the Site Monitor, GSK Medical Monitor, and/or 
GSK study contact. 
4. At the end of the study, when all participants have discontinued study treatment, 
complete drug reconciliation per batch should be available at the site for 
verification in order to allow drug destruction or return procedure. After receiving 
Sponsor approval in writing, the investigational site is responsible for destruction 
of the study treatment according to local regulations. If a site does not have the 
capability for onsite destruction, the Sponsor will provide a return for destruction 
service through a third party. Both the unused and expired study treatment must 
be destroyed, upon authorization of the Sponsor, according to local regulations 
and procedures, and a copy of the destruction form must be filed in the study 
binder. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 64 of 166 
 
5. The medication provided for this study is to be used only as indicated in this 
protocol and only for the participants entered in this study. 
6. Further guidance and information for the final disposition of unused study 
treatment are provided in the Study Reference Manual.  
Accountability  
1. The Investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e., receipt, dispensation, reconciliation, and final 
disposition records) throughout the study. 
2. Details of maintaining drug accountability, including information on the 
accountability log, will be provided in the Pharmacy Manual. 
3. All dispensation and accountability records will be available for Sponsor review. 
The Study Monitor will assume the responsibility for reconciling the study 
treatment accountability log. The pharmacist will dispense study treatment for 
each participant according to the protocol and Pharmacy Manual, if applicable. 
6.3. 
Measures to Minimize Bias  
6.3.1. 
Method of Treatment Assignment: Randomization  
Following informed consent and completion of all Screening assessments, participants 
who meet the inclusion and exclusion criteria will be randomized in a 1:1 ratio to receive 
either dostarlimab plus chemotherapy or pembrolizumab plus chemotherapy. 
Randomization will be completed in a blinded manner using an interactive web response 
system. Randomization will be stratified by PD-L1 status of the tumor (TPS <1% vs 1% 
to 49% vs ≥50%) and smoking status (never vs former/current). 
It is recommended that participants receive the first dose of study treatment on the day of 
randomization. If Screening assessments were performed within 72 hours of Day 1, 
repeat testing is not required.  
6.3.2. 
Blinding  
Dostarlimab and pembrolizumab must be dispensed in a blinded manner. Details of 
blinding will be documented in site-specific blinding plans.  
In the event of a medical emergency where unblinding is deemed necessary to the care of 
the participant, the Investigator may have direct access to the participant’s treatment 
code. Detailed instructions for this process are provided in the Blinding Plan and a 
summary of the general process follows.  
Participants and blinded study staff may also be unblinded to study treatment in cases 
associated with important medical reasons, as determined by the Investigator, and for 
specific non-urgent medical events. The process for unblinding the identity of the 
assigned treatment is outlined in the Blinding Plan; refer to the current version of this 
document for the treatment unblinding process. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 65 of 166 
 
If an individual’s role on the study requires information about treatment assignment (e.g., 
an individual is involved in emergency unblinding), procedures will be used to ensure all 
other personnel remain blinded.  
In the event unblinding has occurred, the circumstances necessitating unblinding (i.e., 
date and details about the situation leading to unblinding) must be documented promptly, 
and the Unblinded Sponsor Clinical Study Manager notified as soon as possible. Only the 
Principal Investigator or delegate should be unblinded to the respective participant’s 
code. Study site personnel and Sponsor personnel directly associated with the conduct of 
the study should not be unblinded.  
If the Investigator decides that unblinding is warranted, the Investigator should make 
every effort to contact GSK prior to unblinding a participant’s treatment assignment 
unless this could delay emergency intervention of the participant. If a participant’s 
intervention assignment is unblinded GSK must be notified within 24 hours after 
breaking the blind. The date and reason that the blind was broken must be recorded in the 
source documentation and case report form, as applicable. 
GSK’s Global Clinical Safety and Pharmacovigilance staff may unblind the treatment 
assignment for any participant with an SAE. If the SAE requires that an expedited 
regulatory report be sent to 1 or more regulatory agencies, a copy of the report, 
identifying the participant’s treatment assignment, may be sent to the Investigators in 
accordance with local regulations and/or GSK policy. 
Participants who require unblinding will be discontinued from study treatment, but will 
remain on study until progression, start of subsequent anticancer treatment, withdrawal of 
informed consent, loss to follow-up, or death. 
6.4. 
Planned Dose Adjustments  
6.4.1. 
Dose Levels and Dose Adjustment  
PD-1 inhibitor (dostarlimab or pembrolizumab) dose reductions are not permitted. 
Chemotherapy dose reductions are provided in Table 10. Recommended dose 
modifications for key chemotherapy toxicities are provided in Table 11 and Table 12. 
These serve as a guide and do not replace Investigator judgment and applicable local 
label recommendation, if more stringent. 
If a dose reduction for toxicity occurs with any agent, the dose may not be re-escalated. 
Participants can have a maximum of 2 dose modifications (if applicable) to each of the 
chemotherapy components of study therapy throughout the course of the study for 
toxicities. If a participant experiences several toxicities and there are conflicting 
recommendations, the most conservative dose adjustment recommended should be 
followed (dose reduction appropriate to the most severe toxicity). Participants who 
require a third dose modification to any particular component will have that agent 
discontinued. 
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the 
opinion of the Investigator, the toxicity is clearly related to one of the treatments. If, in 
the opinion of the Investigator, the toxicity is related to the combination of both 
chemotherapy agents, both drugs should be reduced according to recommended dose 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 66 of 166 
 
modifications. If the toxicity is related to the combination of three agents, all three agents 
should be reduced (if applicable), interrupted, or discontinued according to the 
recommended dose modifications. Participants may have chemotherapy discontinued and 
continue on PD-1 inhibitor alone. The decision for participants to discontinue PD-1 
inhibitor and continue on chemotherapy alone will be made on a case by case basis and 
the Investigator may consider consultation with the Sponsor for this individualized 
decision. 
Chemotherapy may be interrupted for a maximum of 6 weeks. 
Table 10: 
Dose Modifications for Chemotherapies Used in Study 213403 
 
Dose Level 0 
(Starting Dose) 
Dose Level -1 
Dose Level -2 
Dose Level -3 
Pemetrexed 
500 mg/m2 
375 mg/m2 
250 mg/m2 
Discontinue 
Cisplatin 
75 mg/m2 
56 mg/m2 
38 mg/m2 
Discontinue 
Carboplatin 
AUC 5 mg/mL/min 
(maximum dose: 
750 mg) 
AUC 3.75 
mg/mL/min 
(maximum dose: 
562.5 mg) 
AUC 2.5 
mg/mL/min 
(maximum dose: 
375 mg) 
Discontinue 
Abbreviation: AUC=area under the concentration-time curve. 
Table 11: 
Recommended Dose Modifications for Hematological Chemotherapy 
Toxicities 
Hematologic Events 
Pemetrexed 
Dose Level 
(See 
Table 10) 
Cisplatin / 
Carboplatin 
Dose Level 
(See 
Table 10) 
Platelets (cells/μL) 
ANC (cells/μL) 
≥50,000 and 
≥500 
DL 0 
DL 0 
≥50,000 and 
<500 
DL -1 
DL -1 
<50,000 without bleeding and 
Any 
DL -1 
DL -1 
<50,000 with Grade ≥2 bleeding 
and 
Any 
DL -2 
DL -2 
Any and 
<1000 and fever ≥38.5°C 
(101°F) 
DL -1 
DL -1 
Abbreviations: ANC=absolute neutrophil count; DL=dose level. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 67 of 166 
 
Table 12: 
Recommended Dose Modifications for Non‑hematological 
Chemotherapy Toxicities 
Non-hematologic Events 
Pemetrexed 
Dose Level 
(See 
Table 10) 
Cisplatin Dose 
Level (See 
Table 10) 
Carboplatin 
Dose Level 
(See Table 10) 
Event 
NCI-CTCAE 
Grade 
Nausea or vomiting 
Grade 3 or 4 
DL -1 
DL -1 
DL 0 
Diarrhea 
Requiring 
hospitalization 
irrespective of 
grade, or 
Grade 3 or 4 
DL -1 
DL -1 
DL 0 
Mucositis 
Grade 3 or 4 
DL -2 
DL 0 
DL 0 
Neurotoxicity 
Grade 2 
DL 0 
DL -2 
DL 0 
Grade 3 or 4 
DL -1 
Discontinue 
DL -1 
Transaminase elevation 
Grade 3 
DL -1 
DL -1 
DL -1 
Grade 4 
Discontinue 
Discontinue 
Discontinue 
Other non-hematological toxicity Grade 3 or 4 
DL -1 
DL -1 
DL -1 
Abbreviations: DL=dose level; NCICTCAE=National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
6.4.2. 
Guidelines for Events of Special Interest  
The severity of AEs will be graded using the NCI-CTCAE v5.0. Guidelines for dose 
modifications and interruptions for management of common toxicities associated with the 
study treatment(s) are provided in this section.  
6.4.2.1. 
Management of PD-1 Inhibitor-related AEs  
PD-1 inhibitor (dostarlimab or pembrolizumab) treatment may be interrupted or 
discontinued due to toxicity. AEs (both nonserious and serious) associated with 
dostarlimab or pembrolizumab exposure may represent an immunologic etiology. These 
AEs may occur shortly after the first dose or several months after the last dose of study 
treatment. 
PD-1 inhibitor treatment must be withheld for Grade ≥3 toxicities, and certain irAEs, as 
described in Table 13. The recent joint American Society of Clinical Oncology and 
National Comprehensive Cancer Network guidelines for the diagnosis and management 
of irAEs treated with immune checkpoint inhibitor therapy may be used as a supplement 
to Table 13 (Brahmer, Lacchetti et al. 2018). The medical monitor can be contacted if 
there are additional questions about PD-1 inhibitor-related AE management. The 
maximum allowed drug interruption period for PD-1 inhibitors is 12 weeks. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 68 of 166 
 
Table 13: 
Dose Modification Guidelines for PD-1 Inhibitor-related AEs 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade ≤1 and continue to taper over at least 4 weeks. 
For situations where PD-1 inhibitor has been withheld, treatment can be resumed after AE has been reduced to Grade 1 and corticosteroid has been tapered. PD-1 
inhibitor should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone, or 
equivalent, per day, within 12 weeks.  
For severe and life-threatening irAEs, IV corticosteroid should be initiated first, followed by oral steroid. Other immunosuppressive treatment should be initiated if 
irAEs cannot be controlled by corticosteroids. 
Adrenal 
insufficiency 
Grade 2, 3 or 4 
Hold until administration 
of HRT results in return to 
adequate hormone levels 
based on laboratory values 
and restart dosing when 
toxicity resolves to Grade 
1.  
For recurrent or worsening 
Grade ≥2 adrenal 
insufficiency while 
adequate HRT is 
continuing, permanently 
discontinue study 
treatment. 
Start treatment with corticosteroids 
before other HRT to avoid adrenal 
crisis (hydrocortisone slowly titrating 
doses down according to symptoms OR 
prednisone and fludrocortisone titrating 
up or down based on BP, other 
symptoms, and labs); participants with 
severe symptoms may require 
additional fluids (e.g., saline >2 L). 
Monitor for cortisol level (AM), comprehensive 
metabolic panel (Na, K, CO2, glucose) and renin.  
 
Ensure adequate endocrine evaluation (e.g., 
Endocrine consultation). 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 69 of 166 
 
Table 13: 
Dose Modification Guidelines for PD1 Inhibitor related AEs (Continued) 
Immune-related AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
AST / ALT elevation 
or increased bilirubin 
or hepatitis 
Grade 2 with 
AST or ALT 
>3 to 5×ULN 
or total 
bilirubin 
>1.5 to 3×ULN 
Restart dosing when 
toxicity resolves to 
Grade 1 
Administer corticosteroids (initial dose 
of 0.5 to 1 mg/kg methylprednisolone 
or equivalent) followed by taper 
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value(s) return to baseline or are stable. 
See Section 5.6.1 and Appendix 6 for additional 
details on Liver Event Follow-up Assessments. 
Grade ≥3 with 
AST or ALT 
>5×ULN or 
total bilirubin 
>3×ULN  
Permanently discontinue2 
Administer corticosteroids (initial dose 
of 1 to 2 mg/kg methylprednisolone or 
equivalent) followed by taper 
Diarrhea / colitis  
Grade 2 or 3 
Restart dosing when 
toxicity resolves to 
Grade 1 
Administer corticosteroids (initial dose 
of 1 to 2 mg/kg methylprednisolone or 
equivalent) followed by taper 
Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e., peritoneal signs 
and ileus). 
Participants with Grade ≥2 diarrhea where 
colitis is suspected should consider GI 
consultation and an endoscopy to rule out 
colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion. 
Grade 4 or 
recurrent 
Grade 3 
Permanently discontinue 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 70 of 166 
 
Table 13: 
Dose Modification Guidelines for PD1 Inhibitor related AEs (Continued) 
Immune-related AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Severe neurologic 
events (myasthenic 
syndrome/myasthenia 
gravis, Guillain Barré 
Syndrome, transverse 
myelitis) 
Grade 2, 3 or 4 
Permanently discontinue 
Consider high dose corticosteroids and 
other therapies as needed. 
It is highly recommended that 
Investigators discuss any AEs with the 
Sponsor before using infliximab. 
Ensure adequate evaluation (e.g., neurology 
consultation). 
Consider MRI of brain and/or spine depending 
on symptoms. 
Consider inpatient management as clinically 
indicated. 
Hemophagocytic 
lymphohistiocytosis 
Any grade 
Permanently discontinue 
 
 
Hyperthyroidism 
Grade 3 or 4 
Hold until return to 
adequate hormone levels 
based on laboratory values 
and restart dosing when 
toxicity resolves to 
Grade 1. 
Treat with non-selective beta-blockers 
(e.g., propranolol) or thionamides as 
appropriate  
Monitor for signs and symptoms of thyroid 
disorders 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 71 of 166 
 
Immune-related AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Hypophysitis 
Grade 2, 3 or 4 
For Grade 2, 3 or 4, hold 
until administration of 
HRT results in return to 
adequate hormone levels 
based on laboratory values 
and restart dosing when 
toxicity resolves to 
Grade 1. For recurrence or 
worsening of Grade 2 
hypophysitis after steroid 
taper has been completed 
and patient is on adequate 
HRT, permanently 
discontinue. 
Administer corticosteroids and initiate 
HRT as clinically indicated 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Table 13: 
Dose Modification Guidelines for PD-1 Inhibitor-related AEs (Continued) 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
Hypothyroidism 
Grade 3 or 4 
Hold until administration 
of HRT results in return to 
adequate hormone levels 
based on laboratory values 
and restart dosing when 
toxicity resolves to Grade 
1. 
Initiate thyroid replacement hormones 
(e.g., levothyroxine or liothyronine) per 
standard of care 
Monitor for signs and symptoms of thyroid 
disorders.  
Monitor thyroid function tests. 
Ensure adequate evaluation (e.g., endocrine 
consultation). 
Exclude concomitant adrenal insufficiency (AM 
cortisol level). 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 72 of 166 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
Immune-related 
encephalitis 
Any grade 
Permanently discontinue 
Consider IV acyclovir until PCR results 
obtained. 
Trial with methylprednisolone; if 
severe, treatment with 
methylprednisolone. 
If positive for autoimmune 
encephalopathy antibody or no 
improvement after 7 to 14 days, 
consider rituximab. 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Infusion-related 
reaction  
See Table 14 
Myocarditis 
Grade 2, 3 or 4 
Permanently discontinue 
Administer high dose corticosteroids (1 
g/day of IV methylprednisolone) for 3 
to 5 days, followed by oral prednisone 
taper over 4 to 6 weeks based on 
improvement in cardiac function and 
biomarkers. 
If no improvement in 24 hours, 
consider adding other potent 
immunosuppressive agents. 
Ensure adequate evaluation (e.g., Urgent 
cardiology consultation) to confirm etiology 
and/or exclude other causes 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 73 of 166 
 
Table 13: 
Dose Modification Guidelines for PD-1 Inhibitor-related AEs (Continued) 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Restart dosing when 
toxicity resolves to 
Grade 1. If Grade 2 recurs, 
permanently discontinue. 
Administer corticosteroids (initial dose 
of 1 to 2 mg/kg methylprednisolone or 
equivalent) followed by taper 
Monitor participants for signs and symptoms of 
pneumonitis. 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment. 
Add prophylactic antibiotics for opportunistic 
infections. 
Grade 3 or 4, or 
recurrent Grade 
2 
Permanently discontinue 
Rash / skin reactions 
Grade 3 or 
suspected 
DRESS, SJS or 
TEN 
Withhold 
Treat with high potency topical steroids 
to affected areas. 
Treat with prednisone. 
Ensure adequate evaluation (e.g., urgent 
dermatology consultation) to confirm etiology 
and/or exclude other causes 
 
Grade 4 or 
confirmed 
DRESS, SJS or 
TEN 
Permanently discontinue 
Administer 1 to 2 mg/kg/day IV 
methylprednisolone and taper steroid 
when dermatitis is controlled. 
 
Recurrence of AEs 
after resolution to 
Grade ≤1 
Grade 1 or 2 
Withhold 
Based on severity of AEs, administer 
appropriate treatment until symptoms 
improve to Grade ≤2. 
 
Grade 3 or 4 
Permanently discontinue 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 74 of 166 
 
Table 13: 
Dose Modification Guidelines for PD-1 Inhibitor-related AEs (Continued) 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
Renal failure or 
nephritis 
Grade 2 with 
creatinine 
>1.5 to 
≤3×ULN 
Restart dosing when 
toxicity resolves to 
Grade 1. 
Start treatment with prednisone; if 
persistent Grade 2 beyond 1 week, 
prednisone/methylprednisolone. 
Monitor participants for signs and symptoms, 
including monitoring of creatinine and urine 
protein every 3 to 7 days. 
Ensure adequate evaluation (e.g., nephrology 
consultation) to confirm etiology and/or exclude 
other causes. 
Grade 3 with 
creatinine 
>3×ULN 
Permanently discontinue 
Start treatment with prednisone; if 
persistent Grade 2 beyond 1 week, 
prednisone/methylprednisolone. 
Consider adding one of the following 
after 1 week of steroids: azathioprine, 
cyclosporine, cyclophosphamide, 
infliximab, mycophenolate. 
Ensure adequate evaluation (e.g., nephrology 
consultation, renal biopsy) to confirm etiology 
and/or exclude other causes. 
Consider inpatient care. 
Type 1 diabetes 
mellitus (T1DM) or 
hyperglycemia 
Grade 3 to 4 
hyperglycemia 
or T1DM 
(associated with 
metabolic 
acidosis or 
ketonuria) 
Restart dosing in 
appropriately managed 
clinically and 
metabolically stable 
participants; insulin 
replacement therapy is 
required 
Initiate insulin replacement therapy for 
participants with T1DM. 
Administer anti-hyperglycemic in 
participants with hyperglycemia.  
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 
Uveitis 
Grade 2  
Withhold 
Urgent ophthalmology consultation. 
Administer treatment with ophthalmic 
and systemic 
prednisone/methylprednisolone. 
Ensure adequate evaluation (e.g., urgent 
ophthalmology consultation)  
 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 75 of 166 
 
Table 13: 
Dose Modification Guidelines for PD-1 Inhibitor-related AEs (Continued) 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(NCI-CTCAE 
v5.0) 
Action taken with PD-1 
inhibitor1 
irAE management with 
corticosteroid and/or other therapies  
Monitoring and follow-up  
Other irARs 
Based on 
severity and 
type of reaction 
(Grade 2 or 3) 
Restart dosing when 
toxicity resolves to 
Grade 1 
Based on severity of AE, administer 
corticosteroids. When controlled, taper 
steroid. 
Ensure adequate evaluation to confirm etiology 
and exclude other causes. 
 
Grade 4 or 
recurrent 
Grade 3 
Permanently discontinue 
 
 
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; DRESS= drug reaction with eosinophilia and systemic 
symptoms; HRT=hormone replacement therapy; irAR=immune related adverse reaction; PD-1=programmed cell death protein 1; SJS=Stevens Johnson syndrome; 
T1DM=Type 1 diabetes mellitus; TEN=toxic epidermal necrolysis. 
1. This table is reflective of pembrolizumab Summary of Product Characteristics guidance. 
2. For participants with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by ≥50% relative to baseline and lasts for at least 
1 week, then the participant should be discontinued. 
 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 76 of 166 
 
6.4.2.2. 
Management of Chemotherapy-related AEs  
Hematological and nonhematological AEs attributable to pemetrexed, carboplatin, and 
cisplatin should be managed according to guidelines in the prescribing information and 
by local institutional practice. 
6.4.2.3. 
Management of Infusion-related Reactions  
Participants receiving IV study treatment may develop signs and symptoms of an infusion 
reaction during or shortly after drug infusion. These reactions generally resolve 
completely within 24 hours of completion of infusion. Table 14 shows treatment 
guidelines for participants who experience infusion-related reactions associated with 
administration of study treatment, including actions to be taken with the study treatment, 
if necessary. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 77 of 166 
 
Table 14: 
Infusion Reaction Treatment Guidelines 
NCI-CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
treatment not indicated 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the Investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, or IV 
fluids); prophylactic 
medications indicated for 
≤24 hours 
Stop infusion and monitor symptoms. 
Additional appropriate medical therapy may include, but is 
not limited to the following:  
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the Investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (e.g., from 100 mL/h to 50 mL/h). 
Otherwise, dosing will be withheld until symptoms 
resolve, and the participant should be premedicated for the 
next scheduled dose. 
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study treatment 
administration. 
Participant may be 
premedicated 
1.5 hours 
(± 30 minutes) prior 
to infusion of 
dostarlimab or 
pembrolizumab with 
the following:  
• Diphenhydramine 
50 mg PO (or 
equivalent dose of 
antihistamine) 
• Acetaminophen 
500 to 1,000 mg 
PO (or equivalent 
dose of antipyretic) 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may include, but is 
not limited to the following:  
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
• Epinephrine 
Increase monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in the 
opinion of the Investigator. 
Hospitalization may be indicated. 
Participant is permanently discontinued from further 
study treatment administration. 
No subsequent 
dosing. 
Abbreviations: IV=intravenous; NCI-CTCAE=National Cancer Institute-Common Terminology Criteria 
for Adverse Events; NSAID=nonsteroidal anti-inflammatory drug; PO=orally. 
Note: Appropriate resuscitation equipment should be available in the room and a physician is readily 
available during the period of study treatment administration. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 78 of 166 
 
6.5. 
Participant-specific Dose Adjustments  
There are no participant-specific dose adjustments defined for this protocol. 
6.6. 
Study Treatment Compliance  
When participants are dosed at the site, they will receive study treatment directly from 
the Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment. 
6.7. 
Treatment of Overdose  
6.7.1. 
Protocol-defined Overdose  
For this study, an overdose of dostarlimab is defined as any dose that is ≥20% of 500 mg 
Q3W. No specific information is available on the treatment of overdose of dostarlimab. 
In the event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.  
An overdose of pembrolizumab is defined, for this study, as a dose ≥1,000 mg (5 × the 
dose). No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the participant should be observed closely for 
signs of toxicity. Appropriate supportive treatment should be provided, if clinically 
indicated. 
An overdose of pemetrexed, cisplatin, or carboplatin is defined according to the 
respective prescribing information. 
In the event of an overdose, the Investigator should do the following: 
1. Contact the GSK Medical Monitor immediately. 
2. Closely monitor the participant for AE/SAE and laboratory abnormalities until 
study treatment of interest can no longer be detected systemically (at least 130 
days). 
3. Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator 
in consultation with the GSK Medical Monitor based on the clinical evaluation of the 
participant. 
See Section 7.5.4 for details on reporting a study treatment overdose. 
6.8. 
Treatment After the End of the Study  
Post-study treatment will not be provided as part of the protocol. Upon discontinuation 
from their assigned study treatment, participants may receive additional (non-protocol) 
therapy at the discretion of the treating physician. New therapy should be documented in 
the eCRF. Every effort should be made to complete the required withdrawal and 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 79 of 166 
 
follow-up evaluations prior to initiating further therapy or dosing of an investigational 
agent (see Table 4 for follow-up assessments and procedures).  
6.9. 
Concomitant Medications and Non-drug Therapies  
Participants should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate. 
Participants will be instructed to inform the Investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit). Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the eCRF. The minimum 
requirement is that drug name, dose, and the dates of administration be recorded. 
Additionally, a complete list of all prior anti-cancer therapies will be recorded in the 
eCRF. 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification. 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter. 
6.9.1. 
Prohibited Medications and Non-drug Therapies  
Participants are prohibited from using the following medications and non-drug therapies: 
 Systemic anticancer medicines 
 Biological therapy, immunotherapy, or chemotherapy not specified in the protocol 
 Investigational agents 
 Live virus and bacterial vaccines 
 Systemic glucocorticoids other than those used to manage AEs or as pre-medications 
to study therapy 
 Participants taking NSAIDs or salicylates will not take the NSAID or salicylate (other 
than an aspirin dose ≤1.3 grams per day) for 2 days before, the day of, and 2 days 
after receiving pemetrexed. Participants taking NSAIDs or salicylates with a long 
half-life (e.g., naproxen, piroxicam, diflunisal, or nabumetone) will not take the 
NSAIDs or salicylates for 5 days before, the day of, and 2 days after pemetrexed. 
The study treatment product labels must be consulted to determine any additional 
prohibited medications. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 80 of 166 
 
7. 
STUDY ASSESSMENTS AND PROCEDURES  
7.1. 
General Guidelines  
 Study procedures and their timing are summarized in the SoA (Table 4). 
 Protocol waivers or exemptions are not allowed. 
 Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or 
discontinue study treatment. 
 Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
 All Screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 Procedures conducted as part of the participant’s routine clinical management (e.g., 
blood count) and obtained before signing of the ICF may be utilized for Screening or 
baseline purposes, provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA. 
 Results that could unblind the study will not be reported to investigative sites or other 
blinded personnel until the study has been unblinded. 
 Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
7.1.1. 
General Guidance for Treatment Continuity when Participants are 
Unable to Come into the Clinic  
Due to the significant challenges that currently face the healthcare system and patients 
due to Coronavirus disease 2019 (COVID-19), as well as the potential for enduring or 
additional quarantine measures, the following guidance is being provided in this protocol. 
In the spirit of global diversity in the COVID-19 pandemic and its impact on healthcare 
in each individual country as well as the recently issued guidance by several regulatory 
authorities, the autonomy of each investigative site to assess the benefit/risk for their 
patients participating in clinical studies should be maintained. 
Prior to utilization of any of the measures outlined in this section, discussion and 
approval must be obtained from Sponsor/contract research organization.  
It is expected that sites participating in clinical studies will make every effort to ensure 
proper monitoring and well-being of enrolled participants by adhering to safety 
monitoring as outlined in the SoA (Table 4). The use of local laboratories and local 
radiology centers to reduce the need for a participant to come into the clinic are 
supported, if deemed necessary for the well-being of the participant. These local facilities 
should be added to regulatory documents, as required. 
Additionally, regulatory guidance issued in response to the COVID-19 pandemic 
supports the use of central and remote monitoring programs to maintain oversight of 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 81 of 166 
 
clinical sites. Any restrictions in place at the site that will impact monitoring and/or 
participant access to the site and care providers should be communicated to the 
Sponsor/contract research organization.  
A global telemedicine platform that allows for continued monitoring of AEs, concomitant 
medications, protocol deviations, etc, may be engaged. Discussions around utilization of 
this technology should be held on a per-site basis and appropriate documentation of 
utilization should be captured.  
General rules for participants with limited possibility to travel: 
 If possible, replace in-person visits with phone contact or alternative location for 
assessment (e.g., local laboratories and imaging centers).  
 In instances where it is desired to reduce participant exposure in clinic, in-person 
visits every other visit are acceptable if there are no ongoing AEs or new AEs. At this 
time, these missed visits will be considered protocol deviations.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 82 of 166 
 
Table 15: 
Critical Data Collection and Safety Precautions 
Assessment 
Recommendation 
Follow-up assessments 
Contact participant by phone. This discussion should include 
assessment of new therapies and overall survival. 
CBC 
Local laboratory, if possible. Arrangements for the use of a local 
laboratory should be made by the site including the reporting of 
results to the Investigator for review. 
Serum chemistry 
Local laboratory, if possible. Arrangements for the use of a local 
laboratory should be made by the site including the reporting of 
results to the Investigator for review. 
AEs 
Ongoing AEs and SAEs reviewed by phone. 
If hematologic AEs are ongoing, a local CBC is desirable. 
New AEs/SAEs- may be assessed by phone; (please remember to 
submit SAE documentation within 24 hours of learning of the 
event). 
Concomitant medications 
Reviewed by phone and via medical record review. 
Evaluation of response 
CT/MRI if possible. 
PD 
CT/MRI if possible. 
Pregnancy test 
Local laboratory, if available. Arrangements for the use of a local 
laboratory should be made by the site including the reporting of 
results to the Investigator for review. 
Per ICF participant must avoid getting pregnant. 
Abbreviations: AE-adverse event; CBC=complete blood count; CT=computed tomography; ICF=informed 
consent form; MRI=magnetic resonance imaging; PD=progressive disease; 
 
SAE=serious adverse event. 
7.2. 
Screening and Critical Baseline Assessments  
7.2.1. 
Baseline Assessments at Screening  
Refer to the SoA (Table 4) for the full list of assessments collected during the Screening 
Period of this study. 
7.2.2. 
Baseline Tumor Assessment (Documentation of Target and Non-target 
Lesions)  
 All baseline lesion assessments must be performed within 35 days prior to the first 
dose of study treatment.  
 If a participant had a tumor assessment of the clinically indicated areas within the 35 
days before dosing on Cycle 1/Day 1, but prior to signing the main ICF, an additional 
CT/MRI scan for study screening is not required. CT/MRI scans completed during 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 83 of 166 
 
Screening prior to signing the main ICF must have been performed and available for 
submission per the image acquisition guidelines. 
 Lymph nodes that have a short axis of <10 mm are considered non-pathological and 
should not be recorded or followed. 
 Pathological lymph nodes with <15 mm and but 10 mm short axis are considered 
non-measurable. 
 Pathological lymph nodes with 15 mm short axis are considered measurable and can 
be selected as target lesions, however, lymph nodes should not be selected as target 
lesions when other suitable target lesions are available.  
 Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and 
recorded and measured at baseline. These lesions should be selected on the basis of 
their size (lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  
Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available. 
Note: Measurable lesions that have been previously irradiated and have not been 
shown to be progressing following irradiation should not be considered as target 
lesions.  
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable. 
Bone scans, fluorodeoxyglucose-positron emission tomography (FDG-PET) scans, or 
X-rays are not considered adequate imaging techniques to measure bone lesions. 
 All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be grouped by organ. 
Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout Follow-up.  
 Within 35 days prior to the first dose, participants must have a baseline tumor 
assessment of the chest and abdomen (including the entire liver and both adrenal 
glands). Other regions should be imaged as clinically indicated (e.g., pelvis, brain, 
etc). This assessment should be conducted by IV contrast-enhanced computed 
tomography (CT) or magnetic resonance imaging (MRI) scan. MRI should be used 
for abdominal (and pelvic) imaging if CT contrast is contraindicated, and, preferably, 
for IV contrast-enhanced imaging of the brain. The same imaging technique should 
be used in a participant throughout the study. The CT component of positron emission 
tomography (PET)/CT may be used according to RECIST v1.1 guidelines, with full 
radiation dose diagnostic CT and IV CT contrast, and as clinically indicated. At each 
post-baseline assessment, evaluations of the sites of the disease identified by these 
scans are required.  
7.2.3. 
Determination of PD-L1 Status Prior to Randomization  
To be eligible for the study, participants must have documented PD-L1 status by the 
22C3 pharmDx assay (Agilent/Dako). If no prior PD-L1 result is available at the time of 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 84 of 166 
 
Screening, the participant can be tested locally using the aforementioned method, or 
central PD-L1 testing can be completed (refer to the Laboratory Manual for 
country-specific details of central assessment). For participants requiring PD-L1 testing 
at the time of study entry, an archival FFPE tumor tissue specimen, which may have been 
collected at any time prior to Screening, can be submitted for analysis within 28 days of 
the participant’s first dose. Specimens used to confirm diagnosis or collected after the 
participant has been diagnosed with metastatic disease will be preferred for determination 
of PD-L1 status. Both tissue block and freshly cut (within 6 months) slides (10 to 15) are 
acceptable. If no archival FFPE tumor tissue is available, a fresh tumor tissue biopsy 
should be obtained and tested within 28 days of the participant’s first dose. Biopsies 
obtained prior to receipt of adjuvant/neoadjuvant chemotherapy will be permitted if a 
fresh biopsy is not feasible. As the results of baseline PD-L1 status assessment will be 
used as a stratification factor in this study, results must be provided prior to 
randomization. Participants who do not have documented PD-L1 status and cannot 
provide archived or fresh tissue sample for PD-L1 testing will not be eligible for the 
study. 
7.3. 
Efficacy  
7.3.1. 
Post-baseline Imaging and Tumor Assessment  
 The efficacy of each treatment combination will be evaluated by assessment of tumor 
response according to RECIST v.1.1 (Appendix 1) by BICR and by the Investigator. 
Investigator assessment of tumor response and progression according to RECIST v1.1 
will be used for treatment decisions. 
 Tumor assessment method and timing, evaluation of disease, disease progression, and 
response criteria will be conducted according to RECIST v1.1 as follows: 
 Tumor assessment modalities may include imaging (e.g., CT or MRI). 
To support continued tumor assessment while on study, serial imaging will then be 
performed at 6 weeks (42 [±7] days) and again at 12 weeks (84 [±7] days) from the 
randomization date. Following the 12-week scan, imaging will be performed Q9W (every 
63 [±7] days), or more frequently, if clinically indicated. After 48 weeks, participants 
who remain on treatment will have imaging performed Q12W (every 84 [±7] days). 
Imaging should continue to be performed until discontinuation of study treatment due to 
disease progression with clinical instability, start of subsequent anticancer treatment, 
withdrawal of informed consent, or death, whichever comes first. Imaging must be 
performed on a calendar schedule and should not be affected by dose 
interruptions/delays. All radiographic images/scans at the specified time points, as well as 
any unscheduled images/scans, will be collected and stored centrally for BICR, potential 
future evaluation, and archiving. Digital copies of all DICOM-formatted scans must be 
maintained at the Investigative site as source documents. 
 For post-baseline assessments, a window of ±7 days is permitted to allow for 
flexible scheduling. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 85 of 166 
 
 To ensure comparability between the baseline and subsequent assessments, the 
same method of assessment and the same imaging technique will be used when 
assessing response. 
 Following the initial radiologic assessment of progressive disease (PD), clinically 
stable participants should continue study treatment and a follow-up scan should 
be performed at least 4 weeks and no longer than 8 weeks later. The follow-up 
scan will provide additional information to the Investigator for participant 
management and further treatment decisions. Further guidance for the assessment 
of scans acquired after RECIST v1.1-defined PD are provided in Appendix 1. For 
participants who are not clinically stable (clinically progressing) at the initial 
radiologic assessment of PD, study treatment will be discontinued and a follow-up 
scan is not required. Following the initial radiologic assessment of CR or PR, a 
confirmatory follow-up scan should be performed at least 4 weeks later. 
 If EOT occurs between the scheduled radiologic disease assessments, scans do not 
need to be repeated at EOT if fewer than 5 weeks have passed since the time of 
the previous disease assessment that did not document PD. To ensure 
comparability between the baseline and subsequent assessments, the same method 
of assessment and the same imaging technique will be used when assessing 
response. 
7.3.1.1. 
Objective Response Rate  
ORR as a primary efficacy endpoint in this study will be evaluated by RECIST v1.1 
based on BICR and will be defined as the proportion of participants with a best overall 
response (BOR) of confirmed CR or PR in the analysis population.  
 
 
 
7.3.1.2. 
Overall Survival  
OS as a secondary efficacy endpoint in this study will be defined as the time from the 
date of randomization to the date of death by any cause. Following the EOT Visit, 
survival status will be collected for all participants using acceptable means, including 
telephone contact. Participants without documented death at the time of the final analysis 
will be censored at the last date they were known to be alive. 
7.3.1.3. 
Progression-free Survival  
PFS as a secondary efficacy endpoint in this study will be evaluated using RECIST v1.1 
based on Investigator assessment and will be defined as the time from the date of 
randomization to the date of PD or death by any cause, whichever occurs first. 
7.3.1.4. 
Duration of Response  
 
 
 
  
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 86 of 166 
 
7.4. 
Safety  
Refer to the SoA (Table 4) for full list of safety assessments and their frequency and 
timing during this study. 
7.4.1. 
Physical Examinations  
 A full physical examination will include assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems. Height (at Screening only) and 
weight will also be measured and recorded. Full physical examinations will be 
conducted during Screening and at EOT or discontinuation. 
Note: For height and weight measurements, the participant is allowed to wear indoor, 
daytime clothing with no shoes. 
 Symptom-directed physical examinations will include assessments based on 
participants’ current symptoms and may include brief examination of the lungs, 
cardiovascular system, and abdomen (liver and spleen). 
 Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
7.4.2. 
ECOG Performance Status  
 Performance status will be assessed using the ECOG performance status scale 
(Appendix 2). The same observer should assess performance status each time, if 
possible. 
7.4.3. 
Vital Signs  
 Vital sign measurements are to be measured in a semi-supine position after a 
5-minute rest and will include temperature, systolic and diastolic blood pressure, 
pulse rate, and respiratory rate. 
 Three readings of blood pressure and pulse rate should be taken. The first reading 
should be rejected and the second and third readings should be averaged to give the 
measurement to be recorded in the eCRF.  
 Vital signs will be measured more frequently if warranted by clinical condition of the 
participant. On days where vital signs are measured multiple times, temperature does 
not need to be repeated, unless clinically indicated. 
7.4.4. 
Pulse Oximetry  
 Pulse oximetry will be performed using local standard procedures. This assessment 
should be completed prior to study treatment administration when performed during 
the Treatment Period. 
7.4.5. 
Electrocardiograms  
 All participants will undergo electrocardiograms (ECGs). Participants will be in a 
supine or semirecumbent position (about 30 degrees of elevation) and rested for 
approximately 2 minutes before ECGs are recorded. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 87 of 166 
 
7.4.6. 
Clinical Safety Laboratory Assessments  
 See Appendix 3 for the full list of clinical laboratory tests to be performed and to the 
SoA (Table 4) for the timing and frequency of these tests. Clinical laboratory 
assessments will be performed by the local laboratory at the investigational site. 
 The Investigator must review the laboratory report, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
reports must be filed with the source documents. If SAE criteria are met or the 
abnormality is an adverse event of special interest (AESI) (Appendix 8), the event 
should be recorded and reported according to the SAE reporting process 
(Section 7.5.4). 
 Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant, unless judged by the Investigator to be more severe 
than expected for the participant's condition. 
 All laboratory tests with values considered clinically significantly abnormal during 
participation in the study, or within 90 days after the last dose of study treatment, 
should be repeated until the values return to normal/baseline or are no longer 
considered significantly abnormal by the Investigator or GSK Medical Monitor.  
 If clinically significant values do not return to normal/baseline within a period of 
time judged reasonable by the Investigator, the etiology should be identified, and 
the Sponsor should be notified. 
 Hematologic testing may occur more frequently than is specified in the SoA if 
additional testing is medically indicated per the Investigator’s judgment or if an event 
meeting the criteria for study dose adjustment occurs (Section 6.4). 
 All protocol-required laboratory tests must be conducted in accordance with the 
Laboratory Manual and the SoA (Table 4). 
 Additional tests may be performed at a laboratory facility other than the study site, 
but the test results must be reported to the study site, the study site must keep a copy 
of the test results with the participant’s study file, as well as laboratory reference 
ranges for the facility used, and the results must be entered into the eCRF. 
 If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (e.g., AE, SAE, or dose 
modification), then the results must be recorded. 
 Further details on sample collection and analysis can be found in the Laboratory 
Manual. Any suspected case of secondary cancer reported while a participant is 
receiving treatment or followed for post-treatment assessments must be investigated, 
including obtaining and documenting a histological diagnosis. Testing completed as 
part of standard of care is sufficient as long as the methods are deemed acceptable 
after consultation with the GSK Medical Monitor. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 88 of 166 
 
7.4.7. 
Pregnancy Testing  
 Refer to Section 5.1 for pregnancy testing study entry criteria. 
 Pregnancy testing (urine or serum as required by local regulations) should be 
conducted prior to each dose of study treatment (within 72 hours). 
 Monthly pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure to the study treatment, plus at 
least 180 days, minimum, thereafter (or longer as per the required contraception use 
in this study; see Section 5.1). 
 Additional serum or urine pregnancy tests may be performed, as determined 
necessary, by the Investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant’s participation in the study. 
 Any pregnancies that occur while a participant is on study (inclusive of the minimum 
180 days post treatment follow-up period or longer as per the required contraception 
use in this study) are to be reported as described in Section 7.5.5. 
7.5. 
AEs, SAEs, and Other Safety Reporting  
The definitions of AEs, SAEs, and other safety events, including AESIs can be found in 
Appendix 8. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, 
and reporting events that meet the definition of an AE or SAE and remain responsible for 
following-up all events. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 8. 
7.5.1. 
Time Period and Frequency for Collecting AE and SAE Information  
 All AEs and SAEs will be collected from the start of study treatment until the time 
points outlined in Table 16 and the SoA (Table 4). However, any SAEs assessed as 
related to study participation (e.g., study treatment, protocol-mandated procedures, 
invasive tests, or change in existing therapy) or related to a GSK product will be 
recorded from the time a participant consents to participate in the study. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 89 of 166 
 
Table 16: 
Collecting and Reporting AEs, Pregnancy, and Survival 
Parameter 
Time Point 
AEs 
Through 30 days after cessation of study treatment 
SAEs 
Through 90 days after cessation of study treatment (or for a minimum 
of 30 days until the start of alternate anticancer therapy) 
Pregnancy 
Through at least 180 days following the last dose of study treatment 
OR as per local requirements and local approved product labels 
(applies to female participants and female partners of male 
participants; see Section 5.1 for additional details)  
Study drug-related 
SAEs 
Until study closeout 
AESIs 
Until study closeout 
Survival 
Until study closeout 
Abbreviations: AE=adverse event; AESI=adverse event of special interest; SAE=serious adverse event. 
Note: Collection and reporting will begin on the day of informed consent. 
 Medical occurrences that begin before the start of study treatment, but after obtaining 
informed consent, will be recorded as medical history/current medical conditions, not 
as AEs.  
 All SAEs will be recorded and reported to the Sponsor or designee immediately, and, 
under no circumstance, should this exceed 24 hours, as indicated in Appendix 8. The 
Investigator will submit any updated SAE data to the Sponsor within 24 hours of it 
being available. 
 Investigators are not obligated to actively seek information on AEs or SAEs after the 
conclusion of a participant’s study participation. However, if the Investigator learns 
of any SAE, including a death, at any time after a participant has been discharged 
from the study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the Investigator must promptly notify the Sponsor. 
7.5.2. 
Method of Detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrence. 
7.5.3. 
Follow-up of AEs and SAEs  
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All SAEs and AESIs will be followed until the 
event is resolved, stabilized, or otherwise explained, or the participant is lost to follow-up 
(as defined in Section 5.7). Further information on follow-up procedures is given in 
Appendix 8. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 90 of 166 
 
7.5.4. 
Regulatory Reporting Requirements for SAEs  
 Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities toward the safety of participants and the 
safety of a study treatment under clinical investigation are met. 
 The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs), and Investigators. 
 An Investigator who receives an Investigator Safety Report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB, and will notify the IRB/IEC, if 
appropriate, according to local requirements. 
 Investigator Safety Reports must be prepared for suspected unexpected serious 
adverse reactions (SUSARs) according to local regulatory requirements and Sponsor 
policy and forwarded to Investigators, as necessary. 
7.5.5. 
Pregnancy  
 Details of all pregnancies in female participants and female partners of male 
participants will be collected after the start of study treatment and until at least 180 
days following the last dose of study treatment (or longer, per the time period for 
post-treatment contraception requirements in Section 5.1). 
 If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours of learning of the pregnancy 
of the female participant or female partner of a male participant (after obtaining the 
necessary signed informed consent from the female partner). Although pregnancy 
itself is not considered to be an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be reported as an AE or SAE.  
 Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported 
as such. 
 The pregnant female participant or pregnant female partner of a male participant will 
be followed to determine the outcome of the pregnancy. The Investigator will collect 
follow-up information on the pregnant female participant or pregnant female partner 
of a male participant and the neonate and the information will be forwarded to the 
Sponsor. 
 Any post-study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described in 
Section 7.5.4. Although the Investigator is not obligated to actively seek this 
information in former study participants/female partners of male study participants, 
he or she may learn of an SAE through spontaneous reporting. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 91 of 166 
 
 Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study. 
7.5.6. 
Cardiovascular and Death Events  
For any cardiovascular events detailed in Appendix 8 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular and Death sections of the eCRF will be 
required to be completed. These sections include questions regarding cardiovascular 
(including sudden cardiac death) and non-cardiovascular death.  
The cardiovascular eCRFs are presented as queries in response to reporting of certain 
cardiovascular Medical Dictionary for Regulatory Activities (MedDRA) terms. The 
cardiovascular information should be recorded in the specific cardiovascular section of 
the eCRF within 1 week of receipt of a Cardiovascular Event data query prompting its 
completion.  
The Death eCRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within 1 week 
of when the death is reported. 
7.5.7. 
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as SAEs  
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE. Death due to disease under study is to be recorded on the Death eCRF. 
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the participant or if the Investigator considers that there was a 
causal relationship between treatment with study treatment(s), protocol design, or 
protocol procedures and the disease progression, then this must be reported as an SAE. 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 92 of 166 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 93 of 166 
 
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 94 of 166 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 95 of 166 
 
7.11. 
Biomedical Research  
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 96 of 166 
 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 97 of 166 
 
8. 
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES  
8.1. 
Hypothesis  
The primary efficacy endpoint, ORR using RECIST v1.1 based on BICR, of dostarlimab 
plus chemotherapy is similar to that of pembrolizumab plus chemotherapy in participants 
with metastatic non-squamous NSCLC without a known EGFR, ALK, ROS-1, or BRAF 
V600E mutation or other genomic aberration for which an approved targeted therapy is 
available and who have not received prior treatment of metastatic disease. 
8.2. 
Sample Size Considerations  
8.3. 
Data Analysis Considerations  
8.3.1. 
Analysis Populations  
The analysis populations are defined as follows (additional analysis populations may be 
defined in the RAP: 
 Intent-to-treat (ITT) population: 
 
 
 
 
 
 Response evaluable population: 
 
 
 
 
 
 
 
 
 
 Per-protocol population: 
 
 
 
 
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 98 of 166 
 
 Safety population: 
 
 
 
 
 
 
 
 
8.3.2. 
Interim Analysis  
No formal interim analysis will be done for this study. 
8.3.3. 
Supplementary Analyses  
8.4. 
Key Elements of Analysis Plan  
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report. 
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 99 of 166 
 
As it is anticipated that accrual will be spread thinly across centers, and summaries of 
data by center would be unlikely informative, data from all participating centers will be 
pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 
As the duration of treatment for a given participant will depend on efficacy and 
tolerability, the duration of follow-up will vary between participants. 
 
  
8.4.1. 
Participant Disposition  
8.4.2. 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications  
8.4.3. 
Primary Efficacy Analyses  
8.4.4. 
Secondary Efficacy Analyses  
CCI
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 100 of 166 
 
8.4.5. 
Exploratory Efficacy Analyses  
8.4.6. 
Secondary Safety Analyses  
8.4.6.1. 
Extent of Exposure  
8.4.6.2. 
AEs  
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the Investigator according to the NCI-CTCAE v5.0. 
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 101 of 166 
 
 
8.4.6.3. 
Clinical Laboratory Evaluations  
8.4.6.4. 
Other Safety Measures  
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 102 of 166 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 103 of 166 
 
 
 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 104 of 166 
 
9. 
REFERENCES  
Andrade, R. J., M. Robles and M. I. Lucena (2009). "Rechallenge in drug-induced liver 
injury: the attractive hazard." Expert Opin Drug Saf 8(6): 709-714. 
Basch, E., B. B. Reeve, S. A. Mitchell, S. B. Clauser, L. M. Minasian, A. C. Dueck, T. R. 
Mendoza, J. Hay, T. M. Atkinson, A. P. Abernethy, D. W. Bruner, C. S. Cleeland, J. A. 
Sloan, R. Chilukuri, P. Baumgartner, A. Denicoff, D. St Germain, A. M. O'Mara, A. 
Chen, J. Kelaghan, A. V. Bennett, L. Sit, L. Rogak, A. Barz, D. B. Paul and D. Schrag 
(2014). "Development of the National Cancer Institute's patient-reported outcomes 
version of the common terminology criteria for adverse events (PRO-CTCAE)." J Natl 
Cancer Inst 106(9). 
Bergman, B., N. K. Aaronson, S. Ahmedzai, S. Kaasa and M. Sullivan (1994). "The 
EORTC QLQ-LC13: a modular supplement to the EORTC Core Quality of Life 
Questionnaire (QLQ-C30) for use in lung cancer clinical trials. EORTC Study Group on 
Quality of Life." Eur J Cancer 30A(5): 635-642. 
Blank, C., I. Brown, A. C. Peterson, M. Spiotto, Y. Iwai, T. Honjo and T. F. Gajewski 
(2004). "PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor 
(TCR) transgenic CD8+ T cells." Cancer Res 64(3): 1140-1145. 
Borghaei, H., C. J. Langer, S. Gadgeel, V. A. Papadimitrakopoulou, A. Patnaik, S. F. 
Powell, R. D. Gentzler, R. G. Martins, J. P. Stevenson, S. I. Jalal, A. Panwalkar, J. C. 
Yang, M. Gubens, L. V. Sequist, M. M. Awad, J. Fiore, S. Saraf, S. M. Keller and L. 
Gandhi (2019). "24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed 
and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced 
Nonsquamous Non-Small Cell Lung Cancer." J Thorac Oncol 14(1): 124-129. 
Borghaei, H., L. Paz-Ares, L. Horn, D. R. Spigel, M. Steins, N. E. Ready, L. Q. Chow, E. 
E. Vokes, E. Felip, E. Holgado, F. Barlesi, M. Kohlhaufl, O. Arrieta, M. A. Burgio, J. 
Fayette, H. Lena, E. Poddubskaya, D. E. Gerber, S. N. Gettinger, C. M. Rudin, N. Rizvi, 
L. Crino, G. R. Blumenschein, Jr., S. J. Antonia, C. Dorange, C. T. Harbison, F. Graf 
Finckenstein and J. R. Brahmer (2015). "Nivolumab versus Docetaxel in Advanced 
Nonsquamous Non-Small-Cell Lung Cancer." N Engl J Med 373(17): 1627-1639. 
Brahmer, J., K. L. Reckamp, P. Baas, L. Crino, W. E. Eberhardt, E. Poddubskaya, S. 
Antonia, A. Pluzanski, E. E. Vokes, E. Holgado, D. Waterhouse, N. Ready, J. Gainor, O. 
Aren Frontera, L. Havel, M. Steins, M. C. Garassino, J. G. Aerts, M. Domine, L. Paz-
Ares, M. Reck, C. Baudelet, C. T. Harbison, B. Lestini and D. R. Spigel (2015). 
"Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung 
Cancer." N Engl J Med 373(2): 123-135. 
Brahmer, J. R., C. G. Drake, I. Wollner, J. D. Powderly, J. Picus, W. H. Sharfman, E. 
Stankevich, A. Pons, T. M. Salay, T. L. McMiller, M. M. Gilson, C. Wang, M. Selby, J. 
M. Taube, R. Anders, L. Chen, A. J. Korman, D. M. Pardoll, I. Lowy and S. L. Topalian 
(2010). "Phase I study of single-agent anti-programmed death-1 (MDX-1106) in 
refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic 
correlates." J Clin Oncol 28(19): 3167-3175. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 105 of 166 
 
Brahmer, J. R., C. Lacchetti, B. J. Schneider, M. B. Atkins, K. J. Brassil, J. M. Caterino, 
I. Chau, M. S. Ernstoff, J. M. Gardner, P. Ginex, S. Hallmeyer, J. Holter Chakrabarty, N. 
B. Leighl, J. S. Mammen, D. F. McDermott, A. Naing, L. J. Nastoupil, T. Phillips, L. D. 
Porter, I. Puzanov, C. A. Reichner, B. D. Santomasso, C. Seigel, A. Spira, M. E. Suarez-
Almazor, Y. Wang, J. S. Weber, J. D. Wolchok and J. A. Thompson (2018). 
"Management of Immune-Related Adverse Events in Patients Treated With Immune 
Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice 
Guideline." J Clin Oncol: JCO2017776385. 
Cella, D. F., D. S. Tulsky, G. Gray, B. Sarafian, E. Linn, A. Bonomi, M. Silberman, S. B. 
Yellen, P. Winicour, J. Brannon and et al. (1993). "The Functional Assessment of Cancer 
Therapy scale: development and validation of the general measure." J Clin Oncol 11(3): 
570-579. 
D'Addio, F., L. V. Riella, B. G. Mfarrej, L. Chabtini, L. T. Adams, M. Yeung, H. Yagita, 
M. Azuma, M. H. Sayegh and I. Guleria (2011). "The link between the PDL1 
costimulatory pathway and Th17 in fetomaternal tolerance." J Immunol 187(9): 4530-
4541. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe and J. Verweij (2009). "New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-247. 
EORTC‑QLQ‑C30 (2020). "European Organisation for Research and Treatment of 
Cancer. EORTC-QLQ-C30 Core Questionnaire.  
FDA (2009). Guidance for industry. Drug-induced liver injury: premarketing clinical 
evaluation. UDoHaHSFaD. 
Fridman, W. H., F. Pages, C. Sautes-Fridman and J. Galon (2012). "The immune 
contexture in human tumours: impact on clinical outcome." Nat Rev Cancer 12(4): 298-
306. 
"Gadgeel S, Stevenson J, Langer C, et al. Pembrolizumab (pembro) plus chemotherapy as 
front-line therapy for advanced NSCLC: KEYNOTE-021 cohorts A-C. J Clin Oncol 34, 
2016 (suppl; abstr 9016). ." 
Gandhi, L., D. Rodríguez-Abreu, S. Gadgeel, E. Esteban, E. Felip, F. De Angelis, M. 
Domine, P. Clingan, M. J. Hochmair, S. F. Powell, S. Y.-S. Cheng, H. G. Bischoff, N. 
Peled, F. Grossi, R. R. Jennens, M. Reck, R. Hui, E. B. Garon, M. Boyer, B. Rubio-
Viqueira, S. Novello, T. Kurata, J. E. Gray, J. Vida, Z. Wei, J. Yang, H. Raftopoulos, M. 
C. Pietanza and M. C. Garassino (2018). "Pembrolizumab plus Chemotherapy in 
Metastatic Non–Small-Cell Lung Cancer." New England Journal of Medicine 378(22): 
2078-2092. 
Guy, W. (1976). ECDEU Assessment Manual for Psychopharmacology, Revised. 
Rockville, MD, National Institute of Mental Health. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 106 of 166 
 
Hato, S. V., A. Khong, I. J. de Vries and W. J. Lesterhuis (2014). "Molecular pathways: 
the immunogenic effects of platinum-based chemotherapeutics." Clin Cancer Res 20(11): 
2831-2837. 
Herbst, R. S., P. Baas, D. W. Kim, E. Felip, J. L. Perez-Gracia, J. Y. Han, J. Molina, J. H. 
Kim, C. D. Arvis, M. J. Ahn, M. Majem, M. J. Fidler, G. de Castro, Jr., M. Garrido, G. 
M. Lubiniecki, Y. Shentu, E. Im, M. Dolled-Filhart and E. B. Garon (2016). 
"Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-
small-cell lung cancer (KEYNOTE-010): a randomised controlled trial." Lancet 
387(10027): 1540-1550. 
Herbst, R. S., J. V. Heymach and S. M. Lippman (2008). "Lung cancer." N Engl J Med 
359(13): 1367-1380. 
Herzberg, B., M. J. Campo and J. F. Gainor (2017). "Immune checkpoint inhibitors in 
non-small cell lung cancer." Oncologist 22(1): 81-88. 
Howlader, N. N., A. M.; Krapcho, M.; Miller, D.; Brest, A.; Yu, M.; Ruhl, J.; Tatalovich, 
Z.; Mariotto, A.; Lewis, D. R.; Chen, H.S.; Feuer, E.J.; Cronin, K.A. (eds) (2018). " 
SEER Cancer Statistics Review, 1975-2016, National Cancer Institute. based on 
November 2018 SEER data submission, posted to the SEER website, April 2019." 
Huang, X., F. Venet, Y. L. Wang, A. Lepape, Z. Yuan, Y. Chen, R. Swan, H. Kherouf, G. 
Monneret, C. S. Chung and A. Ayala (2009). "PD-1 expression by macrophages plays a 
pathologic role in altering microbial clearance and the innate inflammatory response to 
sepsis." Proc Natl Acad Sci U S A 106(15): 6303-6308. 
Hunt, C. M. (2010). "Mitochondrial and immunoallergic injury increase risk of positive 
drug rechallenge after drug-induced liver injury: a systematic review." Hepatology 52(6): 
2216-2222. 
ICH E15 (2007). "International Council on Harmonisation. ICH Guideline E15 
Definitions for Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic 
Data and Sample Coding Categories.  
Ishida, Y., Y. Agata, K. Shibahara and T. Honjo (1992). "Induced expression of PD-1, a 
novel member of the immunoglobulin gene superfamily, upon programmed cell death." 
EMBO J 11(11): 3887-3895. 
James, L. P., L. Letzig, P. M. Simpson, E. Capparelli, D. W. Roberts, J. A. Hinson, T. J. 
Davern and W. M. Lee (2009). "Pharmacokinetics of acetaminophen-protein adducts in 
adults with acetaminophen overdose and acute liver failure." Drug Metab Dispos 37(8): 
1779-1784. 
Karim, R., E. S. Jordanova, S. J. Piersma, G. G. Kenter, L. Chen, J. M. Boer, C. J. Melief 
and S. H. van der Burg (2009). "Tumor-expressed B7-H1 and B7-DC in relation to PD-
1+ T-cell infiltration and survival of patients with cervical carcinoma." Clin Cancer Res 
15(20): 6341-6347. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 107 of 166 
 
Keir, M. E., M. J. Butte, G. J. Freeman and A. H. Sharpe (2008). "PD-1 and its ligands in 
tolerance and immunity." Annu Rev Immunol 26: 677-704. 
KEYTRUDA Prescribing Information (2020). Merck & Co. KEYTRUDA® 
(pembrolizumab) injection, for intravenous use prescribing information package insert.  
Kroemer, G., L. Galluzzi, O. Kepp and L. Zitvogel (2013). "Immunogenic cell death in 
cancer therapy." Annu Rev Immunol 31: 51-72. 
Langer, C. J., S. M. Gadgeel, H. Borghaei, V. A. Papadimitrakopoulou, A. Patnaik, S. F. 
Powell, R. D. Gentzler, R. G. Martins, J. P. Stevenson, S. I. Jalal, A. Panwalkar, J. C. 
Yang, M. Gubens, L. V. Sequist, M. M. Awad, J. Fiore, Y. Ge, H. Raftopoulos, L. 
Gandhi and K.-. investigators (2016). "Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, 
phase 2 cohort of the open-label KEYNOTE-021 study." Lancet Oncol 17(11): 1497-
1508. 
Liechtenstein, T., N. Perez-Janices, M. Gato, F. Caliendo, G. Kochan, I. Blanco-Luquin, 
K. Van der Jeught, F. Arce, D. Guerrero-Setas, J. Fernandez-Irigoyen, E. Santamaria, K. 
Breckpot and D. Escors (2014). "A highly efficient tumor-infiltrating MDSC 
differentiation system for discovery of anti-neoplastic targets, which circumvents the 
need for tumor establishment in mice." Oncotarget 5(17): 7843-7857. 
Mok, T. S. K., Y. L. Wu, I. Kudaba, D. M. Kowalski, B. C. Cho, H. Z. Turna, G. Castro, 
Jr., V. Srimuninnimit, K. K. Laktionov, I. Bondarenko, K. Kubota, G. M. Lubiniecki, J. 
Zhang, D. Kush, G. Lopes and K.-. Investigators (2019). "Pembrolizumab versus 
chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic 
non-small-cell lung cancer (KEYNOTE-042): a randomised, open-label, controlled, 
phase 3 trial." Lancet 393(10183): 1819-1830. 
Motzer, R. J., B. Escudier, D. F. McDermott, S. George, H. J. Hammers, S. Srinivas, S. S. 
Tykodi, J. A. Sosman, G. Procopio, E. R. Plimack, D. Castellano, T. K. Choueiri, H. 
Gurney, F. Donskov, P. Bono, J. Wagstaff, T. C. Gauler, T. Ueda, Y. Tomita, F. A. 
Schutz, C. Kollmannsberger, J. Larkin, A. Ravaud, J. S. Simon, L. A. Xu, I. M. Waxman, 
P. Sharma and I. CheckMate (2015). "Nivolumab versus everolimus in advanced renal-
cell carcinoma." N Engl J Med 373(19): 1803-1813. 
NCI SEER Lung Cancer (2020). "National Cancer Institute Surveillance, Epidemiology 
and End Results (SEER Program): Cancer Stats Facts - Lung and Bronchus Cancer 2012-
2016.  
NCI SEER NSCLC (2018). "Surveillance, Epidemiology, and End Results (SEER) 
Program SEER*Stat Database: Incidence - SEER 18 Regs Research Data + Hurricane 
Katrina Impacted Louisiana Cases, Nov 2018 Sub (2000-2016) <Katrina/Rita Population 
Adjustment> - Linked To County Attributes - Total U.S., 1969-2017 Counties, National 
Cancer Institute, DCCPS, Surveillance Research Program, released April 2019, based on 
the November 2018 submission." 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 108 of 166 
 
Nishimura, H., Y. Agata, A. Kawasaki, M. Sato, S. Imamura, N. Minato, H. Yagita, T. 
Nakano and T. Honjo (1996). "Developmentally regulated expression of the PD-1 protein 
on the surface of double-negative (CD4-CD8-) thymocytes." Int Immunol 8(5): 773-780. 
Oken, M. M., R. H. Creech, D. C. Tormey, J. Horton, T. E. Davis, E. T. McFadden and P. 
P. Carbone (1982). "Toxicity and response criteria of the Eastern Cooperative Oncology 
Group." Am J Clin Oncol 5(6): 649-655. 
Pages, F., A. Berger, M. Camus, F. Sanchez-Cabo, A. Costes, R. Molidor, B. Mlecnik, A. 
Kirilovsky, M. Nilsson, D. Damotte, T. Meatchi, P. Bruneval, P. H. Cugnenc, Z. 
Trajanoski, W. H. Fridman and J. Galon (2005). "Effector memory T cells, early 
metastasis, and survival in colorectal cancer." N Engl J Med 353(25): 2654-2666. 
Papadimitrakopoulou, V., M. Cobo, R. Bordoni, P. Dubray-Longeras, Z. Szalai, G. Ursol, 
S. Novello, F. Orlandi, S. Ball, J. Goldschmidt, Jr., R. Sanborn, T. Hoang, D. Mendus, Y. 
Deng, M. Kowanetz, X. Wen, W. Lin, A. Sandler and M. Nishio (2018). "OA05.07 
IMpower132: PFS and Safety Results with 1L Atezolizumab + Carboplatin/Cisplatin + 
Pemetrexed in Stage IV Non-Squamous NSCLC." Journal of Thoracic Oncology 13(10): 
S332-S333. 
Papay, J. I., D. Clines, R. Rafi, N. Yuen, S. D. Britt, J. S. Walsh and C. M. Hunt (2009). 
"Drug-induced liver injury following positive drug rechallenge." Regul Toxicol 
Pharmacol 54(1): 84-90. 
Paz-Ares, L., A. Luft, D. Vicente, A. Tafreshi, M. Gumus, J. Mazieres, B. Hermes, F. 
Cay Senler, T. Csoszi, A. Fulop, J. Rodriguez-Cid, J. Wilson, S. Sugawara, T. Kato, K. 
H. Lee, Y. Cheng, S. Novello, B. Halmos, X. Li, G. M. Lubiniecki, B. Piperdi, D. M. 
Kowalski and K.-. Investigators (2018). "Pembrolizumab plus Chemotherapy for 
Squamous Non-Small-Cell Lung Cancer." N Engl J Med 379(21): 2040-2051. 
Pedoeem, A., I. Azoulay-Alfaguter, M. Strazza, G. J. Silverman and A. Mor (2014). 
"Programmed death-1 pathway in cancer and autoimmunity." Clin Immunol 153(1): 145-
152. 
Pena-Cruz, V., S. M. McDonough, F. Diaz-Griffero, C. P. Crum, R. D. Carrasco and G. J. 
Freeman (2010). "PD-1 on immature and PD-1 ligands on migratory human Langerhans 
cells regulate antigen-presenting cell activity." J Invest Dermatol 130(9): 2222-2230. 
Pfannenstiel, L. W., S. S. Lam, L. A. Emens, E. M. Jaffee and T. D. Armstrong (2010). 
"Paclitaxel enhances early dendritic cell maturation and function through TLR4 signaling 
in mice." Cell Immunol 263(1): 79-87. 
Reck, M., D. Rodriguez-Abreu, A. G. Robinson, R. Hui, T. Csoszi, A. Fulop, M. 
Gottfried, N. Peled, A. Tafreshi, S. Cuffe, M. O'Brien, S. Rao, K. Hotta, M. A. Leiby, G. 
M. Lubiniecki, Y. Shentu, R. Rangwala, J. R. Brahmer and K.-. Investigators (2016). 
"Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung 
Cancer." N Engl J Med 375(19): 1823-1833. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 109 of 166 
 
Robert, C., G. V. Long, B. Brady, C. Dutriaux, M. Maio, L. Mortier, J. C. Hassel, P. 
Rutkowski, C. McNeil, E. Kalinka-Warzocha, K. J. Savage, M. M. Hernberg, C. Lebbe, 
J. Charles, C. Mihalcioiu, V. Chiarion-Sileni, C. Mauch, F. Cognetti, A. Arance, H. 
Schmidt, D. Schadendorf, H. Gogas, L. Lundgren-Eriksson, C. Horak, B. Sharkey, I. M. 
Waxman, V. Atkinson and P. A. Ascierto (2015). "Nivolumab in previously untreated 
melanoma without BRAF mutation." N Engl J Med 372(4): 320-330. 
Robert, C., J. Schachter, G. V. Long, A. Arance, J. J. Grob, L. Mortier, A. Daud, M. S. 
Carlino, C. McNeil, M. Lotem, J. Larkin, P. Lorigan, B. Neyns, C. U. Blank, O. Hamid, 
C. Mateus, R. Shapira-Frommer, M. Kosh, H. Zhou, N. Ibrahim, S. Ebbinghaus, A. Ribas 
and K.-. investigators (2015). "Pembrolizumab versus Ipilimumab in Advanced 
Melanoma." N Engl J Med 372(26): 2521-2532. 
Sanmamed, M. F. and L. Chen (2014). "Inducible expression of B7-H1 (PD-L1) and its 
selective role in tumor site immune modulation." Cancer J 20(4): 256-261. 
Santarpia, M., N. Karachaliou and R. Rosell (2017). "Beyond platinum treatment for 
NSCLC: what does the future hold?" Expert Rev Anticancer Ther 17(4): 293-295. 
Senovilla, L., I. Vitale, I. Martins, M. Tailler, C. Pailleret, M. Michaud, L. Galluzzi, S. 
Adjemian, O. Kepp, M. Niso-Santano, S. Shen, G. Marino, A. Criollo, A. Boileve, B. 
Job, S. Ladoire, F. Ghiringhelli, A. Sistigu, T. Yamazaki, S. Rello-Varona, C. Locher, V. 
Poirier-Colame, M. Talbot, A. Valent, F. Berardinelli, A. Antoccia, F. Ciccosanti, G. M. 
Fimia, M. Piacentini, A. Fueyo, N. L. Messina, M. Li, C. J. Chan, V. Sigl, G. Pourcher, 
C. Ruckenstuhl, D. Carmona-Gutierrez, V. Lazar, J. M. Penninger, F. Madeo, C. Lopez-
Otin, M. J. Smyth, L. Zitvogel, M. Castedo and G. Kroemer (2012). "An 
immunosurveillance mechanism controls cancer cell ploidy." Science 337(6102): 1678-
1684. 
Sevko, A., T. Michels, M. Vrohlings, L. Umansky, P. Beckhove, M. Kato, G. V. Shurin, 
M. R. Shurin and V. Umansky (2013). "Antitumor effect of paclitaxel is mediated by 
inhibition of myeloid-derived suppressor cells and chronic inflammation in the 
spontaneous melanoma model." J Immunol 190(5): 2464-2471. 
Socinski, M. A., R. M. Jotte, F. Cappuzzo, F. Orlandi, D. Stroyakovskiy, N. Nogami, D. 
Rodriguez-Abreu, D. Moro-Sibilot, C. A. Thomas, F. Barlesi, G. Finley, C. Kelsch, A. 
Lee, S. Coleman, Y. Deng, Y. Shen, M. Kowanetz, A. Lopez-Chavez, A. Sandler, M. 
Reck and I. M. S. Group (2018). "Atezolizumab for First-Line Treatment of Metastatic 
Nonsquamous NSCLC." N Engl J Med 378(24): 2288-2301. 
Spiess, P. E., J. Dhillon, A. S. Baumgarten, P. A. Johnstone and A. R. Giuliano (2016). 
"Pathophysiological basis of human papillomavirus in penile cancer: Key to prevention 
and delivery of more effective therapies." CA Cancer J Clin 66(6): 481-495. 
Taube, J. M., R. A. Anders, G. D. Young, H. Xu, R. Sharma, T. L. McMiller, S. Chen, A. 
P. Klein, D. M. Pardoll, S. L. Topalian and L. Chen (2012). "Colocalization of 
inflammatory response with B7-h1 expression in human melanocytic lesions supports an 
adaptive resistance mechanism of immune escape." Sci Transl Med 4(127): 127ra137. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 110 of 166 
 
Topalian, S. L., C. G. Drake and D. M. Pardoll (2012). "Targeting the PD-1/B7-H1(PD-
L1) pathway to activate anti-tumor immunity." Curr Opin Immunol 24(2): 207-212. 
Weber, J. S., S. P. D'Angelo, D. Minor, F. S. Hodi, R. Gutzmer, B. Neyns, C. Hoeller, N. 
I. Khushalani, W. H. Miller, Jr., C. D. Lao, G. P. Linette, L. Thomas, P. Lorigan, K. F. 
Grossmann, J. C. Hassel, M. Maio, M. Sznol, P. A. Ascierto, P. Mohr, B. Chmielowski, 
A. Bryce, I. M. Svane, J. J. Grob, A. M. Krackhardt, C. Horak, A. Lambert, A. S. Yang 
and J. Larkin (2015). "Nivolumab versus chemotherapy in patients with advanced 
melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, 
controlled, open-label, phase 3 trial." Lancet Oncol 16(4): 375-384. 
West, H., M. McCleod, M. Hussein, A. Morabito, A. Rittmeyer, H. J. Conter, H. G. 
Kopp, D. Daniel, S. McCune, T. Mekhail, A. Zer, N. Reinmuth, A. Sadiq, A. Sandler, W. 
Lin, T. Ochi Lohmann, V. Archer, L. Wang, M. Kowanetz and F. Cappuzzo (2019). 
"Atezolizumab in combination with carboplatin plus nab-paclitaxel chemotherapy 
compared with chemotherapy alone as first-line treatment for metastatic non-squamous 
non-small-cell lung cancer (IMpower130): a multicentre, randomised, open-label, phase 3 
trial." Lancet Oncol 20(7): 924-937. 
Yao, S. and L. Chen (2014). "PD-1 as an immune modulatory receptor." Cancer Journal 
20(4): 26. 
Zhang, L., J. R. Conejo-Garcia, D. Katsaros, P. A. Gimotty, M. Massobrio, G. Regnani, 
A. Makrigiannakis, H. Gray, K. Schlienger, M. N. Liebman, S. C. Rubin and G. Coukos 
(2003). "Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer." N 
Engl J Med 348(3): 203-213. 
Zhang, L., T. F. Gajewski and J. Kline (2009). "PD-1/PD-L1 interactions inhibit 
antitumor immune responses in a murine acute myeloid leukemia model." Blood 114(8): 
1545-1552. 
Zou, W. and L. Chen (2008). "Inhibitory B7-family molecules in the tumour 
microenvironment." Nat Rev Immunol 8(6): 467-477. 
 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 111 of 166 
 
APPENDIX 1. GUIDELINES FOR ASSESSMENT OF DISEASE, 
DISEASE PROGRESSION, AND RESPONSE 
CRITERIA  
Adapted from RECIST v1.1 (Eisenhauer, Therasse et al. 2009). 
Assessment Guidelines  
Please note the following: 
 The same diagnostic method, including use of contrast when applicable, must be used 
throughout the study to evaluate a lesion. Contrast agents must be used in accordance 
with the Image Acquisition Guidelines. 
 All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers. 
 Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, then confirmation by computed tomography (CT) or 
magnetic resonance imaging (MRI) is required. 
 Fluorodeoxyglucose-positron emission tomography (FDG-PET) is generally not 
suitable for ongoing assessments of disease. However, FDG-PET can be useful in 
confirming new sites of disease where a positive FDG-PET scan correlates with the 
new site of disease present on CT/MRI. FDG-PET may also be used in lieu of a 
standard bone scan, providing that coverage allows interrogation of all likely sites of 
bone disease and FDG-PET is performed at all assessments. 
 If PET/CT is performed, then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the required 
anatomical coverage and prescribed use of contrast. The method of assessment should 
be noted as CT on the electronic case report form (eCRF). 
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended.  
The minimum size of a measurable baseline lesion should be twice the slice thickness, 
with a minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is 
acceptable, but when used, the technical specification of the scanning sequences should 
be optimized for the evaluation of the type and site of disease and lesions must be 
measured in the same anatomic plane by use of the same imaging examinations. 
Whenever possible the same scanner should be used (Eisenhauer, Therasse et al. 2009). 
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered for assessing 
progression due to new lesions, if they are clearly defined and surrounded by aerated 
lung; however, chest CT is preferred over chest X-ray (Eisenhauer, Therasse et al. 2009). 
Brain scan: If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT. 
Bone scan (typically bone scintigraphy): If a bone scan is performed and a new lesion(s) 
is equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to demonstrate 
malignant characteristics of the lesion(s).  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 112 of 166 
 
Note: PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments. 
Guidelines for Evaluation of Disease  
Measurable and Non-measurable Definitions 
 Measurable lesion: A non-nodal lesion that can be accurately measured in at least 1 
dimension (longest dimension) of the following: 
 10 mm in long-axis diameter with MRI or CT when the scan slice thickness is 
no greater than 5 mm. If the slice thickness is greater than 5 mm, the minimum 
size of a measurable lesion must be at least double the slice thickness (e.g., if the 
slice thickness is 10 mm, a measurable lesion must be 20 mm). 
Additionally, lymph nodes can be considered pathologically enlarged and measurable 
if: 
 15 mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5 mm). At baseline and Follow-up, only the 
short axis will be measured (Eisenhauer, Therasse et al. 2009). 
 Non-measurable lesion: All other lesions including lesions too small to be 
considered measurable (longest diameter <10 mm or pathological lymph nodes with 
≥10 mm and <15 mm short axis) and truly non-measurable lesions, which include: 
leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast 
disease, lymphangitic involvement of the skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques (Eisenhauer, Therasse et al. 2009). 
 Measurable disease: The presence of at least 1 measurable lesion. Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized 
as the only measurable lesion. 
 Non-measurable only disease: The presence of only non-measurable lesions. 
Note: Non-measurable only disease is not allowed per protocol. 
Response Criteria  
Evaluation of Target Lesions 
Definitions for assessment of response for target lesion(s) are as follows: 
 Complete response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes must be <10 mm in the short axis. 
 Partial response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters (e.g., percent change from 
baseline). 
 Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 113 of 166 
 
 Progressive disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference the smallest sum of diameters recorded since the 
treatment started (e.g., percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5 mm. 
 Not applicable (NA): No target lesions at baseline. 
 Not evaluable (NE): Cannot be classified by 1 of the 5 preceding definitions. 
Notes 
 If lymph nodes are documented as target lesions, the short axis is added into the sum 
of diameters (e.g., sum of diameters is the sum of the longest diameters for non-nodal 
lesions and the short axis for nodal lesions). When lymph nodes decrease to 
non-pathological size (short axis <10 mm) they should still have a measurement 
reported in order not to overstate progression. 
 If at a given assessment time point all target lesions identified at baseline are not 
assessed, the sum of diameters cannot be calculated for purposes of assessing CR, PR, 
or SD or for use as the nadir for future assessments. However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented. If an assessment of 
PD cannot be made, the response assessment should be NE. 
 All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g., 2 mm). If lesions are present but too small to measure, then 5 
mm should be recorded and should contribute to the sum of diameters, unless it is 
likely that the lesion has disappeared, in which case 0 mm should be reported. 
 If a lesion disappears and reappears at a subsequent time point, then it should 
continue to be measured. The response at the time when the lesion reappears will 
depend on the status of the other lesions. For example, if the disease had reached a 
CR status then PD would be documented at the time of reappearance. However, if the 
response status was PR or SD, the diameter of the reappearing lesion should be added 
to the remaining diameters and response should be determined based on percent 
change from baseline and percent change from nadir. 
Evaluation of Non-Target Lesions  
Definitions for assessment of response for non-target lesion(s) are as follows: 
 CR: The disappearance of all non-target lesions. All lymph nodes identified as a site 
of disease at baseline must be non-pathological (e.g., <10 mm short axis). 
 Non-CR/non-PD: The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline with ≥10 mm short axis. 
 PD: Unequivocal progression of existing non-target lesions. A modest increase in the 
size of 1 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. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 114 of 166 
 
 NA: No non-target lesions at baseline. 
 NE: Cannot be classified by 1 of the 4 preceding definitions. 
Notes 
 In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that, even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
 Sites of non-target lesions that are not assessed at a particular time point based on the 
assessment schedule should be excluded from the response determination (e.g., 
non-target response does not have to be "Not Evaluable"). 
New Lesions  
 New malignancies denoting disease progression must be unequivocal. Lesions 
identified in Follow-up in an anatomical location not scanned at baseline are 
considered new lesions. 
 Any equivocal new lesions should continue to be followed. Treatment can continue at 
the discretion of the Investigator until the next scheduled assessment. If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented. 
Evaluation of Overall Response  
Table 17 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for participants with measurable disease at baseline. 
Table 17: 
Evaluation of Overall Response for Participants with Measurable 
Disease at Baseline 
Notes 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 115 of 166 
 
Evaluation of BOR  
The best overall response (BOR) is the best response recorded from the start of the 
treatment until disease progression/recurrence and will be determined programmatically 
by GSK based on the Investigator’s assessment of response at each time point. 
Evaluation of Scans Subsequent to RECIST v1.1-defined PD  
For clinically stable participant treated through a RECIST v1.1-defined radiological 
progression, a follow-up scan is requested at least 4 weeks and no longer than 8 weeks 
later. The follow-up scan provides additional information to the Investigator for 
participant management and further treatment decisions. As the published RECIST v1.1 
criteria (Eisenhauer, Therasse et al. 2009) do not provide guidance on how to assess scans 
acquired after RECIST v1.1-defined PD, supplemental instructions for Investigators on 
how to evaluate these follow-up scans are as follows: 
A subsequent follow-up scan would be considered as having PD if any of the following 
criteria are met: 
 ≥20% increase and at least a 5-mm increase in the sum of diameters of target lesions 
compared with the nadir sum of diameters at 2 consecutive visits, and a further 
increase of ≥5 mm in the sum of diameters at the follow-up scan timepoint compared 
with the immediate prior time point 
 Significant progression (worsening) of non-target lesions at the follow-up scan 
timepoint compared with the immediately prior scan time point 
 Significant progression (worsening) of previously new lesions (pre-existing new 
lesions) at the follow-up scan time point compared with the immediately prior scan 
time point 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 116 of 166 
 
 Additional brand-new unequivocal lesions at the follow-up scan time point


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 117 of 166 
 
APPENDIX 2. EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS  
Table 18: 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grading 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without 
restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (i.e., light house work, office 
work). 
1 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
4 
Source: (Oken Creech et al. 1982) 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 118 of 166 
 
APPENDIX 3. CLINICAL LABORATORY TESTS  
Screening Only Testing  
HIV and hepatitis B and C testing performed at Screening (or within 3 months prior to 
first dose of study treatment) only; laboratory tests for: 
 HIV-1 or HIV-2 antibodies 
 Hepatitis B surface antigen and hepatitis C antibodies 
Continuous Laboratory Assessments  
Parameters assessed throughout the study are listed in Table 19. Laboratory assessments 
required for the start of each treatment cycle may be performed up to 72 hours prior to 
the day of treatment. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 119 of 166 
 
Table 19: 
Protocol‑required Safety Laboratory Tests 
Laboratory 
Assessment 
Parameters 
Complete blood 
count (CBC) 
 
Differential white blood cell count 
 
Hematocrit (Hct) 
 
Hemoglobin 
 
Mean corpuscular volume (MCV) 
 
Platelet count 
 
Red blood cell count (RBC or erythrocyte count) 
 
White blood cell count 
Serum chemistry  
Alanine aminotransferase (ALT) 
 
Albumin 
 
Alkaline phosphatase (ALP) 
 
Amylase 
 
Aspartate aminotransferase (AST) 
 
Blood urea nitrogen (if not available, then urea) 
 
Calcium 
 
Chloride 
 
Creatinine 
 
Gamma-glutamyl transferase (GGT) 
 
Glucose 
 
Lactate dehydrogenase 
 
Magnesium 
 
Phosphate 
 
Potassium 
 
Sodium 
 
Total bilirubin 
 
Total protein 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 120 of 166 
 
Table 19: 
Protocol‑required Safety Laboratory Tests (Continued) 
Laboratory 
Assessment 
Parameters 
Urinalysis 
 
Bilirubin 
 
Blood 
 
Glucose 
 
Ketones 
 
Leukocyte esterase 
 
Microscopy (if clinically indicated) 
 
Nitrite 
 
Protein 
 
Specific gravity 
Thyroid panel 
 
Thyroid-stimulating hormone (TSH) 
 
Triiodothyronine (T3) or free triiodothyronine (FT3) 
 
Thyroxine (T4) or free thyroxine (FT4) 
(or equivalent tests, where applicable) 
Pregnancy test 
 
Highly sensitive serum or urine human chorionic gonadotropin (hCG) 
pregnancy test (as needed for women of childbearing potential)1        
Other testing 
 
Follicle-stimulating hormone (FSH) and estradiol (as needed in women 
of non-childbearing potential only) 
1 Post‑screening, local urine testing will be standard for the protocol, unless serum testing is required by 
local regulation or Institutional Review Board/Independent Ethics Committee. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 121 of 166 
 
APPENDIX 4. REGULATORY, ETHICAL, AND STUDY 
OVERSIGHT CONSIDERATIONS  
Regulatory and Ethical Considerations  
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 Applicable International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (e.g., advertisements) must be submitted to an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) by the 
Investigator and reviewed and approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation, except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually, or 
more frequently, in accordance with the requirements, policies, and procedures 
established by the IRB/EC 
 Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of the United States Food and Drug Administration 21 Code of Federal 
Regulations (CFR), ICH guidelines, the IRB/IEC, European regulation 536/2014 for 
clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations 
Financial Disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate 
financial information as requested to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 122 of 166 
 
Informed Consent Process  
 The Investigator or their representative will explain the nature of the study to the 
participants or their legally authorized representative and answer all questions 
regarding the study.  
 Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, 
and the IRB/IEC or study center.  
 The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
 Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study.  
 A copy of the ICF(s) must be provided to the participants or their legally authorized 
representative.  
 A participant who is rescreened is not required to sign another ICF if the rescreening 
occurs within 28 days from the previous ICF signature date. 
 GSK (alone or working with others) may use participant’s coded study data and 
samples and other information to carry out this study, understand the results of this 
study, learn more about the study treatment or about the study disease, publish the 
results of these research efforts, and/or work with government agencies or insurers to 
have the study treatment approved for medical use or approved for payment coverage.  
 The ICF contains a separate section that addresses the use of participant data and 
remaining samples for optional further research. The Investigator or authorized 
designee will inform each participant of the possibility of further research not related 
to the study/disease. Participants will be told that they are free to refuse to participate 
and may withdraw their consent at any time and for any reason during the storage 
period. A separate signature will be required to document a participant's agreement to 
allow any participant data and/or remaining leftover samples to be used for further 
research not related to the study/disease. Participants who decline further research 
will tick the corresponding “No” box. 
Data Protection  
 Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier only; 
participant names or any information that would make the participant identifiable will 
not be transferred.  
 The participant must be informed that their personal study-related data will be used 
by the Sponsor in accordance with local data protection law. The level of disclosure 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 123 of 166 
 
must also be explained to the participant who will be required to give consent for 
their data to be used as described in the informed consent.  
 The participant must be informed that his or her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
Committees Structure  
A blinded independent central review (BICR) will be utilized in this study for review of 
radiological images and assessment of tumor response and progression. Details of the 
review will be summarized in the BICR Charter. 
To safeguard the interest and safety of the participants in the study, a safety 
monitoring/review panel will be used to conduct review of incoming data to monitor 
emerging safety signals. If the panel recommends modifications to the design of the 
protocol or discontinuation of the study, selected Sponsor representatives may be 
unblinded in order to act on these recommendations. 
Dissemination of Clinical Study Data  
 Where required by applicable regulatory requirements, an Investigator signatory will 
be identified for the approval of the CSR. The Investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually 
agreeable location. 
 GSK will also provide all Investigators who were involved in the study with the full 
summary of the study results. The Investigator(s) is (are) encouraged to share the 
summary results with the study participants, as appropriate. 
 Under the framework of the SHARE initiative, GSK intends to make anonymized 
participant-level data from this study available to external researchers for scientific 
analyses or to conduct further research that can help advance medical science or 
improve patient care. This helps ensure that the data provided by study participants 
are used to maximum effect in the creation of knowledge and understanding. 
Requests for access may be made through www.clinicalstudydatarequest.com. 
 GSK will provide the Investigator with the randomization codes for their site only 
after completion of the full statistical analysis. 
 A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge. 
Data Quality Assurance  
 All participant data relating to the study will be recorded on the electronic case report 
form (eCRF), unless transmitted to the Sponsor or designee electronically (e.g., 
laboratory data). The Investigator is responsible for verifying that data entries are 
accurate and correct by signing the eCRF.  


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 124 of 166 
 
 Guidance on completion of eCRFs will be provided in the Case Report Form 
Completion Guidelines.  
 Quality tolerance limits (QTLs) will be pre-defined in the Study Reference Manual to 
identify systematic issues that can impact participant safety and/or reliability of study 
results. These pre-defined parameters will be monitored during the study, and 
deviations from the QTLs and remedial actions taken will be summarized in the CSR. 
 The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and must provide direct access to source data 
documents.  
 Monitoring details describing strategy, including definition of study critical data 
items and processes (e.g., risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring, 
involvement of central reading mechanism), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the Monitoring Plan. 
 The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
 The Sponsor assumes accountability for actions delegated to other individuals (e.g., 
Contract Research Organizations [CROs]). 
 Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years from the issue of the final 
CSR/equivalent summary, unless local regulations or institutional policies require a 
longer retention period. No records may be destroyed during the retention period 
without the written approval of the Sponsor. No records may be transferred to another 
location or party without written notification to the Sponsor.  
 When copies of source documents are shared externally for review by a central reader 
mechanism (e.g., endpoint adjudication committee; expert reader), documents are 
stored by the external body for 25 years  
Source Documents  
 Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
Investigator’s site. 
 Data reported on the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
 Definition of what constitutes source data and its origin can be found in the Study 
Reference Manual. 
 The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 125 of 166 
 
 Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
 Copies of documents are shared with external third parties contracted by GSK for 
review by a central reader mechanism (e.g., endpoint adjudication committee; expert 
reader). The non-exhaustive list of documents shared to inform the central reader may 
include, discharge summaries, imaging reports, ECG reports etc. Participant names or 
any information which would make the participant identifiable or is not essential for 
the central reader mechanism will be redacted by the investigator sites prior to 
transfer. Details of the list of documents and the redaction procedure are provided in 
the site manual or equivalent. These documents will be used by the third party solely 
for the purpose indicated within this protocol.  
Study and Site Start and Closure  
First Act of Recruitment  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open, the date of which will be the study start 
date. 
Study/Site Termination  
GSK or designee reserves the right to close the study site or terminate the study at any 
time for any reason, at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include 
but are not limited to the following: 
For study termination: 
 Discontinuation of further study treatment development. 
For site termination: 
 Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, and/or GCP guidelines 
 Inadequate or no recruitment of participants (evaluated after a reasonable amount of 
time) by the Investigator 
 If the study is prematurely terminated or suspended, the Sponsor shall promptly 
inform the Investigators, the IECs/IRBs, the regulatory authorities, and any CROs 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 126 of 166 
 
used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the 
participant and should assure appropriate participant therapy and/or follow-up. 
Publication Policy  
 The results of this study may be published or presented at scientific meetings. If this 
is foreseen, the Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments.  
 The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating Investigator will be designated by mutual 
agreement. 
 Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 127 of 166 
 
APPENDIX 5. CONTRACEPTIVE AND BARRIER GUIDANCE  
It is not known if dostarlimab may have adverse effects on a fetus in utero. However, 
blockade of PD-L1 signaling in murine models of allogeneic pregnancy can eliminate 
fetomaternal tolerance and cause spontaneous abortion, as indicated by increase in 
embryo resorption and a reduction in litter size (D'Addio, Riella et al. 2011). 
Therefore, female participants may only be enrolled if they are women of childbearing 
potential (WOCBP) (see WOCBP definition) who are non-pregnant, non-breastfeeding 
and are willing to use 1 highly effective form of contraception (Table 20), or are 
considered women of non-childbearing potential (WONCBP) (see WONCBP definition). 
Male participants may only be enrolled if they agree to use a male condom (and should 
also be advised of the benefit for a female partner to use a highly effective method of 
contraception, as a condom may break or leak) when having sexual intercourse with a 
WOCBP who is not currently pregnant, or be abstinent from heterosexual intercourse as 
their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree 
to remain abstinent. 
Participants should be informed that taking the study medication may involve unknown 
risks to a fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study, they must adhere to the study contraception requirements for the 
duration of the study and through at least 180 days after the last study treatment (Note: 
duration of contraceptive use after last dose of chemotherapy must be consistent with 
local requirements and local approved product labels; however, the minimum duration is 
180 days after last dose of chemotherapy). If there is any question that a participant will 
not reliably comply with the requirements for contraception, that participant should not 
be entered into the study. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 128 of 166 
 
Table 20: 
Female Contraceptives Allowed During the Study 
FEMALE CONTRACEPTIVES1 ALLOWED DURING THE STUDY INCLUDE THE 
FOLLOWING:        
Highly Effective2 Methods that Have Low User Dependency (Failure rate of <1% per year 
when used consistently and correctly)        
 
Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation3 
 
IUD 
 
IUS3        
 
Bilateral tubal occlusion 
 
Azoospermic partner (vasectomized or due to a medical cause) 
 
Azoospermia is a highly effective contraceptive method, provided that the partner is 
the sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, then an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days. 
Note: Documentation of azoospermia for a male participant can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview. 
Highly Effective2 Methods that Are User Dependent (Failure rate of <1% per year when 
used consistently and correctly) 
 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation3 
 
oral 
 
intravaginal 
 
transdermal 
 
injectable 
 
Progestogen-only hormone contraception associated with inhibition of ovulation3 
 
oral 
 
injectable 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 129 of 166 
 
Table 20: 
Female Contraceptives Allowed During the Study (Continued) 
FEMALE CONTRACEPTIVES1 ALLOWED DURING THE STUDY INCLUDE THE 
FOLLOWING: 
Highly Effective2 Methods that Are User Dependent (continued) (Failure rate of 
<1% per year when used consistently and correctly) 
 
Sexual abstinence 
 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. Periodic 
abstinence (calendar, symptom-thermal, and post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method are not 
acceptable methods of contraception. 
Abbreviations: CTFG=Clinical Trial Facilitation Group; IUD=intrauterine device; IUS=intrauterine 
hormone-releasing system’ WOCBP=woman of childbearing potential. 
1 Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
2 Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from 
those when used consistently and correctly. 
3 Male condoms must be used in addition to hormonal contraception. If locally required, in accordance 
with CTFG guidelines, then acceptable contraceptive methods are limited to those that inhibit ovulation 
as the primary mode of action. Male condoms and female condoms should not be used together (due to 
risk of failure from friction). 
Definition of WOCBP  
Women in the following categories are considered WOCBP (fertile): 
1. Following menarche 
2. From the time of menarche until becoming post-menopausal unless permanently 
sterile 
Definition of WONCPB  
Women in the following categories are considered WONCBP (not fertile): 
1. Premenopausal female with permanent infertility due to 1 of the following (for the 
purpose of this study): 
a. Documented hysterectomy 
b. Documented bilateral salpingectomy 
c. Documented bilateral oophorectomy 
2. Postmenopausal female 
Notes: 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 130 of 166 
 
 A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with more than 1 FSH measurement is 
required.  
 Females on HRT and whose menopausal status is in doubt will be required to use 
1 of the non-estrogen hormonal highly effective contraception methods if they 
wish to continue their HRT during the study. Otherwise, they must discontinue 
HRT to allow confirmation of postmenopausal status before study enrollment. 
 For individuals with permanent infertility due to an alternate medical cause other than 
those previously listed, (e.g., Mullerian agenesis, androgen insensitivity, gonadal 
dysgenesis), Investigator discretion should be applied when determining study entry. 
 If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual 
cycle cannot be confirmed before first dose of study treatment, additional evaluation 
should be considered. 
 Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 131 of 166 
 
APPENDIX 6. LIVER SAFETY REQUIRED ACTIONS AND 
FOLLOW-UP ASSESSMENTS  
Liver chemistry increased monitoring and stopping criteria have been designed to ensure 
participant safety and evaluate liver event etiology (in alignment with the United States 
Food and Drug Administration premarketing clinical liver safety guidance) .  
Liver chemistry monitoring criteria are presented in Table 21.  
Table 21: 
Liver Chemistry Increased Monitoring Criteria 
Criteria 
Actions 
ALT ≥3×ULN and 1.5×baseline value but ALT 
<5×ULN and 2x baseline value and bilirubin 
<2×ULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and who 
can be monitored weekly for 4 weeks 
 
 
If, after 4 weeks of monitoring, ALT <3×ULN 
and <1.5×baseline value, and bilirubin 
<2×ULN, monitor participant twice monthly 
until liver chemistries normalize or return to 
within baseline 
Abbreviations: ALT=alanine aminotransferase; ULN=upper limit of normal. 
Liver chemistry stopping criteria are presented in Table 22. 
Table 22: 
Liver Chemistry Stopping Criteria 
Laboratory Value 
Liver Chemistry Stopping Criteria  
ALT-absolute 
Both ALT 5×ULN and 2x baseline value 
ALT Increase 
Both ALT 3×ULN and ≥ 1.5x baseline value 
persisting for 4 weeks 
Bilirubin12        
ALT 3×ULN and bilirubin  2×ULN (>35% 
direct bilirubin)  
INR2 
ALT 3×ULN and INR>1.5, if INR measured 
Cannot Monitor 
Both ALT 3×ULN and ≥ 1.5x baseline value 
that cannot be monitored for 4 weeks 
Symptomatic3        
Both ALT 3×ULN and ≥ 1.5x baseline value 
associated with symptoms (new or worsening) 
believed to be related to liver injury or 
hypersensitivity 
Abbreviations: ALT=alanine aminotransferase; INR=international normalized ratio; SAE=serious adverse 
event; ULN=upper limit of normal. 
1 Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation 
is not immediately available, discontinue study treatment for that participant if ALT ≥3×ULN and 
bilirubin ≥2×ULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence 
of detectable urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver 
injury.  
2 All events of ALT ≥3×ULN and bilirubin ≥2×ULN (>35% direct bilirubin) or ALT ≥3×ULN and 
INR>1.5, if INR measured that may indicate severe liver injury (possible ‘Hy’s Law’), must be reported 
as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not required, 
and the threshold value stated will not apply to participants receiving anticoagulants. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 132 of 166 
 
3 New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as 
fever, rash or eosinophilia). 
Liver chemistry required follow-up assessments are presented in Table 23. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 133 of 166 
 
Table 23: 
Required Actions and Follow-up Assessments Following ANY Liver 
Stopping Event 
Actions 
Follow-up Assessments 
Immediately discontinue study treatment 
 
Viral hepatitis serology1  
 
Blood sample for PK analysis at the same 
visit as other chemistry laboratory work or 
medical evaluation related to the event, 
preferably within 24 hours of the event2  
 
CPK and LDH. 
 
Fractionate bilirubin, if total bilirubin 
≥2×ULN 
 
Obtain CBC with differential to assess 
eosinophilia 
 
Record the appearance or worsening of 
clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form 
 
Record use of concomitant medications on the 
concomitant medications report form 
including acetaminophen, herbal remedies, 
and other over-the-counter medications 
 
Record alcohol use on the liver event alcohol 
intake case report form 
Report the event to GSK within 24 hours 
Complete the liver event eCRF and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE3        
Perform liver event follow-up assessments  
Monitor the participant until liver chemistries 
resolve, stabilize, or return to within baseline  
Do not restart/rechallenge participant with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted. 
Monitoring – All criteria: 
Repeat liver chemistries (include ALT, AST, 
ALP, and bilirubin) and perform liver event 
follow-up assessments within 24-72 hours  
Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline. 
 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants with 
definite or likely acetaminophen use in the 
preceding week (James, Letzig et al. 2009)).  
Note: Not required in China  
 
Liver imaging (ultrasound, MRI, or CT) and 
/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver Biopsy 
eCRF forms. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 134 of 166 
 
Table 23: 
Required Actions and Follow-up Assessments Following ANY Liver 
Stopping Event (Continued) 
Actions 
Follow-up Assessments 
Monitoring – Bilirubin or INR criteria: 
Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow-up assessments within 24 hours 
 
Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total 
IgG or gamma globulins. 
 
Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 
contribution to liver injury in participants with 
definite or likely acetaminophen use in the 
preceding week (James, Letzig et al. 2009)). 
Note: Not required in China  
 
Liver imaging (ultrasound, MRI, or CT) 
and/or liver biopsy to evaluate liver disease; 
complete Liver Imaging and/or Liver Biopsy 
eCRF forms. 
Monitor participant twice weekly until liver 
chemistries resolve, stabilize or return to within 
baseline 
 
A specialist or hepatology consultation is 
recommended. 
 
Abbreviations: AE=adverse event; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; CBC=complete blood count; CPK=serum creatine phosphokinase; 
CT=computed tomography; eCRF=electronic case report form; HPLC=high performance liquid 
chromatography; IgG=immunoglobulin G; IgM=immunoglobulin M; INR=international normalized ratio; 
LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PK=pharmacokinetics; SAE=serious 
adverse event; SRM=study reference manual; ULN=upper limit of normal. 
1 Includes the following: Hepatitis A IgM antibody, hepatitis B surface antigen and hepatitis B core 
antibody (IgM), hepatitis C RNA, cytomegalovirus IgM antibody, Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing), and hepatitis E IgM antibody. 
2 PK sample may not be required for participants known to be receiving placebo or non-GSK comparator 
treatments. Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide 
the participant’s best approximation. If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SRM.  
3 All events of ALT ≥3×ULN and bilirubin ≥2×ULN (>35% direct bilirubin) or ALT ≥3×ULN and 
INR>1.5, if INR measured that may indicate severe liver injury (possible ‘Hy’s Law’), must be reported 
as an SAE (excluding studies of hepatic impairment or cirrhosis); INR measurement is not required, 
and the threshold value stated will not apply to participants receiving anticoagulants. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 135 of 166 
 
APPENDIX 7. LIVER SAFETY DRUG RESTART OR 
RECHALLENGE GUIDELINES  
If participant meets liver chemistry stopping criteria do not restart/rechallenge participant 
with study treatment unless: 
 GSK Medical Governance approval is granted (as described below), 
 Ethics and/or IRB approval is obtained, if required, and 
 Separate consent for treatment restart/rechallenge is signed by the participant 
If GSK Medical Governance approval to restart/rechallenge participant with study 
treatment is not granted, then participant must permanently discontinue study treatment 
and may continue in the study for protocol-specified follow up assessments. 
Rechallenge Following Liver Stopping Events that are Possibly Related 
to Study Treatment  
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies . Clinical outcomes vary by drug, with 
nearly 50% fatality with halothane re-administered within one month of initial injury. 
However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include: 
 Hypersensitivity with initial liver injury (eg, fever, rash, eosinophilia)  
 Jaundice or bilirubin >2×ULN with initial liver injury (direct bilirubin >35% of total) 
 Participant currently exhibits severe liver injury defined by: ALT >3×ULN, bilirubin 
>2×ULN (direct bilirubin >35% of total), or INR>1.5 
 SAE or fatality has earlier been observed with drug rechallenges (Papay, Clines et al. 
2009, Hunt 2010) 
 Evidence of drug-related preclinical liability (e.g.,reactive metabolites, mitochondrial 
impairment ) 
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a participant for whom there is compelling evidence of benefit from a 
critical or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favorable. 
Approval by GSK for rechallenge with study treatment can be considered where: 
 Investigator requests consideration of rechallenge with study treatment for a 
participant who is receiving compelling benefit with study treatment that exceeds 
risk, and no effective alternative therapy is available. 
 Ethics Committee or IRB approval for rechallenge with study treatment must be 
obtained, as required. 
 If the rechallenge is approved by GSK Medical Governance in writing, the participant 
must be provided with a clear description of the possible benefits and risks of study 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 136 of 166 
 
treatment administration, including the possibility of recurrent, more severe liver 
injury, or death. 
 The participant must also provide signed informed consent specifically for the 
rechallenge with study treatment. Documentation of informed consent must be 
recorded in the study chart. 
 Study treatment must be administered at the dose specified by GSK. 
 Participants approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol. 
 If after study treatment rechallenge the participant meets protocol-defined liver 
chemistry stopping criteria, study treatment should be permanently discontinued. 
 GSK Medical Monitor, and the Ethics Committee or IRB, as required, must be 
informed of the participant’s outcome following study treatment rechallenge. 
 GSK must be notified of any adverse events, as per Section 7.5 and Appendix 8. 
Restart Following Transient Resolving Liver Stopping Events NOT 
Related to Study Treatment  
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g.,biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury. 
Approval by GSK for study treatment restart can be considered where: 
 Investigator requests consideration for study treatment restart if liver chemistries have 
a clear underlying cause (e.g., biliary obstruction, hypotension and liver chemistries 
have improved to normal or are within 1.5 x baseline and ALT <3xULN). 
 Restart risk factors (e.g., fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an HLA 
genetic marker associated with liver injury (e.g., lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded 
 Ethics Committee or IRB approval of study treatment restart must be obtained, as 
required. 
 If restart of study treatment is approved by GSK Medical Governance in writing, the 
participant must be provided with a clear description of the possible benefits and risks 
of study treatment administration, including the possibility of recurrent, more severe 
liver injury or death. 
 The participant must also provide signed informed consent specifically for the study 
treatment restart. Documentation of informed consent must be recorded in the study 
chart. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 137 of 166 
 
 Study treatment must be administered at the dose specified by GSK. 
 Participants approved by GSK Medical Governance for restarting study treatment 
must return to the clinic once a week for liver chemistry tests until stable liver 
chemistries have been demonstrated and then laboratory monitoring may resume as 
per protocol.  
 If after study treatment restart the participant meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions. 
 GSK Medical Monitor, and the Ethics Committee or IRB, as required, must be 
informed of the participant’s outcome following study treatment restart.  
 GSK must be notified of any adverse events, as per Section 7.5 and Appendix 8. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 138 of 166 
 
APPENDIX 8. ADVERSE EVENTS, SERIOUS ADVERSE EVENTS, 
AND SPECIAL SITUATIONS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, FOLLOW-UP, 
EVALUATING, AND REPORTING  
Definitions and Criteria  
Definition of an Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a clinical study participant, 
temporally associated with the use of a study treatment, whether or not considered related 
to the study treatment. 
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment. 
Events Meeting the AE Definition 
 Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., electrocardiogram [ECG], radiological scans, and vital 
signs measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the Investigator (i.e., not related 
to progression of underlying disease). 
 Exacerbation of a chronic or intermittent pre-existing condition including an increase 
in either frequency or intensity of the condition. 
 New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 Signs, symptoms, or the clinical sequelae of a suspected intervention-intervention 
interaction. 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/serious adverse event (SAE) unless it is an intentional overdose taken with 
possible suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
 "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE or 
SAE.  
Events NOT Meeting the AE Definition 
 Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 139 of 166 
 
 The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
 Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
 Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
Definition of SAE  
An SAE is defined as any SAE that, at any dose: 
 Results in death 
 Is life-threatening 
 The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, that hypothetically might have caused death, if it were more severe.  
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AE. If a complication prolongs hospitalization or fulfils any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
 Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
 Results in persistent or significant disability/incapacity 
 The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
 This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained ankle) that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
 Is a congenital anomaly/birth defect 
 Other situations 
 Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent 1 of the other outcomes listed in the definition. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 140 of 166 
 
These events should usually be considered serious. Examples of such events 
include invasive or malignant cancers, intensive treatment of allergic 
bronchospasm, blood dyscrasias, convulsions, or development of intervention 
dependency or intervention abuse. 
Definition of a TEAE 
A treatment-emergent adverse event (TEAE) is any event that was not present prior to the 
initiation of study treatment or any event already present that worsens in either intensity 
or frequency following exposure to study treatment. 
Definition of AESI 
An adverse event of special interest (AESI) is any AE (serious or nonserious) that is of 
scientific and medical concern specific to the study treatment, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor are appropriate.  
AESIs for this study are as follows: 
 Dostarlimab: None 
Definition of Cardiovascular Events 
Investigators will be required to fill out the specific cardiovascular event page of the 
electronic case report form (eCRF) for the following AEs and SAEs which are considered 
cardiovascular events: 
 Myocardial infarction/unstable angina 
 Congestive heart failure 
 Arrhythmias 
 Valvulopathy 
 Pulmonary hypertension 
 Cerebrovascular events/stroke and transient ischemic attack 
 Peripheral arterial thromboembolism 
 Deep venous thrombosis/pulmonary embolism 
 Revascularization 
Definitions of Special Situations 
 Abuse: The persistent or sporadic, intentional excessive use of the study treatment, 
which is accompanied by harmful physical or psychological effects.  
 Misuse: The medicinal product is intentionally and inappropriately used not in 
accordance with the authorized/approved product information. 
 Medication error: Any preventable incident that may cause or lead to inappropriate 
study treatment use or participant harm while the study treatment is in the control of 
the health care professionals or participants. Such incident may be due to health care 
professional practice, product labeling, packaging and preparation, procedures for 
administration, and systems, including the following: prescribing, order 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 141 of 166 
 
communication, nomenclature, compounding, dispensing, distribution, 
administration, education, monitoring, and use. 
 Overdose: A deliberate or accidental administration of study treatment to a study 
participant, at a dose greater than what was assigned to that participant per the study 
protocol and under the direction of the Investigator.  
 Accidental/occupational exposure: The unintentional exposure to a study treatment 
as a result of one’s professional or non-professional occupation, or accidental 
exposure to a non-professional to whom exposure was not intended (i.e., study 
product given to wrong participant).  
 Suspected unexpected serious adverse reaction (SUSAR): A serious adverse 
reaction, the nature and severity of which are not consistent with the information 
about the medicinal product set out in the Investigator’s Brochure (IB) Reference 
Safety Information (RSI) section. 
Recording and Follow-up of AEs and SAEs  
 When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
related to the event. 
 The Investigator will then record all relevant AE/SAE information. 
 It is not acceptable for the Investigator to send photocopies of the participant’s 
medical records to GSK in lieu of completion of the GSK required form. 
 There may be instances when copies of medical records for certain cases are 
requested by GSK. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to GSK. 
 The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Expectedness  
Expectedness (whether an AE is “expected” or “unexpected”) will be determined by the 
Sponsor. An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information provided in the RSI for dostarlimab in 
the IB and for pembrolizumab, pemetrexed, cisplatin, and carboplatin in their respective 
prescribing information. 
Assessment of Intensity  
Investigators should assess the severity of AEs according to the National Cancer 
Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0. In 
general, NCI-CTCAE severity grades are as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated; easily tolerated 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 142 of 166 
 
 Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADLs) (instrumental ADLs 
refer to preparing meals, shopping for groceries or clothes, using the telephone, or 
managing money) 
 Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL (self-care ADLs refer to bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and being not bedridden) 
 Grade 4: Life-threatening consequences; urgent intervention indicated 
 Grade 5: Death related to AE 
A distinction should be made between serious and severe AEs. Severity is a measure of 
intensity, whereas seriousness is defined by the previously stated criteria. For example, a 
mild degree of gastrointestinal bleeding requiring an overnight hospitalization for 
monitoring purposes may be considered an SAE but is not necessarily severe. Similarly, 
an AE that is severe in intensity is not necessarily an SAE. For example, alopecia may be 
assessed as severe in intensity but may not be considered an SAE.  
Assessment of Causality  
The Investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. One of the following categories should be selected based on 
medical judgment, considering all contributing factors: 
 Related: A causal relationship between the medicinal product (or study procedures) 
and AE is a reasonable possibility. For example, the occurrence of the AE cannot be 
explained by other causative factors. The AE, however, can be explained by the 
pharmacological effect of the medicinal product such as a similar event having been 
reported previously, alteration of the dose effect, or the timing or seriousness of the 
AE. Positive rechallenge/dechallenge is supportive. 
 Not related: A causal relationship between the medicinal product (or study 
procedures) and AE is not a reasonable possibility; there is no temporal relationship 
between the medicinal product and the event, or an alternative etiology is more 
reasonable. 
 A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out. 
 The Investigator will use clinical judgment to determine the relationship. 
 Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 143 of 166 
 
 For each AE/SAE, the Investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
 There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the Investigator always assesses causality for every event before 
the initial transmission of the SAE data to GSK. 
 The Investigator may change his/her opinion of causality in light of follow-up 
information and may send an SAE follow-up report with the updated causality 
assessment. 
 The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Reporting of SAEs to GSK via Electronic Data Collection Tool  
 The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool. 
 If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) to report the event within 24 hours. 
 The site will enter the SAE data into the electronic system as soon as it becomes 
available. 
 After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data. 
 If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see next 
section) or to the GSK Medical Monitor or the SAE coordinator by telephone. 
 Contacts for SAE reporting can be found in the Study Reference Manual. 
SAE Reporting to GSK via Paper Data Collection Tool  
 Facsimile transmission of the SAE paper data collection tool is the preferred method 
to transmit this information to the GSK Medical Monitor or the SAE coordinator. 
 In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service. 
 Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the SAE data collection tool within the designated reporting time 
frames. 
 Contacts for SAE reporting can be found in Study Reference Manual. 


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 144 of 166 
 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 145 of 166 
 
APPENDIX 10. ABBREVIATIONS AND DEFINITIONS OF TERMS  
The following abbreviations and specialist terms are used in this study protocol. 
Table 24: 
Abbreviations and Specialist Terms 
Abbreviation or Specialist 
Term 
Explanation 
ADL 
activity of daily living 
AE 
adverse event 
AESI 
adverse event of special interest 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BICR 
blinded independent central review 
BOR 
best overall response 
BRAF 
proto-oncogene B-raf 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
COVID-19 
Corona virus disease 2019 
CR 
complete response 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
CTLA-4 
cytotoxic T-lymphocyte-associated protein 4 
CV 
coefficient of variation 
DICOM 
Digital Imaging and Communications in Medicine 
DRE 
disease-related event 
DRESS 
drug reaction with eosinophilia and systemic symptoms 
ECG 
electrocardiogram 
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 146 of 166 
 
Table 24: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist 
Term 
Explanation 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor 
EOT 
End-of-Treatment 
EU 
European Union 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FFPE 
formalin-fixed paraffin-embedded 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HR 
hazard ratio 
HRT 
hormone replacement therapy 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IND 
Investigational New Drug 
irAE 
immune-related adverse event 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous(ly) 
mAb 
monoclonal antibody 
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 147 of 166 
 
Table 24: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist 
Term 
Explanation 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria 
for Adverse Events 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PD-L1 
programmed death-ligand 1 
PD-L2 
programmed death-ligand 2 
PET 
positron emission tomography 
PFS 
progression-free survival 
PR 
partial response 
Q3W 
every 3 weeks 
Q6W 
every 6 weeks 
Q9W 
every 9 weeks 
Q12W 
every 12 weeks 
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate according to Bazett’s 
formula 
QTcF 
QT interval corrected for heart rate according to Fridericia’s 
formula 
QTL 
quality tolerance limit 
RAP 
Reporting and Analysis Plan 
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 148 of 166 
 
Table 24: 
Abbreviations and Specialist Terms (Continued) 
Abbreviation or Specialist 
Term 
Explanation 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS-1 
receptor tyrosine kinase-1 
SAE 
serious adverse event 
SD 
stable disease 
SJS 
Stevens-Johnson syndrome 
SoA 
schedule of activities 
SUSAR 
suspected unexpected serious adverse reaction 
T1DM 
Type 1 diabetes mellitus 
TEAE 
treatment-emergent adverse event 
TEN 
toxic epidermal necrolysis 
TPS 
tumor proportion score 
ULN 
upper limit of normal 
US 
United States 
WOCBP 
woman of childbearing potential 
WONCBP 
woman of non-childbearing potential 
 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 149 of 166 
 
APPENDIX 11. PROTOCOL AMENDMENT SUMMARIES OF 
CHANGE – PRIOR VERSIONS  
Overall Rationale Amendment 01 (24 July 2020)  
Table 25: 
Summary of Changes for Amendment 1 
Section(s) Affected 
Description of Change 
Brief Rationale 
Headers, cover page, and 
Protocol Amendment Summary 
of Changes 
Headers and cover page were 
updated with new version 
number; headers were 
updated with new document 
number; Protocol Amendment 
Summary of Changes section 
was added per the Sponsor’s 
protocol template as this is the 
first amendment for the 
protocol. 
Section 1.1. Synopsis, Table 3. 
Objectives and Endpoints for 
Study 213403  
 
Section 1.1. Synopsis, Overall 
Design 
 
Section 3. Objectives and 
Endpoints, Table 6. Objectives 
and Endpoints for Study 213403 
 
Section 4.1 Overall Design 
 
Section 5.1 Inclusion Criteria, #2. 
 
Section 8.1. Hypothesis 
Included BRAF V600E 
mutation and other genomic 
aberrations for which an 
approved targeted therapy is 
available in the disease 
eligibility criterion 
Section 6.1 Study Treatments 
Administered, Table 9. Study 
Treatments for Study 213403 
Removed the row for “IMP 
and NIMP” definitions. 
 
Changed the “Use” for 
pembrolizumab from 
“background intervention” to 
“comparator”. 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 150 of 166 
 
 
Amendment 1 DEU-1 (07 January 2021) 
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 neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
Summary of Changes for the Amendment 
Table 26: 
Summary of Changes for Amendment 1 DEU-1 
Section(s) Affected 
Description of Change 
Brief Rationale 
Headers, cover page, Protocol 
Amendment Summary of 
Changes, and Appendix 11. 
Protocol Amendment History 
Headers and cover page were 
updated with new version 
number; headers were 
updated with new document 
number; Protocol 
Amendment Summary of 
Changes section was updated 
to include rationale for this 
amendment and 
administrative information 
for prior amendment was 
moved to new Appendix 11. 
Protocol Amendment History 
Section 1.3. Schedule of 
Activities/Table 4: Schedule 
of Activities for Study 
213403  
Section 6.1.3 Chemotherapy 
(Pemetrexed, Cisplatin, and 
Carboplatin) 
Amended to correct 
inaccurate infusion times for 
chemotherapy agents 
Section 2.2.5.1. Efficacy of 
Dostarlimab in NSCLC 
(renamed section; previously, 
“Dostarlimab in NSCLC”) 
Section 2.2.5.2. Safety of 
Dostarlimab (new section) 
Updated efficacy and safety 
information for dostarlimab 
added 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 151 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 5.6. 
Withdrawal/Stopping Criteria  
Reasons for required 
withdrawal/discontinuation 
was updated to more 
explicitly differentiate 
between scenarios requiring 
discontinuation and potential 
scenarios 
Section 6.3.2. Blinding 
Instructions for emergency 
unblinding during the course 
of the study added 
Section 6.4.1. Dose Levels 
and Dose Adjustment/Table  
 
Instructions for Dose 
Modifications updated in 
Table 12 
Instructions for Dose 
Modifications updated in 
Table 13  
Abbreviation: NSCLC=non-small cell lung cancer. 
 
Amendment of Amendment 1 DEU-1 (07 January 2021) to Amendment 
3  
Summary of Changes for the Amendment  
Table 27: Summary of Changes from Amendment 1 DEU-1 (07 January 2021) to 
Amendment 3 (17 June 2021) 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 152 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Synopsis, Table 3 Objectives 
and Endpoints 
Section 3 Objectives and 
Endpoints, Table 6 
Objectives and Endpoints 
Section 8.3.1. Analysis 
Populations 
Synopsis, Overall Study 
Design 
Synopsis, Table 4 Schedule 
of Activities 
Section 7.5.1. Time Period 
and Frequency for Collecting 
AE and SAE Information 
Correction to timeframe for 
reporting adverse events 
(AEs). Rather than all AEs 
being reported from signing 
of the informed consent, only 
treatment-related serious 
adverse events (SAEs) will 
reported from signing of the 
informed consent and all AEs 
will be reported from the start 
of study treatment. 
Synopsis, Overall Study 
Design 
Synopsis, Table 4 Schedule 
of Activities 
Section 4.1 Overall Design 
Section 7.2.2. Baseline 
Tumor Assessment 
(Documentation of Target 
and Non target Lesions) 
Baseline tumour assessment 
of the chest and abdomen 
should be collected within 35 
days prior to first dose, not 28 
days. 
Synopsis, Overall Study 
Design 
Section 4.1 Overall Design 
Section 7.2.2. Baseline 
Tumor Assessment 
(Documentation of Target 
and Non target Lesions) 
Text updated: 
The CT component of 
positron emission 
tomography (PET)/CT may 
be used according to RECIST 
v1.1 guidelines, with full 
radiation dose diagnostic CT 
and IV CT contrast, and as 
clinically indicated 
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 153 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Synopsis, Table 4 Schedule 
of Activities 
Text updated: 
Treatment cycles are 21 days 
long with dosing scheduled 
on D1 of each cycle.  
All assessments should be 
done prior to drug 
administration and within 
72 h prior to 1st dose of 
study drugs administrated 
in that cycle, unless 
otherwise specified. (VB: 
this includes C1D1 and all 
cycles).  
Visits starting at Cycle 2 
can be performed ±3 days of 
the scheduled date. 
Synopsis, Table 4 Schedule 
of Activities 
For archival (or fresh) tumor 
tissue samples, additional 
instruction added: 
If PD-L1 status is known 
and the participant has 
agreed to provide archival 
sample via the optional 
consent, this sample may be 
provided within 28 days of 
the start of study treatment. 
Synopsis, Table 4 Schedule 
of Activities 
Synopsis, Table 4 Schedule 
of Activities 
Synopsis, Table 4 Schedule 
of Activities 
Section 1.3, Table 4 Schedule 
of Activities 
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 154 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Synopsis, Table 4 Schedule 
of Activities 
Clarification added that 
urinalysis starts at Cycle 6, 
Day 1 
Synopsis, Table 4 Schedule 
of Activities 
Clarification added that 
urinalysis starts at Cycle 2, 
Day 1 
Section 2.2.1 Lung Cancer 
Removed statement on EU 
approval of pembrolizumab 
monotherapy in NSCLC. 
Section 2.2.5.1. Efficacy of 
Dostarlimab in NSCLC 
(renamed section; previously, 
“Dostarlimab in NSCLC”) 
Section 2.2.5.2. Safety of 
Dostarlimab (new section) 
Updated efficacy and safety 
information for dostarlimab 
added. 
Section 2.3.1 Risk 
Assessment, Table 5 Risk 
Assessment 
Add additional detail on the 
potential risks of exposure to 
ionizing radiation, due to the 
inclusion in the study of CT 
scans. 
Section 5.1 Inclusion Criteria; 
Section 7.4.7 Pregnancy 
Testing;  
Section 7.5.1 Time Period 
and Frequency for Collecting 
AE and SAE Information;  
Section 7.5.5 Pregnancy; and 
Appendix 5, Contraceptive 
and Barrier Guidance 
The protocol was revised to 
note the duration of 
contraception for female and 
males post chemotherapy 
must be consistent with local 
regulations with a minimum 
of 180 days for males and 
females, consistent with 
dostarlimab guidance. 
Section 5.1 Inclusion Criteria 
Reworded inclusion criteria 
3:  
Target Measurable lesions 
situated in a previously 
irradiated area are may be 
considered measurable target 
lesions if progression has 
been demonstrated in such 
lesions and if there are other 
target lesions.  
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 155 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 5.2 Inclusion Criteria 
Reworded exclusion criteria 
8: 
Participant has an additional 
malignancy or a history of 
prior malignancy, with the 
exception of adequately 
treated basal or squamous 
skin cancer, cervical 
carcinoma in situ, or 
superficial bladder 
carcinoma in situ cancer 
without evidence of disease, 
other in situ cancers, or had 
a malignancy treated with 
curative intent and with no 
evidence of disease 
recurrence for 5 years since 
the initiation of that therapy. 
Section 5.2 Inclusion Criteria 
Appendix 3. Clinical 
Laboratory Tests 
Removed the requirement for 
participants who test positive 
for the presence of hepatitis B 
core antibody to be excluded. 
Section 5.6. 
Withdrawal/Stopping Criteria 
Reasons for required 
withdrawal/discontinuation 
was updated to more 
explicitly differentiate 
between scenarios requiring 
discontinuation and potential 
scenarios 
Section 6.1.3. Chemotherapy 
(Pemetrexed, Cisplatin, and 
Carboplatin) 
The protocol was amended to 
provide additional flexibility 
for local guidelines with 
relation to infusion times for 
chemotherapy agents. 
Section 7.1.1. General 
Guidance for Treatment 
Continuity when Participants 
are Unable to Come into the 
Clinic 
Instructions for the collection 
of PROs updated in Table 15. 
Section 7.3.1.1. Objective 
Response Rate 
Added definition of best 
overall response as 
confirmed CR or PR. 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 156 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Appendix 1. Guidelines for 
Assessment of Disease, 
Disease Progression, and 
Response Criteria 
Amended the use of X-rays 
for the assessment of 
measurable lesions to the 
assessment of progression 
due to new lesions. 
Appendix 1. Guidelines for 
Assessment of Disease, 
Disease Progression, and 
Response Criteria 
Remove the definition of a 
measurable lesion as 10 mm 
caliper/ruler measurement by 
clinical examination or 
medical photography 
Appendix 3. Clinical 
Laboratory Tests 
Added statement to clarify 
laboratory assessments for 
each cycle can occur up to 72 
hours before treatment 
Appendix 8. Adverse Events, 
Serious Adverse Events, and 
Special Situations: 
Definitions and Procedures 
for Recording, Follow-up, 
Evaluating, and Reporting 
Removed all references to the 
eCRF requirement for 
documenting causality 
review. 
 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 157 of 166 
 
Amendment 2 (10 September 2020)  
Overall Rationale for the Amendment  
Summary of Changes for the Amendment  
Table 28: 
Summary of Changes for Amendment 02 
Section(s) Affected 
Description of Change 
Brief Rationale 
Headers, cover page, and 
Protocol Amendment 
Summary of Changes 
Headers and cover page were 
updated with new version 
number; headers were 
updated with new document 
number; Protocol 
Amendment Summary of 
Changes section was updated 
to include rationale for this 
version. 
Section 1.1 Protocol 
Summary, Rationale 
Corrected typographical error 
incorrectly capturing 
GARNET lung cancer 
population as previously 
“untreated” NSCLC patients 
Section 5.1 Inclusion Criteria; 
Section 7.4.7 Pregnancy 
Testing;  
Section 7.5.1 Time Period 
and Frequency for Collecting 
AE and SAE Information;  
Section 7.5.5 Pregnancy; and 
Appendix 5, Contraceptive 
and Barrier Guidance 
The protocol was revised to 
note the duration of 
contraception for female and 
males post chemotherapy 
must be consistent with local 
regulations with a minimum 
of 180 days for males and 
females, consistent with 
dostarlimab guidance. 
Section 6.1.3 Chemotherapy; 
and 1.3 Schedule of Activities 
The protocol was amended to 
provide additional flexibility 
for local guidelines with 
relation to infusion times for 
chemotherapy agents 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 158 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 5.6 
Withdrawal/Stopping 
Criteria; and Section 1.3 
Schedule of Activities 
Criteria for treatment 
withdrawal/stopping rules 
was clarified to include the 
text “or other adverse event” 
to the criterion of 
unacceptable toxicity 
 
Amendment 3 (17 June 2021)  
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 neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
Summary of Changes for the Amendment  
Table 29: 
Summary of Changes for Amendment 03 
Section(s) Affected 
Description of Change 
Brief Rationale 
Headers, cover page, and 
Protocol Amendment 
Summary of Changes 
Headers and cover page were 
updated with new version 
number; headers were 
updated with new document 
number; Protocol 
Amendment Summary of 
Changes section was updated 
to include rationale for this 
version. 
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 159 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, Table 3 
Objectives and Endpoints 
Section 3 Objectives and 
Endpoints, Table 6 
Objectives and Endpoints 
Section 8.3.1. Analysis 
Populations 
Section 1.1 Synopsis, Table 3 
Objectives and Endpoints 
Section 3 Objectives and 
Endpoints, Table 6 
Objectives and Endpoints 
Section 1.1 Synopsis, Overall 
Study Design 
Section 1.3, Table 4 Schedule 
of Activities 
Section 4.1 Overall Design 
Section 7.5.1. Time Period 
and Frequency for Collecting 
AE and SAE Information 
Correction to timeframe for 
reporting adverse events 
(AEs). Rather than all AEs 
being reported from signing 
of the informed consent, only 
treatment-related serious 
adverse events (SAEs) will 
reported from signing of the 
informed consent and all AEs 
will be reported from the start 
of study treatment. 
Section 1.1 Synopsis, Overall 
Study Design 
Section 1.3, Table 4 Schedule 
of Activities 
Section 4.1 Overall Design 
Section 7.2.2. Baseline 
Tumor Assessment 
(Documentation of Target 
and Non target Lesions) 
Baseline tumour assessment 
of the chest and abdomen 
should be collected within 35 
days prior to first dose, not 28 
days. 
CCI
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 160 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, Overall 
Study Design 
Section 4.1 Overall Design 
Section 7.2.2. Baseline 
Tumor Assessment 
(Documentation of Target 
and Non target Lesions) 
Text updated: 
The CT component of 
positron emission 
tomography (PET)/CT may 
be used according to RECIST 
v1.1 guidelines, with full 
radiation dose diagnostic CT 
and IV CT contrast, and as 
clinically indicated 
Section 1.3, Table 4 Schedule 
of Activities 
Text updated: 
Treatment cycles are 21 days 
long with dosing scheduled 
on D1 of each cycle.  
All assessments should be 
done prior to drug 
administration and within 
72 h prior to 1st dose of 
study drugs administrated 
in that cycle, unless 
otherwise specified. 
Visits starting at Cycle 2 
can be performed ±3 days of 
the scheduled date. 
Section 1.3, Table 4 Schedule 
of Activities 
For archival (or fresh) tumor 
tissue samples, additional 
instruction added: 
If PD-L1 status is known 
and the participant has 
agreed to provide archival 
sample via the optional 
consent, this sample may be 
provided within 28 days of 
the start of study treatment. 
Section 1.3, Table 4 Schedule 
of Activities 
Additional assessment 
“Evaluate genomic 
aberration” added 
Section 1.3, Table 4 Schedule 
of Activities 
Additional instruction added 
for optional blood sample for 
genetic testing to clarify 
sample may be obtained after 
randomization during first 
cycle if not collected at 
screening.  
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 161 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 1.3, Table 4 Schedule 
of Activities 
Section 1.3, Table 4 Schedule 
of Activities 
Section 1.3, Table 4 Schedule 
of Activities 
Clarification added that 
urinalysis starts at Cycle 6, 
Day 1 
Section 1.3, Table 4 Schedule 
of Activities 
Clarification added that 
thyroid panel starts at Cycle 
2, Day 1 
Section 2.2.1 Lung Cancer 
Removed statement on EU 
approval of pembrolizumab 
monotherapy in NSCLC. 
Section 2.2.5.1. Efficacy of 
Dostarlimab in NSCLC 
(renamed section; previously, 
“Dostarlimab in NSCLC”) 
Section 2.2.5.2. Safety of 
Dostarlimab (new section) 
Updated efficacy and safety 
information for dostarlimab 
added. 
Section 2.3.1 Risk 
Assessment, Table 5 Risk 
Assessment 
Add additional detail on the 
potential risks of exposure to 
ionizing radiation, due to the 
inclusion in the study of CT 
scans. 
Section 5.1 Inclusion Criteria 
Reworded inclusion criteria 
3:  
Target Measurable lesions 
situated in a previously 
irradiated area are may be 
considered measurable target 
lesions if progression has 
been demonstrated in such 
lesions and if there are other 
target lesions.  
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 162 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 5.2 Exclusion Criteria Reworded exclusion criteria 
8: 
Participant has an additional 
malignancy or a history of 
prior malignancy, with the 
exception of adequately 
treated basal or squamous 
skin cancer, cervical 
carcinoma in situ, or 
superficial bladder 
carcinoma in situ cancer 
without evidence of disease, 
other in situ cancers, or had 
a malignancy treated with 
curative intent and with no 
evidence of disease 
recurrence for 5 years since 
the initiation of that therapy. 
Section 5.2 Exclusion Criteria 
10 
Appendix 3. Clinical 
Laboratory Tests 
Removed the requirement for 
participants who test positive 
for the presence of hepatitis B 
core antibody to be excluded. 
Section 5.6. 
Withdrawal/Stopping Criteria 
Reasons for required 
withdrawal/discontinuation 
was updated to more 
explicitly differentiate 
between scenarios requiring 
discontinuation and other 
potential scenarios 
Section 6.1.3. Chemotherapy 
(Pemetrexed, Cisplatin, and 
Carboplatin) 
Pemetrexed should be 
administered according to the 
local label, thus guidance on 
infusion rate has been 
removed. 
Section 6.3.2. Blinding 
Instructions for emergency 
unblinding during the course 
of the study added 
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 163 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 6.4. Planned Dose 
Adjustments 
Instructions for Dose 
Modifications for Non-
hematological Chemotherapy 
Toxicities updated in 
Table 12. 
Removed the requirement for 
PD-1 inhibitors be withheld 
in the event of all drug-
related toxicities. 
Instructions for Dose 
Modification Guidelines for 
PD-1 Inhibitor Related AEs 
updated in Table 13. 
Section 7.1.1. General 
Guidance for Treatment 
Continuity when Participants 
are Unable to Come into the 
Clinic 
Section 7.3.1.1. Objective 
Response Rate 
Added definition of best 
overall response as 
confirmed CR or PR. 
Section 7.11. Biomedical 
Research 
Re-titled from Section 7.11. 
Future Biomedical Research 
Appendix 1. Guidelines for 
Assessment of Disease, 
Disease Progression, and 
Response Criteria 
Amended the use of X-rays 
for the assessment of 
measurable lesions to the 
assessment of progression 
due to new lesions. 
CCI
CCI
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 164 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
Appendix 1. Guidelines for 
Assessment of Disease, 
Disease Progression, and 
Response Criteria 
Remove the definition of a 
measurable lesion as 10 mm 
caliper/ruler measurement by 
clinical examination or 
medical photography 
Appendix 3. Clinical 
Laboratory Tests 
Added statement to clarify 
laboratory assessments for 
each cycle can occur up to 72 
hours before treatment 
Appendix 8. Adverse Events, 
Serious Adverse Events, and 
Special Situations: 
Definitions and Procedures 
for Recording, Follow-up, 
Evaluating, and Reporting 
Removed all references to the 
eCRF requirement for 
documenting causality 
review. 
 
Amendment 4 (30 November 2021)  
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 neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. 
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 165 of 166 
 
Summary of Changes for the Amendment 04  
Table 30: 
Summary of Changes for Amendment 04 
Section(s) Affected 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis - 
Treatment Groups and 
Duration  
Section 4.1 Overall Design - 
Treatment Groups and 
Duration  
Section 8.2 Sample Size 
Considerations 
Removed number of 
participants limit per strata 
Section 1.3 Schedule of 
Activities (Table 4) 
Section 6.4.2.1. Management 
of PD-1 Inhibitor-related AEs 
(Table 13: Dose Modification 
Guidelines for PD-1 
Inhibitor-related AEs) 
 
Removed superscript 
“Permanently discontinue” 
for Grade 4 severity was 
removed from adrenal 
insufficiency, hypophysitis, 
hypothyroidism and 
hyperthyroidism.  
CCI
CCI


RPS-CLIN-050714 
 
CONFIDENTIAL 
 
 
Clinical Study Protocol 213403 Version 05 
Page 166 of 166 
 
Section(s) Affected 
Description of Change 
Brief Rationale 
 Updated dose 
modifications for adrenal 
insufficiency to include 
endocrine consultation as 
follow-up. 
 Expanded dose 
modifications for 
Guillain-Barré syndrome 
to include several severe 
neurological events 
(myasthenic 
syndrome/myasthenia 
gravis and transverse 
myelitis were added), to 
include Grade 2, to 
include corticosteroid and 
other therapy guidelines, 
and to include neurology 
consultation as follow-up. 
 Updated dose 
modifications for 
myocarditis. 
 Added DRESS to dose 
modifications for 
rash/skin reactions. 
 Added corticosteroid and 
other therapy guidelines 
and consultation 
follow-up for Other 
irARs. 
Removed the incorrect 
footnote that the decision to 
withhold or discontinue PD-1 
inhibitor is at the discretion of 
the Investigator or treating 
physician. 
 
CCI


Signature Page for RPS-CLIN-050714 v2.0
Signature Page for RPS-CLIN-050714 v2.0
Approval
I am signing for the reasons as stated in the document.
14-Feb-2023 21:46:10 GMT+0000
PPD

SAP_005.pdf: 
Statistical Analysis Plan Version 5
Study ID:  213403
Study Official Title: A Randomized, Phase 2, Double-blind Study to Evaluate the 
Efficacy of Dostarlimab Plus Chemotherapy Versus Pembrolizumab Plus Chemotherapy 
in Metastatic Non-Squamous Non-Small Cell Lung Cancer
NCT ID: NCT04581824
Date of Document: 22-Aug-2024


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
1 
Division 
: 
Worldwide Development 
Information Type 
: 
Statistical Analysis Plan (SAP) 
Title Page 
Protocol Title: 
A Randomized, Phase 2, Double-blind Study to Evaluate the 
Efficacy of Dostarlimab Plus Chemotherapy versus 
Pembrolizumab Plus Chemotherapy in Metastatic Non-Squamous 
Non-Small Cell Lung Cancer 
Protocol Number: 
213403 
Compound Number: GSK4057190 (Dostarlimab) 
Short Title: 
Efficacy Comparison of Dostarlimab Plus Chemotherapy vs 
Pembrolizumab Plus Chemotherapy in Participants with Metastatic 
Non-squamous Non-small Cell Lung Cancer 
Acronym: 
 
 
PERLA 
Sponsor Name:  
GlaxoSmithKline Research & Development Limited 
Regulatory Agency Identifier Number(s) 
Registry 
ID 
IND Number 
150997 
EudraCT 
Number 
2020-002327-11 
SAP Author(s): 
Author 
Principal Statistician, Study Lead 
Statistician, Development 
Biostatistics Oncology 
Statistician, Veramed 
Senior Statistician, Veramed 
PPD
PPD
PPD


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
2 
SAP Team Review Confirmations (Veeva Vault Confirmation): 
Reviewer 
Oncology Clinical Development 
 Clinical Scientist, Oncology 
Clinical Development  
 Safety Scientist 
SERM Principal Physician, Safety Physician 
Clinical Pharmacology (Oncology) 
Principal Programmer, Study Lead Programmer, 
Development Biostatistics Programming 
Oncology 
 Study Delivery Lead, Clinical 
Development  
  
 
, Medical Writing-Oncology  
 Project Statistician, 
Development Biostatistics Oncology 
SAP Biostatistics Line Approval (Pharma TMF eSignature): 
Approver 
 Project Statistician, 
Development Biostatistics Oncology 
Copyright 2024 the GlaxoSmithKline group of companies. All rights reserved. 
Unauthorized copying or use of this information is prohibited. 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
3 
TABLE OF CONTENTS 
PAGE 
VERSION HISTORY ....................................................................................................... 6 
1. 
INTRODUCTION .................................................................................................... 13 
1.1. 
Objectives, Estimands and Endpoints ......................................................... 13 
1.1.1. 
Objectives and Endpoints ............................................................ 13 
1.1.2. 
Estimands .................................................................................... 15 
1.2. 
Study Design .............................................................................................. 16 
2. 
STATISTICAL HYPOTHESES ............................................................................... 18 
2.1. 
Multiplicity Adjustment ................................................................................ 18 
3. 
ANALYSIS SETS ................................................................................................... 19 
4. 
STATISTICAL ANALYSES ..................................................................................... 20 
4.1. 
General Considerations .............................................................................. 20 
4.1.1. 
General Methodology .................................................................. 20 
4.1.2. 
Baseline Definition ....................................................................... 21 
4.1.3. 
Multicenter Studies ...................................................................... 21 
4.1.4. 
Visit Windows .............................................................................. 21 
4.1.5. 
Study Population Summaries ....................................................... 21 
4.2. 
Primary Endpoint Analyses ......................................................................... 22 
4.2.1. 
Definition of endpoint ................................................................... 22 
4.2.2. 
Main analytical approach ............................................................. 22 
4.2.3. 
Sensitivity analyses ..................................................................... 23 
4.3. 
Secondary Endpoints Analyses .................................................................. 23 
4.3.1. 
Definition of endpoints ................................................................. 23 
4.3.1.1. 
Overall Survival (OS) .................................................. 23 
4.3.1.2. 
Progression-Free Survival per RECIST v1.1 
(PFS) .......................................................................... 24 
4.3.2. 
Main analytical approach ............................................................. 25 
4.3.2.1. 
Overall Survival (OS) .................................................. 25 
4.3.2.2. 
Progression-Free Survival per RECIST v1.1 
(PFS) .......................................................................... 25 
4.4. 
Supportive Secondary Endpoint(s) ............................................................. 26 
4.4.1. 
Adverse Events/Serious Adverse Events ..................................... 26 
4.4.1.1. 
Adverse Events of Special Interest ............................. 28 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
4 
4.7. 
Interim Analyses ......................................................................................... 40 
4.8. 
Changes to Protocol Defined Analyses ....................................................... 40 
5. 
SAMPLE SIZE DETERMINATION ......................................................................... 41 
6. 
SUPPORTING DOCUMENTATION ....................................................................... 41 
6.1. 
Appendix 1 Abbreviations and Trademarks ................................................. 41 
6.1.1. 
List of Abbreviations .................................................................... 41 
6.1.2. 
Trademarks ................................................................................. 43 
7. 
REFERENCES ....................................................................................................... 45 
 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
5 
LIST OF TABLES 
PAGE 
Table 1 ............ SAP Version History Summary ................................................................. 6 
Table 2 ............ Estimands .............................................................................................. 15 
Table 3 ............ Analysis Sets ......................................................................................... 19 
Table 6 ............ Adverse Events of Special Interest ......................................................... 29 
 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
6 
VERSION HISTORY 
Table 1 
SAP Version History Summary 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
1 
15 March 
2022 
Version 04 
30 
November 
2021 
Not Applicable 
Original version 
2 
27 July 
2022 
Version 04 
30 
November 
2021 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
7 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
3 
07 June 
2023 
Version 05 
14 February 
2023 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
8 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
4 
16 April 
2024 
Version 05 
14 February 
2023 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
9 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
10 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
11 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
5 
22 Aug 
2024 
Version 05 
14 February 
2024  
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
12 
SAP 
Version 
Document 
Date 
Protocol 
Version 
(Date) on 
which SAP 
is Based 
Change 
Rationale 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
13 
1. 
INTRODUCTION 
The purpose of this SAP is to describe the planned analyses to be included in the Clinical 
Study Report for Study 213403 (PERLA). Details of the final analyses are provided. 
Descriptive study population analyses such as summary of demography and baseline 
characteristics and additional detail with regards to data handling conventions and the 
specification of data displays will be provided in the Output and Programming 
Specification (OPS) document. 
1.1. 
Objectives, Estimands and Endpoints 
1.1.1. 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To compare the ORR of PD1 inhibitor dostarlimab vs 
pembrolizumab administered in combination with 
chemotherapy as evaluated using RECIST v1.1 based 
on BICR in participants with metastatic nonsquamous 
NSCLC, without a known EGFR, ALK, ROS1, or BRAF 
V600E mutation or other genomic aberration for which 
an approved targeted therapy is available, who have 
received no prior treatment of metastatic disease 
• 
The primary efficacy endpoint ORR will be 
evaluated by RECIST v1.1 based on BICR and 
will be defined as the proportion of participants 
with BOR of CR or PR in the analysis population. 
Secondary 
• 
To evaluate the following measures of clinical 
benefit of PD-1 inhibitor administered in 
combination with chemotherapy: 
− 
OS 
− 
PFS evaluated using RECIST v1.1 based 
on Investigator assessment 
• 
OS will be defined as the time from the date of 
randomization to the date of death by any cause. 
• 
PFS will be evaluated using RECIST v1.1 based 
on Investigator assessment and will be defined as 
the time from the date of randomization to the 
date of PD or death by any cause, whichever 
occurs first. 
• 
To evaluate the safety of PD-1 inhibitor in 
combination with chemotherapy 
Assess the incidence of TEAEs, SAEs, irAEs, TEAEs 
leading to death, and AEs leading to discontinuation 
occurring while participants are on treatment or up to 90 
days after the last dose of study treatment. Clinical 
laboratory parameters (hematology, chemistry, thyroid 
function, urinalysis), vital signs, ECOG performance 
status, ECG parameters, physical examinations, and 
usage of concomitant medications will be collected. 
Exploratory 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
14 
Objectives 
Endpoints 
Exploratory (continued) 
Abbreviations: 
; ALK=anaplastic lymphoma kinase; BICR=blinded 
independent central review; 
e; BRAF= proto-oncogene B-raf; 
 
; CR=complete response; 
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
15 
; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; EGFR=epidermal growth factor receptor; 
 
 
 
EOT=End-of-Treatment; 
 
 irAE=immune-related adverse event; 
; NSCLC=non-small cell lung cancer; ORR=objective response rate; OS=overall 
survival; PD=progressive disease; PD-1=programmed cell death protein 1; 
 
PFS=progression-free survival; 
 
 
 RECIST=Response Evaluation Criteria in Solid 
Tumors; ROS-1=receptor tyrosine kinase-1; SAE=serious adverse event; TEAE=treatment-emergent adverse event; 
 
 
1.1.2. 
Estimands 
Table 2 
Estimands 
Objective 
Estimand 
Category  
Estimand 
Population 
Variable/ 
Endpoint 
Intercurrent Event 
Strategy 
Population 
Level 
Summary 
Measure 
Primary Objective: 
To compare the 
ORR of dostarlimab 
vs pembrolizumab 
administered in 
combination with 
chemotherapy as 
evaluated using 
RECIST v1.1 based 
on BICR in 
participants with 
metastatic non-
squamous NSCLC, 
without a known 
EGFR, ALK, ROS-1, 
or BRAF V600E 
mutation or other 
genomic aberration 
for which an 
approved targeted 
Primary  
Participants with 
metastatic non-
squamous 
NSCLC, without a 
known EGFR, 
ALK, ROS-1, or 
BRAF V600E 
mutation or other 
genomic 
aberration for 
which an 
approved targeted 
therapy is 
available, who 
have received no 
prior treatment of 
metastatic disease 
ORR 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
16 
Objective 
Estimand 
Category  
Estimand 
Population 
Variable/ 
Endpoint 
Intercurrent Event 
Strategy 
Population 
Level 
Summary 
Measure 
therapy is available, 
who have received 
no prior treatment of 
metastatic disease 
1.2. 
Study Design 
Overview of Study Design and Key Features 
  
Abbreviations: 1L=first-line; NSCLC=non-small cell lung cancer. 
Note: Both arms will be stratified by PD-L1 status (TPS <1% vs 1% to 49% vs ≥50%) and smoking status (never vs 
former/current) 
Design Features • 
This is a randomized, Phase 2, double-blind, 2-arm study to compare 
the efficacy and safety of PD-1 inhibitors dostarlimab and 
pembrolizumab, when administered in combination with chemotherapy, 
in male and female participants 18 years and older with non-squamous 
NSCLC without a known sensitizing epidermal growth factor receptor 
(EGFR), anaplastic lymphoma kinase (ALK), receptor tyrosine kinase-1 
(ROS-1), or proto-oncogene B-raf (BRAF) V600E mutation or other 
genomic aberration for which an approved targeted therapy is available 
who have not received previous systemic anticancer therapy for 
metastatic disease. 
• 
Approximately 240 participants will be randomized in a 1:1 ratio into the 
dostarlimab plus chemotherapy arm or the pembrolizumab plus 
chemotherapy arm, such that approximately 120 evaluable participants 
in each of the 2 arms complete the study. 
• 
Randomization will be stratified by:  
o 
PD-L1 status of the tumor (TPS <1% versus 1% to 49% versus 
≥50%); 


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
17 
Overview of Study Design and Key Features 
o 
Smoking status (never versus former/current).  
• 
The study consists of a Screening Period (Day -28 to Day -1) for 
completion of all Screening assessments and subsequent 
randomization, a Treatment Period, an EOT Visit (within 7 days of the 
decision to discontinue treatment for any reason), a Safety Follow-up 
Period with a visit at 30 (+7) and 90 (+7) days after the last dose of 
study treatment, and a Post-treatment Follow-up Period with 
assessments occurring 180 days after the last dose of study treatment 
and every 90 (±14) days thereafter, continuing until death, withdrawal of 
consent, or the end of study data collection. 
• 
The study will last approximately 5 years. During the Treatment Period 
participants will take part in up to 35 cycles with a visit frequency of 
Q3W (cycles are 21 [±3] days). 
Study 
intervention 
• 
Dostarlimab will be administered through a 30-minute infusion at a 
dose of 500 mg IV Q3W up to a maximum of 35 cycles total 
(approximately 24 months). 
• 
Pembrolizumab will be administered through a 30-minute infusion at a 
dose of 200 mg Q3W up to a maximum of 35 cycles total 
(approximately 24 months). 
• 
Chemotherapy (standard of care) will be administered to participants in 
both treatment arms: 
o 
Pemetrexed will be administered at 500 mg/m2 IV through a 10-
minute IV infusion Q3W, up to a maximum of 35 cycles total 
(approximately 24 months).  
o 
Platinum chemotherapy (Cisplatin / Carboplatin) will be 
administered for the first 4 cycles only, following Pemetrexed 
administration. 
▪ 
If selected by the Investigator, Cisplatin (75 mg/m2) will be 
administered via IV infusion (approximately 30 minutes after 
pemetrexed infusion) Q3W for the first 4 cycles. 
▪ 
If selected by the Investigator, Carboplatin will be 
administered at area under the concentration-time curve 5 
mg/mL/min (AUC 5 mg/mL/min) Q3W immediately following 
the pemetrexed infusion for 4 cycles. 
Study 
intervention 
Assignment 
• 
Participants who meet eligibility criteria will be randomized in a 1:1 ratio 
into the dostarlimab plus chemotherapy arm or the pembrolizumab plus 
chemotherapy arm, such that approximately 120 evaluable participants 
in each of the 2 arms complete the study. The randomization will be 
stratified by PD-L1 status of the tumor (TPS <1% vs 1% to 49% vs 
≥50%) and smoking status (never vs former/current). 


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
18 
Overview of Study Design and Key Features 
Interim Analysis • 
No formal interim analysis is planned for this study. 
 
 
 
 
Supplementary 
Analysis 
End of Study 
Analysis 
2. 
STATISTICAL HYPOTHESES  
The primary efficacy endpoint, ORR using RECIST v1.1 based on BICR, of dostarlimab 
plus chemotherapy is similar to that of pembrolizumab plus chemotherapy in participants 
with metastatic non-squamous NSCLC without a known EGFR, ALK, ROS-1, or BRAF 
V600E mutation or other genomic aberration for which an approved targeted therapy is 
available and who have not received prior treatment of metastatic disease. 
2.1. 
Multiplicity Adjustment 
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
19 
3. 
ANALYSIS SETS 
The analysis sets are presented in Table 4. 
Table 3 
Analysis Sets 
Analysis Set 
Screened 
Enrolled 
Intent-to-treat (ITT) 
Response Evaluable 
Per protocol  
(PP) 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
20 
Analysis Set 
Definition / Criteria 
Analyses Evaluated 
Safety 
1. 
4. 
STATISTICAL ANALYSES 
4.1. 
General Considerations 
4.1.1. 
General Methodology 
The ITT Set will be used for all Study Population analyses and Efficacy analyses and the 
Safety Analysis Set will be used for all safety analyses, unless otherwise stated. 
Analysis and summaries performed on the ITT set will be presented by treatment 
assigned to the participant during randomization unless otherwise specified. 
 
 
 
 
 
 
 
 
  
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
21 
4.1.2. 
Baseline Definition 
 
4.1.3. 
Multicenter Studies 
In this multicenter global study, enrolment will be presented by country and site. 
4.1.4. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. 
 
 
 
 
4.1.5. 
Study Population Summaries 
The OPS document will provide additional details regarding the participant disposition 
and study population summaries, including, but not limited to the following: 
• 
Participant status and disposition 
• 
Treatment status and reasons for discontinuation of study treatment 
• 
Screen status and reasons for screen failures 
• 
Participants by country and site ID 
• 
Important protocol deviations 
• 
Study populations 
• 
Demographics and baseline characteristics (including age, gender, ethnicity, race, 
and stratification factors: smoking status and PD-L1 status) 
• 
Medical history / physical exam 
• 
Advanced/Metastatic NSCLC history 
• 
Prior anti-cancer therapy, prior radiotherapy and prior surgery  
• 
Subsequent anti-cancer therapy  
• 
Prior and concomitant medications 
• 
Concomitant procedures 
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
22 
4.2. 
Primary Endpoint Analyses 
The primary efficacy endpoint objective response rate (ORR) will be evaluated by 
RECIST v1.1 based on blinded independent central review (BICR).  The primary analysis 
of ORR will be based on the ITT population, and a supportive sensitivity analysis will be 
performed on the response evaluable population and per-protocol population.  
4.2.1. 
Definition of endpoint 
ORR per RECIST v1.1 is defined as the proportion of patients who have a complete 
response (CR) or partial response (PR) as their best overall response (BOR) based on 
BICR. 
Best Overall Response (BOR) 
The best overall response is the best response recorded from the date of randomization until 
disease progression or initiation of new anti-cancer therapy, whichever is earlier, as 
assessed by the BICR per RECIST v1.1, using all scans regardless of whether they were 
scheduled or not. The order from best to worst of the available responses is CR, PR, stable 
disease (SD), progressive disease (PD) and not evaluable (NE).  In order to assign a BOR 
of CR or PR, a participant initial response must be confirmed by repeat assessment 
performed no less than 4 weeks after the initial criteria for response were met.  
4.2.2. 
Main analytical approach 
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
23 
4.2.3. 
Sensitivity analyses 
4.3. 
Secondary Endpoints Analyses 
The secondary efficacy endpoints overall survival (OS) and progression free survival 
(PFS) using RECIST v1.1 based on Investigator assessment will be evaluated. They will 
be summarized using the ITT population. 
4.3.1. 
Definition of endpoints 
4.3.1.1. 
Overall Survival (OS) 
Overall Survival (OS), defined as the interval of time (in months) from randomization to 
the date of death due to any cause, regardless of whether the patient withdraws from 
randomized therapy or receives another anti-cancer therapy.  
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
24 
4.3.1.2. 
Progression-Free Survival per RECIST v1.1 (PFS) 
Progression-free survival (PFS) per RECIST v1.1 based on investigator assessment, 
defined as the interval of time (in months) between the date of randomization and the 
earlier of the date of disease progression (PD) as assessed by the investigator per RECIST 
1.1 criteria and the date of death due to any cause.  
Determination of dates of PFS events and dates for censoring are described in Table 4. 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
25 
4.3.2. 
Main analytical approach 
4.3.2.1. 
Overall Survival (OS) 
4.3.2.2. 
Progression-Free Survival per RECIST v1.1 (PFS) 
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
26 
4.4. 
Supportive Secondary Endpoint(s) 
4.4.1. 
Adverse Events/Serious Adverse Events 
The safety analyses will be based on the Safety Analysis Set, unless otherwise specified. 
For reporting, adverse events will be coded using the standard MedDRA coding 
dictionary 
 
 
 Adverse events will be graded by the investigator according to 
the NCI-CTCAE, Version 5.0. A Standardized MedDRA Query (SMQ) will be used to 
identify all COVID-19 AEs. 
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
27 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
28 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
29 
4.5. 
Exploratory Endpoints Analyses 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
30 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
31 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
32 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
33 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
34 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
35 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
36 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
37 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
38 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
39 
4.6. 
Other Analyses 
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
40 
4.7. 
Interim Analyses 
No formal interim analysis is planned for this study. 
 
 
 
4.8. 
Changes to Protocol Defined Analyses 
Changes from the originally planned statistical analysis specified in the protocol 
amendment 5 (Dated: 14-FEB-2023) are outlined below. 
Protocol 
Statistical Analysis Plan 
Rationale for Changes 
• 
No formal interim analysis 
will be done for this study. 
• 
There is no protocol defined 
adverse events of special 
interest (AESI) for 
Dostarlimab. 
• 
Analyses of AESIs are 
based on pre-defined 
MedDRA PTs. 
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
41 
Protocol 
Statistical Analysis Plan 
Rationale for Changes 
5. 
SAMPLE SIZE DETERMINATION 
6. 
SUPPORTING DOCUMENTATION 
6.1. 
Appendix 1 Abbreviations and Trademarks 
6.1.1. 
List of Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine Aminotransferase 
BICR 
Blinded Independent Central Review 
BoR 
Best Overall Response 
CI 
Confidence Interval 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCO 
Data Cut-Off 
DCR 
Disease Control Rate 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
42 
Abbreviation 
Description 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Record Form 
EGFR 
Epidermal Growth Factor Receptor 
GSK 
GlaxoSmithKline 
HR 
Hazard Ratio 
irAE 
Immune Related Adverse Event 
ITT 
Intent-To-Treat 
MedDRA 
Medical Dictionary for Regulatory Affairs 
NE 
Not Evaluable 
NQ 
Non-quantifiable 
NSCLC 
Non-Small Cell Lung Cancer 
OPS 
Output and Programming Specification  
ORR 
Objective Response Rate 
OS 
Overall Survival 
PCI 
Potential Clinical Importance  
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PP 
Per-Protocol 
PR 
Partial Response 
PT 
Preferred Term 
QTc 
QT Interval Corrected for Heart Rate 
Q3W 
Every Three Weeks 
RECIST  
Response Evaluation Criteria in Solid Tumors 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SMQ 
Standardized MedDRA Query 
SOC 
System Order Class 
CCI
CCI
CCI
CCI
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
43 
Abbreviation 
Description 
TEAE 
Treatment Emergent Adverse Event 
TOI 
Term of Interest 
ULN 
Upper Limit of Normal 
6.1.2. 
Trademarks 
Trademarks of the GlaxoSmithKline Group 
of Companies 
 Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 MedDRA 
6.2. 
Appendix 2: Exclusions from Per Protocol Population 
The per-protocol population include all participants in the ITT who do not have protocol 
deviations that may significantly impact the interpretation of efficacy results. 
 
 
  
 
 
 
CCI
CCI
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
44 
CCI


CONFIDENTIAL 
 
 
Statistical Analysis Plan 213403 V5 
45 
7. 
REFERENCES 
CCI