A Phase III RCT Comparing Low Dose Immunotherapy (Nivolumab) Combined With Standard Chemotherapy vs Standard Chemotherapy as First-line Treatment in Patients With Locally Advanced or Metastatic NSCLC
Phase: PHASE3
Conditions: NSCLC (Non-small Cell Lung Carcinoma), First Line Therapy, Locally Advanced/Metastatic NSCLC
Sponsor: Dr Arvindran A/L Alaga

 
 
 
 
Title:  A Phase III Randomized Controlled Trial Comparing Low Dose 
Immunotherapy (Nivolumab) Combined with Standard 
Chemotherapy vs. Standard Chemotherapy as First-line Treatment 
in Patients with Locally Advanced or Metastatic Non-Small-Cell 
Lung Carcinoma (NSCLC)  
 
Proposal No.: IIT-LEDANG2023001, version 4.0 dated 5 March 2025 
 
Sponsor: 
 
Ministry of Health, Malaysia (MOH) 
 
Co-Sponsor: 
 
Institute for Clinical Research-National Institutes of Health (ICR-NIH) 
Principal Investigator (PI) 
 
Hospital Sultanah Bahiyah 
Dr. Arvindran a/l Alaga 
Principal Investigator (PI) at the Site: 
 
Hospital Tengku Ampuan Afzan 
Prof. Dr. How Soon Hin 
Hospital Sultanah Nur Zahirah 
Dr. Nor Azlina Samsudin 
Hospital Raja Perempuan Zainab II 
Dr. Azza Omar 
Hospital Raja Permaisuri Bainun 
Dr. Lam Yoke Fong 
Institut Kanser Negara 
Dr. Suhana Yusak 
Hospital Sultan Ismail 
Dr. Kumutha Chalaya 
University Malaya Medical Centre 
Prof. Dr. Pang Yong Kek 
Beacon Hospital 
Dr. Tho Lye Mun 
Biostastisticians: 
International Islamic University Malaysia 
 
Dr. Muhamad Adil Zainal Abidin  
Steering Committee: 
Columbia Asia Hospital  
Hospital Umum Sarawak 
University College London 
 
Dr. Ahmad Sufian Ab Rahman 
Dr. Voon Pei Jye 
Dr Allan Hackshaw 
Central Laboratory Testing: 
Cancer Research Malaysia: 
 
Dr. Lim Kue Peng  
Dr. Joanna Lim 
 
 

 
 
 
 
Trial Coordination/Data Management: 
Cancer Research Malaysia: 
Prof. Dr. Cheong Sok Ching 
Nor Syuhada Ahmad Bashah 
MOH Research Grant Management: 
Clinical Research Centre,  
Hospital Sultanah Bahiyah: 
 
 
 Dr. Mohd Azri Mohd Suan 
 

 
 
 
 
SYNOPSIS  
 
Study title  
A Phase III Randomized Controlled Trial Comparing Low Dose 
Immunotherapy (Nivolumab) Combined with Standard Chemotherapy vs. 
Standard Chemotherapy as First-line Treatment in Patients with Locally 
Advanced or Metastatic Non-Small-Cell Lung Carcinoma (NSCLC)  
Sponsor  
Co-Sponsor 
Ministry of Health, Malaysia (MOH) 
Institute for Clinical Research-National Institutes of Health (ICR-NIH) 
Clinical Phase  
Phase III 
Investigators 
(MOH Sites) 
Hospital Sultanah Bahiyah: Dr. Arvindran a/l Alaga (Respiratory physician) 
Hospital Tengku Ampuan Afzan: Prof. Dr. How Soon Hin (Respiratory 
physician) 
Hospital Sultanah Nur Zahirah: Dr. Nor Azlina Samsudin (Respiratory 
physician) 
Hospital Raja Perempuan Zainab II: Dr. Azza Omar (Respiratory physician) 
Hospital Raja Permaisuri Bainun: Dr. Lam Yoke Fong (Respiratory 
physician) 
Institut Kanser Negara: Dr. Suhana Yusak (Oncologist) 
Hospital Sultan Ismail: Dr. Kumutha Chalaya (Oncologist) 
Investigators (non-
MOH sites) 
University Malaya Medical Centre: Prof Pang Yong Kek (Respiratory 
Physician) 
Beacon Hospital: Dr Tho Lye Mun (Oncologist) 
Study sites  
MOH tertiary hospitals, University Hospitals and Private Hospitals with 
respiratory physicians and/or oncologists 
Study period  
Trial duration: 48 - 60 months (18 months enrollment; treatment duration up 
to 24 months 

 
 
 
 
Objectives 
Primary Objective 
• To determine the progression-free survival (PFS) of six-weekly 
Nivolumab 40mg combined with standard chemotherapy versus standard 
chemotherapy alone in NSCLC. 
Secondary Objectives 
• To evaluate the overall survival (OS) of six-weekly Nivolumab 40mg 
combined with standard chemotherapy in NSCLC.  
• To evaluate Patient-Reported Outcome Measure (PROM) for six-weekly 
Nivolumab 40mg combined with standard chemotherapy in NSCLC. 
• To assess the safety and tolerability profile of study regimens measured by 
the incidence of treatment-emergent adverse events (TEAEs), treatment-
related discontinuation, treatment-related death and serious adverse events 
(SAEs) using CTCAE 5.0. 
• To evaluate the overall response rate (ORR) per RECIST 1.1 of six-weekly 
Nivolumab 40mg combined with standard chemotherapy in NSCLC 
Methodology 
This is a multicentre, two-arm randomized, parallel group design trial to 
evaluate superiority and safety of low dose Nivolumab (40mg) combined 
with standard chemotherapy versus standard chemotherapy alone in patients 
with non-small cell lung cancer. Eligible subjects who satisfy the inclusion 
and exclusion criteria will be randomized 2:1 into 2 arms (Low dose 
nivolumab arm consisting of six-weekly 40mg Nivolumab plus 4-6* cycles 
of Cisplatin or Carboplatin plus Pemetrexed or Gemcitabine or Docetaxel or 
Paclitaxel per local practice, versus standard chemotherapy alone, consisting 
4-6* cycles of Cisplatin or Carboplatin plus Pemetrexed or Gemcitabine or 
Docetaxel or Paclitaxel per local practice.  
Study outcomes 
Primary efficacy endpoint 
• PFS 
Secondary efficacy endpoints 
• OS  
• Patient-Reported Outcome Measure (PROM)  
• Incidence of adverse events and treatment-emergent adverse events 
(TEAEs), and treatment-related death using CTCAE 5.0. 
Sample size 
The study aims to recruit about 123 patients (with 2:1 allocation in favour of 
nivolumab), to detect an PFS differences equivalent to hazard ratio of 0.55 

 
 
 
 
(15% rate in chemotherapy alone to 35% in chemo plus nivolumab) with 
80% power and two-sided significance test at 5%.  
The interim analysis sample size is 21 patients in nivolumab arm to detect 
ORR of 45% again null of 20% at 80% power and one-sided significance test 
at 5%. 
Study Population Participants with Locally Advanced or Metastatic Non-Small-Cell Lung
Carcinoma (NSCLC) who meet all the inclusion/exclusion criteria. 
The Full Analysis Set (FAS) population will serve as the primary population
for the analysis of efficacy data in this study. The FAS population consists of
all participants who:  
• Receive at least one dose of study treatment, and  
• Have a baseline scan with measurable disease per RECIST 1.1.  
Inclusion Criteria: 
1. Male/female participants who are at least 18 years of age on the day of
signing informed consent. 
2. Histologically confirmed, treatment naïve, locally advanced, or metastatic
(stage IIIB – IV (per AJCC version 8), squamous or non-squamous
NSCLC with documented PD-L1 expression and not eligible for definitive
chemo-radiation curative therapy and surgery.  
3. Patients must be treatment naïve with respect to locally advanced or
metastatic disease. Patients who received prior treatment with curative
intent for early stage disease and develop recurrent advanced/ metastatic
disease must have completed treatment at least 6 months prior to first dose
of IP. 
4. Have an Eastern Cooperative Oncology Group (ECOG) performance
status of 0 or 1. Evaluation of ECOG is to be performed within 7 days
prior to the first dose of study intervention.  
5. At least 1 measurable lesion by RECIST 1.1 in solid tumors criteria. 
6. Participants must have adequate organ function including the following
laboratory values at the screening visit as per Table 2 
7. If a participant has brain or meningeal metastases, the participant must 
meet the following criteria: a) Metastatic brain lesions do not require
immediate intervention. Note: Asymptomatic, treated and stable as well

 
 
 
 
as not requiring steroids for at least 2 weeks prior to start study treatment. 
b) Carcinomatous meningitis is excluded regardless of clinical stability. 
8. A male participant must agree to use a contraception starting with the first
dose of study treatment through the treatment period and for at least 90
days after the last dose of study treatment and refrain from donating sperm
during this period. 
9. A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies: a) Not
a woman of childbearing potential (WOCBP), OR, b) A WOCBP who
agrees to follow the contraceptive guidance during the treatment period
and for at least 180 days after the last dose of study treatment. 
10. 
Can provide evaluable archival tumor tissue sample or willing to
provide tissue from newly obtained core or excisional biopsy or fine
needle aspirate (FNA) cell block form of tumor lesion not previously
irradiated. Note: Formalin fixed, paraffin embedded (FFPE) tissue blocks
or slides allowed.  
Exclusion Criteria: 
1. Presence of EGFR, ALK or ROS1 mutation(s).  
2. Patients with locally advanced disease who can receive other potentially
curative therapies, such as patients who can afford to pay for or can
otherwise access clinically approved doses of immunotherapy. 
3. Prior treatment with any anti-PD-1, anti-PD-L1 or any other antibody
targeting an immune checkpoint. 
4. Use of any live vaccines against infectious diseases within 28 days of
first dose of IP(s). 
5. Underlying medical conditions that, in the Investigator’s or Sponsor-PI’s
opinion, will make the administration of IP(s) hazardous, including but
not limited to interstitial lung disease, including history of interstitial
lung disease or non-infectious pneumonitis (lymphangitic spread of
NSCLC is not disqualifying), or active viral, bacterial, or fungal
infections requiring parenteral treatment within 14 days of the initiation
of the IP. 
6. Concurrent medical condition requiring the use of supra-physiologic
doses of corticosteroids (> 10 mg/day of oral prednisone or equivalent)
or immunosuppressive medications (absorbable topical corticosteroids
are not excluded). 

 
 
 
 
7. Active hepatitis B and C infection or human immunodeficiency virus
antibody (HIV-1 and/or HIV-2) positive at screening.  
8. Known hypersensitivity to recombinant proteins, or any excipient
contained in the IP formulations. 
9. Known history of autoimmune disease currently on immunosuppressive
medications.  
10. Known history of second malignancy within two years prior enrolment. 
11. Prognosis of three months or less.  
12. A WOCBP who has a positive urine pregnancy test within 72 hours prior 
to treatment allocation. If the urine test positive or cannot be confirmed
as negative, a serum pregnancy test will be required. 
Test treatment, 
dose, and mode of 
administration  
Drug:  
 
 
Nivolumab 
Dose/Potency:  
 
40 mg 
Dose Frequency: 
 
Every six weeks 
Route of Administration: 
IV infusion  
Regimen/ Treatment Period: Day 1 of each cycle (6-week cycle) 
Duration of 
treatment with 
study medication  
up to 24 months 
 
GANTT CHART 
 
Activity 
Q3 
2024 
Q4 
2024 
Q1 
2025 
Q2 
2025 
Q3 
2025 
Q4 
2025 
H1 
2026 
H2 
2026 
H1 
2027 
H2 
2027 
H1 
2028 
H2 
2028 
Proposal defence, MREC submission, 
KPK approval, <sebut harga= process, 
contracts drafting and execution   
 
 
 
 
 
 
 
 
Study set up (IP purchase, investigator 
site file preparation, trial insurance, site 
initiation) 
 
 
 
 
 
 
 
 
Recruitment of patient 1-31 (Arm 1: 21; 
Arm 2: 10) 
 
 
 
 
 
 
 
 
Completion of treatment patient 1-21 in 
Arm 1 
 
 
 
 
 
 
 
 

 
 
 
 
Interim Analysis (n=21 patients in Arm 
1) 
 
 
 
 
 
 
 
 
Recruitment of patient 32-123 
 
 
 
 
 
 
 
 
Completion of treatment patient 32-123 
 
 
 
 
 
 
 
 
Data lock and analysis 
 
 
 
 
 
 
 
 

 
 
 
 
TABLE OF CONTENTS 
ABBREVIATION .................................................................................................................................................... 12 
GENERAL INFORMATION ..................................................................................................................................... 14 
1. 
BACKGROUND AND RATIONALE .................................................................................................................. 16 
1.1. Checkpoint inhibitors for the treatment of NSCLC ........................................................................................... 16 
1.2. Poor access to curative checkpoint inhibitors because of cost ........................................................................ 17 
1.3. Clinical evidence of efficacy of low dose checkpoint inhibitor treatment........................................................ 18 
1.4. Rationale for the LEDANG Study ..................................................................................................................... 20 
2. 
OBJECTIVES ................................................................................................................................................. 22 
2.1. Primary Objective ............................................................................................................................................ 22 
2.2. Secondary objective ........................................................................................................................................ 22 
2.3. Exploratory objectives ..................................................................................................................................... 22 
3. 
TRIAL DESIGN .......................................................................................................................................... 23 
 
23 
3.1 Primary Efficacy Endpoint(s): ........................................................................................................................... 23 
3.2 Secondary Efficacy and Safety Endpoint(s) ....................................................................................................... 24 
3.3 
Randomization .......................................................................................................................................... 24 
3.4 
Stratification ............................................................................................................................................. 24 
3.5 
Assignment of Allocation Number ............................................................................................................ 25 
3.6 
Trial Interventions ..................................................................................................................................... 25 
3.7 
Timing of Dose Administration.................................................................................................................. 25 
3.8 
Study Visits ................................................................................................................................................ 26 
3.8.1 
Screening Visit ...................................................................................................................................... 26 
3.8.2 
Treatment Visit ..................................................................................................................................... 26 
3.8.3 
End of Treatment Visit .......................................................................................................................... 26 
3.8.4 
Post Treatment Visits ............................................................................................................................ 27 
3.8.4.1 Safety Follow Up Visits ..................................................................................................................... 27 
3.8.4.2 Efficacy Follow Up Visits ................................................................................................................... 27 
3.8.4.3 Survival Follow Up Calls .................................................................................................................... 27 
3.9 
Biospecimen Collection, Storage and Use ................................................................................................. 28 
3.9.1 
Tumor Tissue Collection ........................................................................................................................ 28 
3.9.2 
Correlative Blood and Stool Sampling .................................................................................................. 29 
3.10 
Clinical Criteria for Early Trial Termination ................................................................................................ 29 
4. 
SELECTION AND WITHDRAWAL OF SUBJECTS .............................................................................................. 29 
4.1 
Study Population ....................................................................................................................................... 29 
4.1.1 
Analysis Population ............................................................................................................................... 30 
4.1.2 
Inclusion Criteria: .................................................................................................................................. 30 
4.1.3 
Exclusion Criteria: ................................................................................................................................. 32 

 
 
 
 
4.2 
Subject Informed Consent ......................................................................................................................... 33 
4.3 
Subject Withdrawal ................................................................................................................................... 34 
4.4 
Subject Discontinuation Criteria ................................................................................................................ 34 
5. 
TREATMENT AND PROCEDURES .................................................................................................................. 35 
5.1. Allowed Concomitant Medications ................................................................................................................. 35 
5.2. Prohibited Concomitant Medications .............................................................................................................. 35 
5.3. Rescue Medications & Supportive Care ........................................................................................................... 36 
5.3.1. Supportive Care Guidelines for Nivolumab .......................................................................................... 36 
5.3.2. Supportive Care Guidelines for Cisplatin/ Carboplatin ......................................................................... 37 
5.3.3. Supportive Care Guidelines for Pemetrexed/ Gemcitabine/ Docetaxel/ Paclitaxel .............................. 37 
6. 
ASSESSMENT OF EFFICACY .......................................................................................................................... 40 
6.1. Primary Efficacy Analysis ................................................................................................................................. 40 
6.2. Secondary Efficacy Analysis ............................................................................................................................. 41 
6.3. Summaries of Baseline Characteristics, Demographics and Others ................................................................ 41 
6.4. Exploratory Analysis ........................................................................................................................................ 41 
7. 
ASSESSMENT OF SAFETY ............................................................................................................................. 42 
7.1. Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events ........................... 41 
7.1.1. Time Period and Frequency for Collecting AE, SAE and Other Reportable Safety Event Information .. 43 
7.1.2. Method of Detecting AEs, SAEs, and Other Reportable Safety Events ................................................. 44 
7.1.3. Follow-Up of AE, SAE and Other Reportable Safety Event Information ................................................ 44 
7.1.4. Pregnancy and Exposure During Breastfeeding .................................................................................... 44 
7.1.5. Events of Clinical Interest (ECIs) ............................................................................................................ 44 
8. 
STATISTICAL ANALYSIS PLAN ........................................................................................................................ 45 
8.1. Hypothesis ....................................................................................................................................................... 45 
8.2. Study Size ........................................................................................................................................................ 45 
8.3. Software .......................................................................................................................................................... 47 
8.4. Data Handling for Cut-Off Date ....................................................................................................................... 47 
8.5. Handling of Missing Data ................................................................................................................................ 47 
8.6. Intention-to-Treat Analysis Set ........................................................................................................................ 47 
8.7. Per Protocol Analysis Set ................................................................................................................................. 48 
8.8. Significance Level ............................................................................................................................................ 48 
8.9. Presentation of Continuous and Qualitative Variables .................................................................................... 48 
9. 
ADMINISTRATIVE, ETHICS, AND REGULATORY DETAILS ............................................................................... 48 
9.1. Quality Control and Quality Assurance ........................................................................................................... 48 
9.2. Ethics ............................................................................................................................................................... 49 
9.2.1. Medical Research and Ethics Committee (MREC)/ Local Ethics Committee (LEC) ................................ 49 
9.2.2. Data Privacy and Confidentiality ........................................................................................................... 49 
9.2.3. Record Retention .................................................................................................................................. 49 

 
 
 
 
9.3. Study Insurance ............................................................................................................................................... 50 
9.4. Publications ..................................................................................................................................................... 50 
10. 
REFERENCES ............................................................................................................................................ 52 
11.0   APPENDIX ........................................................................................................ Error! Bookmark not defined. 
Appendix 1: Schedule of Activities .......................................................................................................................... 55 
Appendix 2: Sample Size Calculation Method for Complete Analysis ..................................................................... 61 
Appendix 3: Sample Size Calculation Method for Interim Analysis ........................................................................ 62 
Appendix 4: Imaging and Treatment After First Radiologic Evidence of Progressive Disease&&&&&&&&&&&..63 
 

12 
 
 
 
ABBREVIATION 
  
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
activated Partial Thromboplastin Time 
AST 
Aspartate Transaminase 
BUN 
Blood Urea Nitrogen  
CNB 
Core Needle Biopsy 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Response 
CrCI 
Creatinine Clearance  
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT TAP 
Computed Tomography of Thorax, Abdomen and Pelvis 
DOR 
Duration of Response 
DOT 
Duration of Treatment 
EB 
Excisional Biopsy 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
ECI 
Event of Clinical Interest 
EGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
FBR 
Future Biomedical Research  
FNAC 
Fine Needle Aspirate Cell  
GFR 
Glomerular Filtration Rate 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 

13 
 
 
 
IP 
Investigational Product 
IRB 
Institutional Review Board 
irAE 
Immune related Adverse Event 
ITT 
Intention to Treat 
LA/M 
Locally Advanced/ Metastatic  
LDH 
Lactate Dehydrogenase 
MTI 
Maximally Tolerated Imbalance 
NSCLC 
Non Small Cell Lung Carcinoma  
ORR 
Objective Response Rate 
OS 
Overall Survival  
PD 
Progressive Disease 
PD-L1 
Programmed Death-Ligand 1 
PFS 
Progression Free Survival  
PR 
Partial Response 
PROM 
Patient Reported Outcome Measures 
PT 
Prothrombin Time 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROS1 
Repressor of Silencing 1 
SAE 
Serious Adverse Event 
SD  
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
T3 
Triiodothyronine 
T4 
Thyroxine 
TEAE 
Treatment-Emergent Adverse Events 
TPS 
Tumor Proportion Score 
TSH 
Thyroid Stimulating Hormone 
ULN 
Upper Limit of Normal  
WBC 
White Blood Cell 

14 
 
 
 
WOCBP 
Woman of Childbearing Potential  
 
GENERAL INFORMATION  
 
Sponsor: 
Ministry of Health, Malaysia (MOH) 
 
Roles and Responsibilities  
Role 
Investigator’s Name 
Institution  
Sponsor/Principal 
Investigator 
Dr. Arvindran a/l Alaga 
Hospital Sultanah Bahiyah (HSB) 
PI at the Site 
Prof. Dr. How Soon Hin 
Hospital 
Tengku 
Ampuan 
Afzan 
(HTAA) 
PI at the Site 
Dr. Nor Azlina Samsudin 
Hospital 
Sultanah 
Nur 
Zahirah 
(HSNZ) 
PI at the Site 
Dr. Azza Omar 
Hospital Raja Perempuan Zainab II 
(HRPZ II) 
PI at the Site 
Dr. Lam Yoke Fong  
Hospital Raja Permaisuri Bainun 
(HRPB) 
PI at the Site 
Dr. Suhana Yusof 
Institut Kanser Negara (IKN) 
PI at the Site 
Dr. Kumutha Chalaya 
Hospital Sultan Ismail (HSI) 
PI at the Site 
Dr. Tho Lye Mun 
Beacon Hospital (BH) 
PI at the Site 
Prof. Dr. Pang Yong Kek 
University Malaya Medical Centre 
(UMMC) 
 
Funding for this trial is being sought through the Medical Research Grant via Institute of Clinical 
Research (ICR) for the Ministry of Health sites and charitable donations from Cancer Research 
Malaysia for the non-Ministry of Health sites.  The MRG will be managed centrally by Dr.  Mohd 
Azri Mohd Suan at Clinical Research Centre of Hospital Sultanah Bahiyah (CRC HSB). 
 
The recruitment for this Investigator-Initiated Trial (IIT) will take place at 9 investigator sites, 7 
Ministry of Health hospitals, 1 private hospital and 1 public university. All investigators have 
completed and satisfied the feasibility assessment in terms of their facilities, expertise, patient 
populations, and resources to support implementation of this IIT. 
 

15 
 
 
 
CRMY plays the following role in this trial:  
• As the co-developer of the Study Design and Protocol 
• As co-funder of the Study (by providing funds required for additional non-KKM sites) 
• As the Central Laboratory to facilitate PD-L1 TPS staining and reporting; molecular testing 
and reporting; to process biospecimens collected for biomarker research including PD-1 
receptor occupancy tests. 
• As Trial Coordinators and Data Managers to support Sponsor-PI on the study management, 
data management, identification of investigator sites, preparation of site readiness, study 
monitoring, budget coordination and etc.  
• As point of contact on administrative matters (e.g. submission of protocol/ amendment to 
ethics committee, trial progress update and etc.) 
 
Conflict of Interest Declaration  
All investigators to be requested to declare they have no conflict of interest.  
 
 
 

16 
 
 
 
1. BACKGROUND AND RATIONALE 
 
Lung cancer is one of the most common cancers in Malaysia, accounting for about 10% of all 
cancer cases (Malaysian National Cancer Registry Report, 2007-2011) and it is the most common 
cause of cancer-related deaths, accounting for almost 20% of all cancer deaths (International 
Agency for Research on Cancer in Malaysia, National Cancer Registry).  The survival rate of 
lung cancer is the lowest amongst all cancers, at only 9% 5 year survival (Malaysian Study on 
Cancer Survival MySCAN 2018).  Notably, there have been significant advances in the 
development of treatments for lung cancer, but these are largely unavailable to patients because 
of cost: this then is the area of greatest medical need – to find ways to improve access to these 
treatments and to improve survival for lung cancer patients in Malaysia. 
1.1. Checkpoint inhibitors for the treatment of NSCLC 
Cancer largely develops as a result of the accumulation of somatic mutation and other genetic 
alterations that impair cell division, checkpoints, etc., which results in abnormal cell proliferation 
and eventually tumorigenesis – such mutations are called <driver mutations=. Lung cancer is a 
heterogeneous disease, characterized by different molecular drivers. Patients with non-small cell 
lung cancer with driver mutations in EGFR or alteration of ALK achieve better survival when 
treated with EGFR inhibitors and ALK inhibitors respectively, and patients without driver 
mutations can achieve better survival when treated with checkpoint inhibitor immunotherapy (a 
form of therapy that releases a natural brake on the immune system so that immune cells called T 
cells can recognize and attack cancer cells)  (Duma et al., 2019; Ia et al., 2019). Such checkpoint 
immunotherapies include Pembrolizumab, Nivolumab, Atezolizumab and Cemiplimab (Malhotra 
et al., 2017; Pelosci, A., 2022). 
The response of patients to immunotherapy depends in part on whether treatment is given alone or 
in combination with chemotherapy, and on the patient population. In a first line setting, 
Pembrolizumab prolonged median overall survival (OS) of patients with NSCLC with PDL1>50% 
from 14.2 months with chemotherapy to 30 months with immunotherapy (Reck et al., 2019, 
KEYNOTE 024). When used in combination with chemotherapy, Pembrolizumab in a first line 
setting prolonged median overall survival from 10.7 months to 22 months in patients with 
advanced NSCLC without driver mutation regardless of PDL1 status (Gadgeel & Rodr, J Clin 
Oncol 2020; Gandhi et al., NEJM 2018, KEYNOTE 189), and patients with PDL>50% had the 
best OS (27.7 months). Notably, the PFS at 1 year was 34.1% (95% CI 28.8 to 39.5) in the 

17 
 
 
 
Pembrolizumab-combination group and 17.3% (95% CI, 120 to 23.5) in the placebo-combination 
group (Gandhi et al., NEJM 2018).  
Similarly, in a first line setting, another checkpoint immunotherapy, Atezolizumab, prolonged 
median overall survival of patients with NSCLC with PDL1>1% from 13.1 to 20.2 months 
(Herbst et al., 2020; IMpower110 study), and improved overall survival of patients ineligible for 
platinum based chemotherapy from 9.2 months to 10.3 months (Lee et al., Lancet 2023; IPSOS 
study). 
Similarly, in the first line setting in mNSCLC patients with tumor PD-L1 <1%, addition of 
nivolumab to chemotherapy improved duration of response from 4.8 to 8.3 months and 5-year 
estimated OS rates were 19%, 10%, and 7% with nivolumab plus ipilimumab, nivolumab plus 
chemotherapy and chemotherapy, respectively (HR 0.8, 0.64-1.0 comparing nivolumab-
chemotherapy combination and chemotherapy) (Brahmer J Clin Oncol 2023, CHECKMATE 
227). Similar clinical benefit patterns were observed with PFS, ORR, and DOR in both the PD-
L1>1% and <1% populations. In patients who responded with tumor PD-L1<1%, responses 
lasting >5 years occurred in an estimated 21% and 13% in the nivolumab plus ipilimumab and 
nivolumab plus chemotherapy arms; no patients remained in response in the chemotherapy arm 
at 5 years (HR0.73, 0.58-0.93) (Brahmer J Clin Oncol 2023, CHECKMATE 227). 
Finally, in the EMPOWER Lung 3 trial, median progression free survival with cemiplimab plus 
chemotherapy was 8.2 months (95% CI 6.4-9.3) versus 5.0 months (95% CI 4.3-6.2) for the 
placebo plus chemotherapy arm (HR = 0.56, 95% CI, 0.44-0.70, p<0.0001). The estimated 
proportion of patients receiving cemiplimab plus chemotherapy who were alive and had no 
disease progression at 12 months was 38.1% (95% CI, 32.4-32.8) versus 16.4% (05% CI, 10.5-
23.4) for the placebo plus chemotherapy arm (Gogishvili et al., Nat Med 2022). PFS benefits also 
consistently favoured cemiplimab plus chemotherapy in all predefined subgroups.  
 
Taken together, these results show that checkpoint immunotherapy, especially when used in 
combination with chemotherapy, significantly improves the survival of lung cancer patients with 
no driver mutations and these treatments are now the standard of care in the majority of high 
income countries. 
1.2. Poor access to curative checkpoint inhibitors because of cost 
Unfortunately, although some studies have shown that Pembrolizumab may be cost effective in 
first line treatment of advanced PDL1-high NSCLC in high income countries (Ding et al., 2020; 

18 
 
 
 
Huang et al., 2019), the use of checkpoint inhibitors remains restricted in developing countries 
due to its high cost (Bou et al., 2020). In Malaysia, checkpoint inhibitors are not provided for 
free in government hospitals and an evaluation conducted by the Ministry of Health Health 
Technology Assessment unit concluded that immunotherapy was not cost-effective in both the 
1st and 2nd line setting for the treatment of NSCLC (ICER of MYR142,000 to 264,000 per QALY 
gained when compared to conventional platinum-based chemotherapy) (Ramli et al., 2022). 
Excluding the cost of hospital admission, investigation, and medical consultations, the cost of 
checkpoint inhibitors is between RM300,000 to RM600,000 for 35 doses. As this is unaffordable 
to the majority of patients, the majority of patients do not receive checkpoint immunotherapies, 
leading to missed opportunities to save lives (Rajadurai et al., 2020). 
1.3. Clinical evidence of efficacy of low dose checkpoint inhibitor treatment 
Intriguingly, there is suggestive evidence that a lower and more affordable dosing schedule of 
checkpoint inhibitors may still have therapeutic effect, and this may provide an opportunity to 
improve survival of lung cancer patients in low and middle income countries. A prospective trial 
(Checkmate 153) showed that although progression free survival was better in patients receiving 
2 years of checkpoint immunotherapy compared to those receiving 1 year of treatment (65% 
compared to 40%, HR=0.42), there was no difference in overall survival (Waterhouse et al., JCO 
2020). Several case reports and case series have demonstrated patients whose checkpoint inhibitor 
therapy was discontinued due to severe side effects or cost issues can experience prolonged 
responses without the need of further treatment. Specifically, 22 patients with advanced NSCLC 
who were treated with less than 6 months of checkpoint inhibitors in the second line setting or 
more, had a median OS of 11 months (95% CI:7.1,12.9) which was similar to 9-12 months seen in 
clinical trials in which checkpoint inhibitors were given for 35 doses or till disease progression 
(Iivanainen et al., Oncology 2019). Significantly, a retrospective analysis of patients who received 
either standard dose of 3mg/kg every 2 weeks (n=29) or low dose nivolumab (20 or 100 mg fixed 
dose every 3 weeks, n=18) because of inability to pay for full dose, observed that there was no 
statistical difference in objective response of 13.8% in the standard dose group and 16.7% in the 
low dose group (p=0.788, Yee et al., ESMO Open 2018).  
There is also suggestive evidence that a lower dose of checkpoint inhibitors may achieve a 
similar treatment response as the approved dose. First, Phase 1 studies using Nivolumab showed 
that there was significant inhibition of PD1 at 2 months following infusion, suggesting that 
extending the treatment interval from the current recommended interval of 3 weeks to up to 12 

19 
 
 
 
weeks could still retain clinical benefit to patients (Brahmer et al, J Clin Oncol 2010). Second, 
in the phase 1 dose-escalation study of Nivolumab, where six-patient cohorts were treated at 0.3, 
1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg (Brahmer et al, J Clin 
Oncol 2010), pharmacodynamics tests indicated a sustained mean occupancy of 70% of PD-1 
molecules on circulating T cells was similar at 0.3mg/kg and 1mg/kg dose, suggesting that even 
if the plasma levels may be different, the effectiveness of the therapy may be achieved at a lower 
dose. Finally, dose escalation studies suggest that whilst the clinically recommended dose is 
10mg/kg, patients receiving the lowest dose of 0.1 mg/kg still showed high response.  For 107 
patients with advanced melanoma who were treated with Nivolumab at doses ranging from 0.1 
to 10 mg/kg, there was no dose-efficacy relationship for ORR, varying from 20.0% (95% CI: 
5.7,43.7) in 10 mg/kg to 41.2% (95% CI: 18.4, 67.1) in 3 mg/kg, whereas the lowest dose of 0.1 
mg/kg still showed high activity, with an ORR of 35.3% (95 % CI: 14.2, 16.7) (Topalian et al, 
NEJM 2014).  
Recently, a Phase 3 randomized controlled trial in head and neck cancer has shown that patients 
receiving 20mg Nivolumab (instead of 120mg-360mg) every 3 weeks in combination with 
chemotherapy has better overall survival than those receiving chemotherapy alone (10.1 months 
compared to 6.7 months; Patil et al., J Clin Oncol 2023). The median PFS in the Nivolumab-
combination arm was 6.6 months (95% CI 4.4 to 8.9) compared to 4.6 months (95% CI 4.2 to 
5.3) in the chemotherapy arm.   
Taken together, there is compelling evidence from dose escalation studies, case series, 
retrospective analyses and one randomized controlled trial in head and neck cancers, that a shorter 
duration (early cessation), extended treatment interval (from 3 weeks to 6 weeks or longer), or 
lower dose of checkpoint immunotherapy may result in improved survival for lung cancer patients. 
Several ongoing randomised trials are evaluating dose optimisation, broadly testing early 
cessation, extended interval administration or reduced doses (reviewed in Hirsch et al., Nat Med 
2022).   
Type 
Trial 
(indication) 
Design  
Planned 
n  
Country  
Registration 
number 
Early 
cessation 
SAVE 
(NSCLC) 
Full dose immune checkpoint therapy 
after chemotherapy randomized to stop 
at 1 year vs continuation 
 
216  
Japan  
JCOG1701 
 
DIAL 
(NSCLC)  
Randomized between 6 months and 2 
years of full dose pembrolizumab after 
chemotherapy 
 
114  
France  
NCT05255302 

20 
 
 
 
Extended 
interval 
NCT04295863 
(Any)  
1x vs 2x Standard of care interval for 
full dose immune checkpoint therapy 
 
264  
USA  
NCT04295863 
 
REFINE-Lung 
(NSCLC)  
MAMS initially full dose 
pembrolizumab every 6 vs 12 weeks  
 
1,750  
UK  
NCT05085028 
 
 
NCT04032418 
(NSCLC)  
Pembrolizumab full dose at 3 vs 12 
weeks intervals after combination 
chemotherapy 
 
152  
USA  
NCT04032418 
 
 
PULSE 
(NSCLC)  
Pembrolizumab full dose at 3 vs 6 
weeks intervals after combination 
chemotherapy 
 
1,100  
France  
TBC 
Low 
dose 
NVALT-30 
Dedication 
NSCLC  
Randomized between pembrolizumab 
and pembrolizumab 25% dose 
reduction 
 
750 
The 
Netherlands  
EudraCT 
2020-000493-
15 
 
 
CTRI-DELLI 
HNSCC  
Low-dose nivolumab (20 mg twice 
weekly) vs chemotherapy 
 
TBC  
India  
CTRI/2020/ 
02/023441 
 
1.4. Rationale for the LEDANG Study 
Notably, as the early cessation and extended regimens are testing full dose and the pembrolizumab 
dose reduction trial is testing only a 25% reduction, these regimens will still be unaffordable in a 
low income setting. One low dose nivolumab trial is planned in Head and Neck cancer (CTR1-
DELLI) but to the best of our knowledge, none have been planned in lung cancer. This then is the 
area of greatest medical need: to determine the efficacy of a lower (and more affordable) dosing 
schedule of checkpoint immunotherapy in the lung cancer – the most common cause of cancer-
related deaths in Malaysia. In this proposal, we aim to investigate that the effectiveness of lower 
dose of immunotherapy in improving lung cancer survival.  
1. Why Nivolumab? As the mechanism of action and the data (where available) appear 
broadly similar across different checkpoint inhibitors, we have chosen to evaluate low dose 
nivolumab as the smallest vial strength of nivolumab is 40mg vial (compared to 100mg for 
other checkpoint inhibitors). By choosing nivolumab, we will be able to avoid vial sharing 
between patients.  
2. Why 6 weekly? Given that there PD1 receptor occupancy was >80% for up to 12 weeks, 
we aim is to evaluate a dosing schedule that is affordable to patients.  
3. Why first line setting? There are 2 reasons for conducting a trial in a first line setting: 

21 
 
 
 
a. The therapeutic benefit of checkpoint immunotherapy is greater in a first line 
setting and it is already approved as standard of care in high income settings. 
Conducting a trial in a second line setting now would mean that a first line trial 
would need to be conducted later and this would further delay the potential benefit 
of treatment to low income patients. 
b. The therapeutic benefit of checkpoint immunotherapy in a 2nd line setting is lower, 
which means that a larger and more expensive study will be required. 
 
CHECKMATE 057 
CHECKMATE 227 
Setting 
2nd line and above, PDL1 all 
1st line, PDL1<1% 
Comparators 
Nivo 360 mg vs docetaxel 
Nivo 360 mg-chemo combination vs 
chemo 
OS 
12.2 months vs 9.4 months 
(HR0.73 95% CI 0.59-0.89 p=0.002) 
18.8 vs 15.6 months (NSQ NSCLC) (n.s.) 
18.3 vs 12.0 months (SQ NSCLC) (sig) 
18.3 vs 14.7 months (all) (sig) 
(HR0.81 95% CI 0.67-0.97) 
OS (1 year) 
51% vs 39% 
67.3% vs 59.2% (NSQ NSCLC)  
66.1% vs 48.5% (SQ NSCLC) 
66.9% vs 56.2% (all NSCLC) 
PFS 
2.3 months vs 4.2 months 
8.7 vs 5.8 months (NSQ NSCLC) (sig) 
7.1 vs 4.4 months (SQ NSCLC) (sig) 
8.4 vs 5.5 months (all) (sig) 
PFS (1 year) 
19% vs 8% 
39.5% vs 25.7% (NSQ NSCLC)  
31.7% vs 9.3% (SQ NSCLC) 
37.3% vs 21.3% (all NSCLC) 
ORR 
19% vs 12% (p=0.02) 
51.5% vs 30.2% (Paz Ares Annals Oncol) 
37.3% vs 23.1% (Brahmer JCO 2023) 
Reference 
Borghaei NEJM 2015 
Paz-Ares Ann Oncol 2019 
 
4. Why is the primary outcome PFS?  In the CHECKMATE 227 full dose Nivo+chemo 
combination vs chemotherapy trial, an improvement in OS and PFS were observed in the 
all patient analysis (Paz-Ares et al., Ann Oncol 2019). The number of patients needed in an 
OS analysis is >1,000 and the Study team has proposed to evaluate PFS as the sample size 
required is 123. 
5. Why is this an investigator-initiated study? Although the data from dose escalation 
studies, case series, retrospective analyses and other cancers (eg. Head and neck cancer) 
are compelling in suggesting potential patient benefit at an affordable cost in a LMIC 
setting, a well-designed prospective study, such as the proposed superiority Phase 3 trial 
with sufficient sample size is needed to confirm the efficacy of low-dose nivolumab. 
Notably, pharmaceutical companies may consider non-inferiority trials, however, the 

22 
 
 
 
samples sizes required are typically significantly larger, and hence academic investigator-
initiated studies such as LEDANG is necessary to evaluate potential efficacy at a dose 
affordable in LMIC settings. 
With this data, we hope to enable health policies that address the cancer health equity gaps, 
specifically access to lifesaving cancer treatments. 
2. OBJECTIVES  
2.1. Primary Objective 
• To determine the progression-free survival (PFS) of six-weekly Nivolumab 40mg 
combined with standard chemotherapy versus standard chemotherapy alone in NSCLC.  
2.2. Secondary objective 
• To evaluate the overall survival (OS) of six-weekly Nivolumab 40mg combined with 
standard chemotherapy in NSCLC. 
• To evaluate Patient-Reported Outcome Measure (PROM) for six-weekly Nivolumab 40mg 
combined with standard chemotherapy in NSCLC  
• To assess the safety and tolerability profile of study regimens measured by the incidence 
of treatment-emergent adverse events (TEAEs), treatment-related discontinuation, 
treatment-related death and serious adverse events (SAEs) using CTCAE 5.0. 
• To evaluate the overall response rate (ORR) per RECIST 1.1 of six-weekly Nivolumab 
40mg combined with standard chemotherapy in NSCLC 
 
2.3. Exploratory objectives 
• To analyze pre-planned subgroup analysis based on age, gender, ethnicity, histology, PD-
L1, and ECOG.  
• To assess if variation in checkpoint inhibitor binding to the receptor impact treatment 
response through PD1 receptor occupancy studies.  
2.4. Future Biomedical Research (FBR) 
The specimens collected during clinical trial will be analysed to further investigate the 
association of response to the checkpoint immunotherapy through multiple scientific 
disciplinary, this includes:   
 

23 
 
 
 
• To identify other factors predictive of clinical response (e.g. immune repertoire, other 
biomarkers) through techniques including immunohistochemistry, proteomics, gene 
and transcriptional analyses 
• To explore correlation between genetic variation and clinical response 
• To conduct on-treatment microbiome profiling and determine the correlation with 
clinical response 
To monitor the changes in circulatory immune cells throughout the treatment period 
3. TRIAL DESIGN 
 
This is a randomised controlled phase III trial. An interim efficacy analysis is planned after 21 
patients have been recruited to the nivolumab arm, to check that the overall tumor response rate 
(ORR) is consistent with the expected rate of 45%. If the ORR is noticeably lower, the trial may 
stop early as this indicates that the efficacy of nivolumab is insufficient.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1 Primary Efficacy Endpoint(s):  
Progression-Free Survival (PFS). PFS is defined as the time from randomisation to either the date 
of progression or death from any cause (whichever comes first); and those who are alive and 
progression-free are censored at the date they were last known to be alive.  
Stage IIIC/IV NSCLC 
No prior systemic 
therapy 
No oncogene driver 
mutations 
ECOG 0-1 
No known brain mets/ 
pneumonitis/ 
autoimmune disease 
PDL1 status positive 
Statistical calculation: 
Primary endpoint: PFS 
H0: 0.15, H1: 0.35 , HR: 0.55 
Power: 0.8 
Overall FWER: 0.05, two-sided alpha: 0.05 
Randomisation 2:1 
Attrition rate: 10% 
Sample size: 123 patients 
R 
2:1 
Cisplatin/carboplatin plus 
pemetrexed/gemcitabine/docetaxel/paclitaxel 
3 weekly [4-6 cycles] plus  
40 mg Nivolumab 6 weekly 
N =82 
Cisplatin/carboplatin plus 
pemetrexed/gemcitabine/docetaxel/paclitaxel 
3 weekly [4-6 cycles] 
N =41 
Stratified by 
PDL1 status, 
histology 
(adeno vs 
squamous) 
Maintenance 
Nivolumab every 6 
weeks until disease 
progression (up to 
17 doses) 
Follow up every 6 
weeks 

24 
 
 
 
3.2 Secondary Efficacy and Safety Endpoint(s)  
1. Overall Survival (OS) - OS will be measured from the date of treatment commencement to 
the date death from any cause. Participants without documented death at the time of the 
final analysis will be censored at the date of the last follow-up. 
2. Patient-Reported Outcome Measure [Time Frame: up to 2 years]: Measurement will be 
performed at baseline, and every 6 weeks thereafter for both arms for the first 6 months. 
After that, measurement will be performed every 3 months until the end of treatment follow 
up or the last study follow up related to adverse event for study discontinuation that is due 
to the AE. 
3. Number of participants experiencing an Adverse Event (AE) [Time Frame: from first dose 
to last dose of treatment plus follow-up – up to 27 months]. AE will be graded according 
to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse 
Events) version 5.0. Frequency and intensity of adverse events (CTCAE v.5) as measured 
at each visit and during safety follow up (90 days after discontinuation of treatment). 
3.3 Randomization 
Maximally-Tolerated-Imbalance (MTI) Randomization method will be used in this trial to conduct 
the randomization. This method is designed to prevent selection bias which can impact the 
effectiveness of the trial and data integrity. The National Cancer Institute provides an easy-to-use 
tool called Clinical Trial Randomization Tool to generate randomized clinical trial arms. The 
participants randomization will be controlled centrally by CRMY. Participant must be consented 
and confirmed on the eligibility prior to randomization. Site investigator or study coordinator to 
send email clintrial@cancerresearch.my on the eligibility confirmation to receive information on 
the participant enrolment arm.  
3.4  Stratification  
Treatment allocation/randomization will be stratified according to the following factors:  
a. PD-L1 status: TPS g 50%, and TPS < 50%.   
b. Histology:  Adenocarcinoma versus squamous  
 

25 
 
 
 
3.5  Assignment of Allocation Number 
All consented participants will be given a unique allocation number, Screen ID which will be 
automatically generated when the first data entered in the REDCap eCRF. It will be used to identify 
the participants for all the procedures and assessments that occur prior to enrolment. If the 
participants pass the screening and fulfill the eligibility criteria, then the enrolment ID will be 
centrally assigned by CRMY along with the randomization arm details. The enrolment ID must 
not be re-used for different participants.  
A single participant cannot be assigned more than one allocation number.  
3.6  Trial Interventions 
Table 1: Trial Interventions 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/ Treatment 
Period 
Use 
Nivolumab 
40 mg 
Every six 
weeks 
IV infusion  
Day 1 of each cycle (6-
week cycle) 
Experimental 
Regimen 
Cisplatin, 
Carboplatin, 
Pemetrexed, 
Docetaxel, 
Paclitaxel 
As per local 
practice 
Every three 
weeks 
IV infusion  
Day 1 of each cycle (3-
week cycle) for 4-6 
cycles 
Gemcitabine 
As per local 
practice 
Every three 
weeks 
IV infusion 
Day 1 and 8 of each 
cycle (3-week cycle) for 
4-6 cycles 
Note: Any variation from the standard regimen outlined in the protocol will need to have prior approval from the 
medical monitor/ trial committee.  
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, and usage of trial treatments in accordance with 
the protocol and any applicable laws and regulations.  
3.7 Timing of Dose Administration 
Trial interventions should be administered according to the regimen schedule each cycle after all 
procedures/assessments have been completed. Trial interventions may be administered up to 3 
days before or after the scheduled day of each cycle due to administrative reasons per the 
investigator’s judgement. All trial interventions will be administered on an outpatient basis. 

26 
 
 
 
Participants may receive a maximum of 6 cycles of Cisplatin or Carboplatin plus Pemetrexed or 
Gemcitabine or Docetaxel or Paclitaxel. Maintenance dose of Pemetrexed is allowed for patients 
with adenocarcinoma who showed response to the initial 4 to 6 cycles of chemotherapy. 
Dosing interruptions are permitted in the case of medical/ surgical events or logistical reasons (e.g., 
elective surgery, unrelated medical events, patient vacation, and holidays) not related to study 
therapy. Patients should be placed back on study therapy within 3 weeks of the scheduled 
interruption. The reason for the interruption should be documented in the participant's study record. 
3.8 Study Visits 
3.8.1 Screening Visit  
Within 28 days prior to treatment allocation, potential participants will be evaluated to determine 
that they fulfill the entry requirements. Screening procedures may be repeated.  
Participant may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Participants who are rescreened will retain their original allocation number. Results of a test 
performed prior to the participant signing consent as part of routine clinical management are 
acceptable in lieu of a screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. Screening procedures are to be completed within 28 days prior 
to the first dose trial treatment except for the following: 
• Laboratory tests and ECOG PS are to be performed within 7 to 10 days prior to the first dose 
of trial treatment. 
• For women of reproductive potential, a serum pregnancy test will be performed within 72 hours 
prior to the first dose of trial treatment. A urine test may be considered if serum test is not 
appropriate.  
3.8.2 Treatment Visit   
Detailed visit requirements are outlined in Appendix 1.  
3.8.3 End of Treatment Visit  
End of Treatment Visit will be performed at the time of discontinuation study intervention.  
Participants who discontinue study intervention prior to completion of the treatment period should 
be encouraged to continue to be followed for all remaining study visits as per Schedule of 
Activities.  

27 
 
 
 
All participants who have received at least one dose of Nivolumab in arm 1 will be evaluable for 
safety analysis. All participants who are registered into the study but fail to receive the first dose 
of study drug and those who are lost to follow up before disease evaluation will be replaced. 
The primary reason for discontinuation will be clearly documented in the participant’s medical 
record and recorded in the CRF.  
3.8.4 Post Treatment Visits  
3.8.4.1  Safety Follow Up Visits 
The mandatory Safety Follow-Up Visit should be conducted approximately 90 days after the last 
dose of study intervention or before the initiation of a new anti-cancer treatment, whichever comes 
first. The safety follow-up plan for grade 3 and above AEs and SAEs should be performed 
periodically until resolution to grade 1.  
3.8.4.2 Efficacy Follow Up Visits  
Participants who complete the protocol-required cycles of study intervention of who discontinue 
study intervention for a reason other than disease progression will begin the Efficacy Follow-Up 
Phase and should be assessed every 6 weeks (42 ± 7 days) by radiologic imaging to monitor disease 
status. After 1 year, the imaging time point will occur every 9 weeks (± 7 days). Every effort should 
be made to collect information regarding disease status until the start of new anti-cancer therapy, 
disease progression, death, or end of the study. Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. Participants who completed all efficacy 
assessments and/or will not have further efficacy assessments must enter the Survival Follow-up 
Phase. 
3.8.4.3 Survival Follow Up Calls  
Participant survival follow-up status will be assessed approximately every 12 weeks to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
The first survival follow-up assessment should be scheduled as described below: 
• For participants who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last). 

28 
 
 
 
• For participants who completed assessments in the Efficacy Follow-up Phase, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up visit 
has been performed. 
3.9 Biospecimen Collection, Storage and Use 
3.9.1 Tumor Tissue Collection 
At screening, all subjects will submit newly obtained core needle or excisional biopsy or fine 
needle aspirate (in cell block form) to central lab for characterization of PD-L1 status and 
molecular and biomarker testing. Next generation sequencing is preferred but depending on sample 
availability or quantity, other molecular tests (e.g. RT-PCR, PCR), IHC or FISH will be accepted. 
To determine eligibility, positivity for only three genes (EGFR, ALK or ROS1) will be used. 
Existing reports with EGFR, ALK and ROS1 will be accepted. Existing PD-L1 reports (28-8, 
22C3, SP263) will be accepted based on the high concordance on the Blueprint Harmonization 
Projects (Hirsch 2017 J Thorac Oncol; Tsao 2018, J Thorac Oncol).  
Specimens can be obtained from primary lung tumor or metastatic sites. These specimens may be 
the diagnostic sample for patients with a new diagnosis of metastatic NSCLC.  
Note: Tumor lesions used for newly obtained biopsies should not be the same lesions used as 
RECIST target lesions unless there are no other lesions suitable for biopsy. 
Alternatively, archival formalin-fixed, paraffin embedded (FFPE) slides of up to 3 years prior to 
trial enrolment are acceptable (i.e., 20-25 unstained FFPE slides and 1 H&E slide, each with 5 
microns in thickness) if newly obtained biopsy samples cannot be obtained. A newly obtained 
biopsy is preferrable over archival tumor samples. It is highly recommended if patients can provide 
both FFPE samples and tumor biopsy. Any excess tissue surplus for diagnostic requirements will 
be stored for FBR. Tissue in all forms are acceptable except for PD-L1 testing, which requires 
specifically unstained tissue slides.  
Biospecimens surplus to diagnostic requirements from patients treated in Ministry of Health 
hospitals will be stored at a location to be determined by the Institute of Clinical Research, for 
biomarker research to identify factors associated with response to therapy, and may only be used 
with the explicit approval of the Sponsor-PI and Co-PI (CRMY) of the study. Biospecimens from 
patients treated in non-Ministry of Health hospitals will be stored at CRMY, for biomarker 
research to identify factors associated with response to therapy, and may only be used with the 
explicit approval of the Sponsor-PI and Co-PI (CRMY) of the study.  

29 
 
 
 
3.9.2 Correlative Blood and Stool Sampling  
All enrolled patients must provide ~24ml of blood at screening, every 6 weekly before 
(Nivolumab/Chemotherapy) dosing until radiographic confirmed disease progression and up to 3 
consecutive imaging timepoints or post discontinuation of treatment or end of treatment (EOT). 
For treatment arm 1, blood (~24mL) will be used for evaluation of PD1 receptor occupancy, while 
for treatment arm 2, it will be stored for FBR with patient consent. Additionally, an extra ~16mL 
of blood will be collected from treatment arm 1 patient who consent to FBR. FBR consented 
patient may provide stool with collection window -5+3 days following the correlative blood 
sampling. If the screening imaging was performed as a routine scan prior to giving consent in 
participation of this trial, the blood and stool samples for FBR will be taken within 28 days prior 
to treatment allocation.  
 
The collected blood and stool samples from patients treated in Ministry of Health hospitals will be 
stored at a location to be determined by the Institute of Clinical Research for future disease-related 
research and may only be used with the explicit approval of the Sponsor-PI and Co-PI (CRMY) 
of the study. The blood and stool samples from patients treated in non-Ministry of Health hospitals 
will be stored at CRMY and may only be used with the explicit approval of the Sponsor-PI and 
Co-PI (CRMY) of the study. Detailed blood and stool samples collection, processing and shipment 
are provided in the Biospecimen Guideline by CRMY central laboratory. 
3.10 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
a. The minimum criterion of 18 responders for the first 40 patients in the intervention arm is 
not achieved during Phase 2 analysis.  
b. The quality or quantity of data recording is inaccurate or incomplete. 
c. Poor adherence to protocol and regulatory requirements. 
d. Incidence or severity of adverse drug reaction in this study indicates a potential health 
hazard to participants. 
4. SELECTION AND WITHDRAWAL OF SUBJECTS  
4.1  Study Population 
Participants with Locally Advanced or Metastatic Non-Small-Cell Lung Carcinoma (NSCLC) who 
meet all the inclusion/exclusion criteria listed below. 

30 
 
 
 
4.1.1 Analysis Population  
The Full Analysis Set (FAS) population will serve as the primary population for the analysis of 
efficacy data in this study. The FAS population consists of all participants who:  
a. Receive at least one dose of study treatment, and  
b. Have a baseline scan with measurable disease per RECIST 1.1.  
4.1.2 Inclusion Criteria: 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent. 
2. Histologically confirmed, treatment naïve, locally advanced, or metastatic (stage IIIB – IV 
(per AJCC version 8), squamous or non-squamous NSCLC with documented PD-L1 
expression  and is not eligible for definitive chemo-radiation curative therapy and surgery.  
3. Patients must be treatment naïve with respect to locally advanced or metastatic disease. 
Patients who received prior treatment with curative intent for early stage disease and 
develop recurrent advanced/ metastatic disease must have completed treatment at least 6 
months prior to first dose of IP. 
4. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.  
5. At least 1 measurable lesion by RECIST 1.1 in solid tumors criteria. 
6. Participants must have adequate organ function including the following 
laboratory values at the screening visit as per Table 2: 
 
 

31 
 
 
 
Table 2. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
g1500/µL 
Platelets 
g100 000/µL 
Hemoglobin 
g9.0 g/dL or g5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
f1.5 × ULN OR 
g30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN 
Note: Pemetrexed is not recommended to be used if  
<45ml/min  for participant with creatinine levels >1.5 × 
institutional ULN 
Hepatic 
 
Total bilirubin 
f1.5 ×ULN OR direct bilirubin fULN for participants with 
total bilirubin levels >1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
f2.5 × ULN (f5 × ULN for participants with liver metastases) 
Coagulation 
 
International normalized ratio (INR) 
OR prothrombin time (PT) 
Activated partial thromboplastin time 
(aPTT) 
f1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 
 
7. If a participant has brain or meningeal metastases, the participant must meet the following 
criteria:  
a. Metastatic brain lesions do not require immediate intervention. 
Note: Asymptomatic, treated and stable as well as not requiring steroids for at least 
2 weeks prior to start study treatment.  
b. Carcinomatous meningitis is excluded regardless of clinical stability. 
8. A male participant must agree to use a contraception starting with the first dose of study 
treatment through the treatment period and for at least 90 days after the last dose of study 
treatment and refrain from donating sperm during this period. 

32 
 
 
 
9. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP) OR  
b. A WOCBP who agrees to follow the contraceptive guidance during the treatment 
period and for at least 180 days after the last dose of study treatment. 
10. Can provide evaluable archival tumor tissue sample or willing to provide tissue from newly 
obtained core or excisional biopsy or fine needle aspirate (FNA) cell block form of tumor 
lesion not previously irradiated. Note: Formalin fixed, paraffin embedded (FFPE) tissue blocks 
or slides allowed. 
 
4.1.3 Exclusion Criteria: 
1. Presence of EGFR, ALK , ROS1 mutation(s).  
2. Patients with locally advanced disease who can receive other potentially curative therapies, 
such as patients who can afford to pay for or can otherwise access clinically approved doses 
of immunotherapy. 
3. Prior treatment with any anti-PD-1, anti-PD-L1 or any other antibody targeting an immune 
checkpoint. 
4. Use of any live vaccines against infectious diseases within 28 days of first dose of IP(s). 
5. Underlying medical conditions that, in the Investigator’s or Sponsor-PI’s opinion, will 
make the administration of IP(s) hazardous, including but not limited to a. Interstitial lung 
disease, including history of interstitial lung disease or non-infectious pneumonitis 
(lymphangitic spread of NSCLC is not disqualifying), Active viral, bacterial, or fungal 
infections requiring parenteral treatment within 14 days of the initiation of the IP. 
6. Concurrent medical condition requiring the use of supra-physiologic doses of 
corticosteroids (> 10 mg/day of oral prednisone or equivalent) or immunosuppressive 
medications (absorbable topical corticosteroids are not excluded). 
7. Active hepatitis B and C infection or human immunodeficiency virus antibody (HIV-1 
and/or HIV-2) positive at screening.  
8. Known hypersensitivity to recombinant proteins, or any excipient contained in the IP 
formulations. 
9. Known history of autoimmune disease currently on immunosuppressive medications.  
10. Known history of second malignancy within two years prior enrolment.  

33 
 
 
 
11. Prognosis of three months or less.  
12. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment 
allocation. If the urine test positive or cannot be confirmed as negative, a serum pregnancy 
test will be required.  
4.2  Subject Informed Consent  
The Investigator must obtain documented consent from each potential participant or each 
participant’s legally acceptable representative prior to participating in a clinical trial or Future 
Biomedical Research (FBR). Signing the informed consent for FBR samples is optional. If there 
are changes to a participant’s status during the study (e.g., health requirements) the investigator 
must ensure appropriate consent is in place.  
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of the 
person conducting the consent discussion. A copy of the signed and dated consent form should be 
given to the participant before participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the participant must receive the IRB/ERC’s approval/favorable 
opinion in advance of use. The participant or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
participant’s willingness to continue participation in the trial.  The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
If the investigator recommends continuation of study intervention beyond disease progression 
(Appendix 4), the consent by participant or his/her legally acceptable representative will be 
recorded in patient’s study note. 

34 
 
 
 
4.3  Subject Withdrawal  
A participant must be withdrawn from the study if the participant or the participant’s legally 
acceptable representative withdraws consent from the study. If a participant withdraws from the 
study, they will no longer receive study intervention or be followed at scheduled protocol visits. 
4.4  Subject Discontinuation Criteria 
Discontinuation of study intervention does not represent withdrawal from the study. As certain 
data on clinical events beyond study intervention discontinuation may be important to the study, 
they must be collected through the participant’s last scheduled follow-up, even if the participant 
has discontinued study intervention. Therefore, all participants who discontinue study intervention 
prior to completion of the protocol-specified treatment period will continue to be monitored in this 
study and participate in the study visits and procedures unless the participant has withdrawn from 
the study. 
Participants may discontinue study intervention at any time for any reason or be discontinued from 
the study intervention at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study intervention by the investigator or the 
Sponsor-PI if study intervention is inappropriate, the study plan is violated, or for administrative 
and/or other safety reasons.   
A participant must be discontinued from study treatment for any of the following reasons: 
a. The participant or participant’s legally acceptable representative requests to discontinue 
study intervention. 
b. After prolonged study intervention interruption that prohibits restarting study intervention 
if agreed upon with the Sponsor-PI. 
c. Radiographic disease progression. 
d. Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. 
e. Any study intervention-related toxicity specified as a reason for permanent 
discontinuation. 
f. The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor-PI, places the participant at unnecessary risk from 
continued administration of study treatment. 
g. The participant has a confirmed positive serum pregnancy test. 

35 
 
 
 
h. Investigator’s decision to withdraw the participant. 
i. Non-compliance with trial treatment or procedure requirements. 
j. The participant is lost to follow-up. 
k. Administrative reasons. 
l. Completed 35 treatments (approximately 2 years) with Nivolumab. 
5. TREATMENT AND PROCEDURES  
5.1. Allowed Concomitant Medications  
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) including 
all prescription, over the counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF. 
All concomitant medications received within 28 days prior to the first dose of trial intervention 
and up to 30 days after the last dose of trial intervention should be recorded.  If participants 
experience an SAE or ECI, concomitant medications administered 30 days after the last dose of 
trial intervention are to be recorded. 
5.2. Prohibited Concomitant Medications  
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this trial: 
a. Antineoplastic systemic chemotherapy or biological therapy  
b. Immunotherapy not specified in this protocol 
c. Chemotherapy not specified in this protocol 
d. Investigational agents other than Nivolumab 
e. Radiation therapy  
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion. The participant must have clear measurable disease 
outside the radiated field. Administration of palliative radiation therapy will be considered 
clinical progression for the purposes of determining PFS.  
f. Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 

36 
 
 
 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.  
g. Systemic glucocorticoids for any purpose other than to modulate symptoms from an event 
of clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor-PI. Additionally, a 
short, limited course of steroids may be used to treat medical conditions and/or AEs during 
the study after Sponsor-PI notification and consultation. 
Note: Inhaled steroids are allowed for management of asthma/ COPD. 
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV contract 
dye) or use of corticosteroids as pre-medication for chemotherapeutic agents specified in 
the protocol is permitted. 
h. Herbal and natural remedies that may affect PK of anti-cancer medicines. 
Participants who, in the assessment by the investigator, require the use of any of the treatments for 
clinical management should be removed from the study. All treatments that the investigator 
considers necessary for a participant’s welfare may be administered at the discretion of the 
investigator in keeping with the community standards of medical care. 
5.3. Rescue Medications & Supportive Care 
5.3.1. Supportive Care Guidelines for Nivolumab 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in Table 
3.  Where appropriate, these guidelines include the use of oral or IV treatment with corticosteroids, 
as well as additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms may 
worsen when the steroid dose is decreased.  For each disorder, attempts should be made to rule out 
other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care.  The treatment guidelines are intended to be applied when the 
investigator determines the events to be related to Nivolumab. 

37 
 
 
 
5.3.2. Supportive Care Guidelines for Cisplatin/ Carboplatin 
Please refer to the product label or local standards of care for cisplatin/ carboplatin supportive 
measures. 
5.3.3. Supportive Care Guidelines for Pemetrexed/ Gemcitabine/ Docetaxel/ Paclitaxel  
Please refer to the product label or local standards of care for pemetrexed/ gemcitabine/ docetaxel/ 
paclitaxel supportive measures. 
Table 3. Dose Modification and Toxicity Management Guidelines For Immune-Related 
AEs Associated With Nivolumab Monotherapy And IO Combinations 
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other 
immunosuppressive treatment should begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is 
not f10 mg/day within 12 weeks of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is f Grade 1 and continue at least 4 weeks to avoid 
relapses of irAE. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to f Grade 1 
after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Nivolumab 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
Pneumo
nitis  
Grade 2 
Withhold  
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics 
for opportunistic infections 
•  Monitor participants for signs and 
symptoms of pneumonitis 
•  Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and initiate 
corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhe
a/Coliti
s  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper 
 
·  Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without 
fever) and of bowel perforation 
(ie, peritoneal signs and ileus) 
•  Participants with gGrade 2 
diarrhea suspecting colitis should 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 

38 
 
 
 
irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Nivolumab 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
consider GI consultation and 
performing 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 
AST or 
ALT 
Elevati
on or 
Increas
ed 
Bilirubi
n 
Grade 2 a 
Withhold 
•  Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests 
(consider weekly or more 
frequently until liver enzyme value 
returned to baseline or is stable) 
Grade 3 b or 
4 c 
Permanently 
discontinue 
•  Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper. Second 
immunosuppressive needs to 
be added if AST/ALT does 
not improve in 48 hours. 
Consultation with 
hepatologist would then be 
recommended +/- 
consideration for liver 
biopsy. 
 
T1DM 
or 
Hypergl
ycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycem
ia associated 
with 
evidence of 
-cell failure 
Withhold d 
•  Initiate insulin replacement 
therapy for participants with 
T1DM 
·  Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes 

39 
 
 
 
irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Nivolumab 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
·  Administer antihyperglycemic 
in participants with 
hyperglycemia 
 
Hypoph
ysitis 
Grade 2 
Withhold 
•  Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated 
•  Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperth
yroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
•  Monitor for signs and symptoms of 
thyroid disorders 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hypoth
yroidis
m 
Grade 2, 3 or 
4 
Continue 
•  Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care 
•  Monitor for signs and symptoms of 
thyroid disorders 
Nephrit
is: 
grading 
accordi
ng to 
increase
d 
creatini
ne or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurolo
gical 
Toxiciti
es 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocar
ditis 
Grade 1 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 2, 3 or 
4 
Permanently 
discontinue 

40 
 
 
 
irAEs 
Toxicity 
Grade 
(CTCAE 
v5.0) 
Action With 
Nivolumab 
Corticosteroid and/or 
Other Therapies 
Monitoring and Follow-up 
Exfoliat
ive 
Dermat
ologic 
Conditi
ons 
Suspected 
SJS, TEN, or 
DRESS 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Confirmed 
SJS, TEN, or 
DRESS 
Permanently 
discontinue 
All 
Other 
irAEs 
Persistent 
Grade 2 
Withhold 
•  Based on severity of AE 
administer corticosteroids 
•  Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology 
Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-
oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic 
Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if 
baseline normal; >3.0 to 10.0 x baseline if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue Nivolumab is at the discretion of the investigator or treating physician. If 
control achieved or f Grade 2, Nivolumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis 
and sclerosing cholangitis). 
 
 
6. ASSESSMENT OF EFFICACY 
6.1. Primary Efficacy Analysis 
The primary efficacy analysis is the PFS. This study intends to prove the superiority based on the 
comparison between the 2 arms. PFS will be analyzed where the PFS will be compared between 
the two treatment arms by using log-rank test and stratified log-rank test by stratification factors 
(PD-L1 level) at the overall significance level of 5%. Survival curves are estimated using the 
Kaplan-Meier estimator. The median PFS time, 95% confidence interval are presented for each 
arm. The final PFS analysis ends when the last patient randomized follow up for 24 months.  

41 
 
 
 
 The confirmed 1-year PFS by treatment group will be calculated along with the two-sided CI 
using the Clopper-Pearson method (exact CI for a binomial proportion computed using 
GenBinomApps package in R). The alpha value is specified to 0.05. The hypothesis will be tested 
using a two-sample binomial proportions test. The test statistic z is assumed to have a standard 
Normal distribution. The significance level for this test will be set at 2 sided alpha = 0.05 with 
95% confidence interval for the difference in proportions will be presented. 
Using the intent-to-treat cohort, relative risk estimates will be obtained from a Cox proportional 
hazards model for discrete time observations. Significance test and relative risk (hazard ratio) 
estimates for the treatment will be obtained adjusted for potential confounder and effect modifier 
in the multivariable Cox regression. 
6.2. Secondary Efficacy Analysis 
Sample size calculations have not been made for the secondary objectives as the secondary 
analyses are exploratory, nonetheless hypothetical testing will be conducted as the findings of this 
study may guide future research. The secondary efficacy analysis is analyzed in the same way for 
overall survival (OS), ORR and AE. The ORR will be analyzed using two-sample binomial 
proportion test while OS will be analyzed using Kaplan Meier estimator, log-rank test, and Cox 
regression. All statistical tests for the secondary analysis are exploratory and two-sided. 
6.3. Summaries of Baseline Characteristics, Demographics and Others 
Baseline characteristics will be assessed using tables and/or graphs. No statistical hypothesis tests 
will be performed on these characteristics. The number and percentage of subjects screened, 
allocated, the primary reasons for screening failure, and the primary reason for discontinuation 
will be displayed. Demographic variables (e.g., age, gender, ethnicity, etc), baseline characteristics 
(e.g., number and percentage of subjects who developed locally advanced disease, number and 
percentage of subjects who developed metastatic disease, sites of recurrent metastatic, etc.) and 
prior and concomitant therapies will be summarized by treatment either by descriptive statistics of 
categorical or continuous variables. Two-sided Fisher’s exact tests and chi-square tests for 
categorical variables and independent-samples Student’s t-tests for continuous variables will be 
used to test for the differences between the two arms. Safety data (i.e., AEs, serious adverse events 
(SAEs) and events of clinical interest (ECIs)) will be summarized by descriptive statistics. 

42 
 
 
 
6.4.Exploratory Analysis 
The specimens collected during clinical trial will be analysed to further investigate the association 
of response to the checkpoint immunotherapy: 
• Receptor occupancy studies to determine whether variation in binding of the checkpoint 
inhibitor to the receptor may be associated with response to treatment. Both nivolumab 
binding and Ki-67 in T cells has been reported to predict patient response to nivolumab 
(Osa 2018). Recent study also demonstrated patient with low receptor occupancy but not 
high receptor occupancy will benefit from nivolumab re-challenge at recurrence (Nose 
2022). In this study, we propose to study live PBMCs (isolated 24-48 hours from 
collection) for the following: (1) dosing frequency that saturate the receptor (2) 
sustainability of the receptor occupancy and (3) correlate receptor occupancy with 
treatment response.  
6.5. Future Biomedical Research 
• Microbial compositions in the lung (via bronchoalveolar lavage fluid) and gut have been 
shown to differ in responders versus non-responders in nivolumab-treated NSCLC 
(Hakozaki 2020, Masuhiro 2022). Dysbiosis may affect response to immune checkpoint 
inhibitors (Jin 2019) with one possible mechanism being the reduction of chemokines (such 
as CXCL9) (Masuhiro 2022). As there are limited studies in respiratory and gut microbiota 
in association with ICI efficacy, even more so in low-dose settings, we would like to 
investigate this in the tumor, stool and pleural effusion samples (where available). 
7. ASSESSMENT OF SAFETY  
The safety analysis set includes all subjects who received at least one dose of any trial treatment. 
Analyses performed on the safety analyses set will consider subjects as treated. The safety analyses 
set will be used for safety analyses. 
7.1. Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety 
Events 
Progression of the cancer under study is not considered an adverse event unless it is considered 
drug related by the investigator.  
Adverse events, SAEs, and other reportable safety events will be reported by the participant or, 
when appropriate, by a caregiver, surrogate, or the participant's legally authorized representative. 

43 
 
 
 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety events 
for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE 
or SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and 
causality. 
7.1.1. Time Period and Frequency for Collecting AE, SAE and Other Reportable Safety 
Event Information  
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but 
before treatment allocation must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from the 
study, or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
• All AEs from the time of treatment allocation through 90 days following cessation of study 
intervention must be reported by the investigator. 
• All AEs meeting serious criteria, from the time of treatment allocation through 90 days 
following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator. 
• All pregnancies and exposure during breastfeeding, from the time of treatment allocation 
through 120 days following cessation of study intervention, or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator. 
• Additionally, any SAE brought to the attention of an investigator at any time outside of the 
period specified above must be reported immediately to Sponsor-PI and medical monitors 
if the event is considered drug-related. 
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in 
former study participants. 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 

44 
 
 
 
be reasonably related to the study intervention or study participation, the investigator must 
promptly notify Sponsor-PI and medical monitors. 
All initial and follow up AEs, SAEs and other reportable safety events will be recorded and 
reported to Sponsor-PI and medical monitors within 1 business day and to IRB/IECs in accordance 
with applicable specific ethics requirements.  
7.1.2. Method of Detecting AEs, SAEs, and Other Reportable Safety Events  
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the preferred 
method to inquire about AE occurrence. 
7.1.3. Follow-Up of AE, SAE and Other Reportable Safety Event Information  
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including 
pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), cancer, and 
overdose will be followed until resolution, stabilization, until the event is otherwise explained, or 
the participant is lost to follow-up. In addition, the investigator will make every attempt to follow 
all nonserious AEs that occur in allocated participants for outcome.  
7.1.4. Pregnancy and Exposure During Breastfeeding  
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to the 
investigator or their designee) that occurs during the study are reportable to Sponsor-PI and 
medical monitors. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
7.1.5. Events of Clinical Interest (ECIs) 
Selected non-serious and SAEs are also known as ECIs and must be reported to Sponsor-PI and 
medical monitors.  

45 
 
 
 
Events of clinical interest for this study include:  
a. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified laboratory testing 
or unscheduled laboratory testing.*  
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is to 
specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology. 
 
8. STATISTICAL ANALYSIS PLAN 
8.1. Hypothesis 
 The null hypothesis is that there is no significant differences of 1-year PFS rate between the two 
arms. Alternative hypothesis is that there is a 20% differences of 1-year PFS rate between the two 
arms. 
8.2. Study Size 
Efficacy data associated with both nivolumab and chemotherapy come from several clinical trials, 
as follows. (a) KEYNOTE-189 where the PFS at 1-year was 34.1% (95% CI 28.8 to 39.5) in the 
Pembrolizumab-combination group and 17.3% (95% CI, 120 to 23.5) in the placebo-combination 
group (Gandhi et al., 2018); (b) the EMPOWER Lung 3 trial, where the PFS at 1-year was 38.1% 
(95% CI, 32.4-32.8) in the Cemiplimumab-chemotherapy combination group versus 16.4% (05% 
CI, 10.5-23.4) for the placebo plus chemotherapy arm (Gogishvili et al., Nat Med 2022). Notably, 
the proportion of patients who had PDL1 >50%, 1-49% and <1% in both the KEYNOTE-189 and 
EMPOWER Lung 3 trials was appropriately equally distributed, whereas we plan to recruit at least 
50% of patients with PDL1>50%, and therefore anticipate that the PFS in the Nivolumab-
combination group is likely to be similar or greater than that of KEYNOTE-189 and EMPOWER 
Lung 3 Trials.   
 
 
KEYNOTE 189 
EMPOWER Lung3 
CHECKMATE 227 
Setting 
1st line, stratified for 
PDL1 
[~1/3 
each 
PDL1>50%, 1-49% and 
<1%] 
1st line, stratified for 
PDL1 
[~1/3 
each 
PDL1>50%, 1-49% and 
<1%] 
1st line, PDL1<1% 

46 
 
 
 
Comparators Pembrolizumab-chemo 
combination vs chemo 
Cemiplimumab-chemo 
combination vs chemo 
Nivo 360 mg-chemo 
combination vs chemo 
OS 
(median not reached) vs 
11.3 months (HR0.45) 
21.9 vs 13.0 months 
(HR0.71) 
18.3 vs 14.7 months 
(HR0.81) 
OS (1 year) 
69.2% vs 49.4% 
65.7% vs 56.1% 
66.9 vs 56.2% (n.s.) 
PFS 
8.8 vs 4.9 months  
[HR 0.52 (0.43–0.64)] 
8.2 vs 5.0 months  
[HR 0.56 (0.44–0.70)] 
8.4 vs 5.5 months  
[HR 0.62 (0.52–0.73)] 
PFS (1 year) 34.1% vs 17.3% 
38.1% vs 16.4%  
37.3% vs 21.3% (p=ns) 
ORR 
47.6% vs 18.9% (p=0.02) 
[difference 28.7%] 
43.3% vs 22.7% (p=0.02) 
[difference 20.6%] 
37% vs 23% (p=0.02) 
[difference 21.3%] 
Reference 
Gandhi NEJM 2018 
Gogishvili 
Nat 
Med 
2022 
Paz-Ares Ann Oncol 
2019; Brahmer JCO 
2023 
 
We assume the 1-year PFS rate in the chemotherapy alone group to be 15% and we aim to detect 
a rate of 35% with nivolumab; both consistent with other trials. We specify a 35% rate for 
nivolumab because it is towards the lower end of the range of the results seen in the prior trials 
and so reflects a slight loss of efficacy when using a lower dose. This effect (15 vs 35%) is 
equivalent to a hazard ratio of 0.55. Using a logrank test for time-to-event data, 80% power, 5% 
two-sided statistical significance, 2:1 allocation ratio in favour of the nivolumab group, 24 months 
of recruitment then 12 months of follow up we require a total trial size of 111 patients (37 in the 
control group and 74 given nivolumab). To allow for ~10% loss to follow up, we will aim for 
about 123 patients. 
There will be an interim analysis when 21 patients were recruited in the intervention arm to check 
that efficacy in the nivolumab group is consistent with what is expected. For this, we will use ORR 
because it is an accepted measure of treatment response and it can be assessed early. The ORR 
should be about 45% using nivolumab plus chemotherapy (pembro-chemo 47.6% Gandhi et al., 
NEJM 2018; cemiplimumab-chemo 43.3% Gogishvilli et al., Nat Med 2022; nivo-chemo (in 
patients with PDL1<1%) 37% Brahmer al., JCO 2023), and it is about 20% using chemotherapy 
alone (KEYNOTE 189 18.9% Gandhi et al., NEJM 2018; EMPOWER Lung3  22.7% Gogishvilli 
et al., Nat Med 2022; CHECKMATE 227 23% Brahmer al., JCO 2023),. Using methods for a 
single arm trial (with 80% power and 5% one-sided statistical significance), we will assess ORR 
in the first 21 patients recruited to the nivolumab group (who start treatment), of which at least 8 
need to have an ORR to indicate sufficiently high response, because this means that the true ORR 
is higher than the lowest acceptable rate of 20% using chemotherapy alone (KEYNOTE 189 18.9% 
Gandhi et al.,, NEJM 2018: EMPOWER Lung3  22.7% Gogishvilli et al., Nat Med 2022; 
CHECKMATE 227 23% Brahmer al., JCO 2023). Although this analysis is based on the 

47 
 
 
 
nivolumab group only, we will also confirm that the ORR rate in the controls is materially lower. 
The Independent Data Monitoring Committee will examine the interim analysis, along with other 
efficacy and safety outcomes, and make a decision whether the trial continues to recruit the target 
of 123 patients or stop early.  
Sample size calculation for the main objective was calculated using two arm survival calculator 
and the interim analysis using one arm binomial calculator from CRAB SWOG Statistical Tools 
Calculators (https://stattools.crab.org) (Appendix 2 and 3).    
8.3.Software 
All statistical analyses will be performed using R software version 4.3.1 or higher when available. 
8.4. Data Handling for Cut-Off Date 
There will be interim lock and final database lock. Interim lock will be done after the first 21 
patients enrolled in the intervention arm for the 3 months ORR analysis. The final database lock 
will be done after the last randomized patient followed up at 1-year. Data after cut-off do not 
undergo cleaning process. To provide overall estimates of the treatment effect, data will be pooled 
across the center, but the center factor will not be considered in statistical models or for subgroup 
analyses. The variable for the treatment allocation will be coded unknown to statistician to ensure 
blinding. 
8.5. Handling of Missing Data 
Unless others wise specified, missing data will not be replaced. Missing statistics when cannot be 
calculated will be presented as <nd=. In all subject data listing imputed value will be presented. 
Overall, no imputation for missing data will be made. The following will be conducted: 
a. Categorical data: When calculating proportion for categorical variable, subject with 
missing data will be excluded from the denominator. 
b. Continuous data: Observed data are based on the analysis and summary of continuous 
variables and the number of subjects with missing data will be presented. 
c. Time to-event data: Censoring rule shall be followed. 
8.6. Intention-to-Treat Analysis Set 
This will be an intention-to-treat analysis, where all eligible patients that initiated treatment 
analyzed according to randomized study arm. The reason for the exclusion of those that did not 
initiate treatment will be captured. 

48 
 
 
 
8.7. Per Protocol Analysis Set 
The per protocol analysis set includes all ITT subjects who does not meet one or more of the 
following criteria: 
a. Deviations from the inclusion and exclusion criteria 
b. Randomization error 
c. Use of prohibited medication 
d. No availability of primary endpoint measurement 
8.8. Significance Level 
The overall significance level is 5% two sided. The confirmatory statistical test for the primary 
and secondary endpoint will be described later. All other statistical analyses performed on the 
secondary and other endpoints defined in this are to be exploratory in nature. The statistical test 
performed on the primary and secondary endpoints in comparing treatment arm and control arm 
will be two-sided and the statistical test for exploratory and safety analyses will be two-sided. The 
confidence interval will be two-sided with a confidence level of 95%. 
8.9. Presentation of Continuous and Qualitative Variables 
Continuous variables will be summarized using descriptive statistics i.e., number of non-missing 
values and number of missing values, [i.e., n (missing)], mean, median, standard deviation 
(StDev), minimum, maximum and first and third quartile (Q1 and Q3). Qualitative variables will 
be summarized by counts and percentages. Unless otherwise stated the calculation of proportions 
will include the missing category. Therefore, counts of missing observations will be included in 
the denominator and presented as a separate category. In case the analysis refers only to certain 
visits percentages will be based on the number of subjects still present in the study at that visit, 
unless otherwise specified. 
 
9. ADMINISTRATIVE, ETHICS, AND REGULATORY DETAILS 
9.1. Quality Control and Quality Assurance 
During study conduct, the Principal Investigator will be responsible in ensuring that periodic 
monitoring visits are conducted to ensure that the protocol and Good Clinical Practices (GCPs) are 
being followed. The study monitors may review source documents to confirm that the data 
recorded on CRFs is accurate.  

49 
 
 
 
The study site may be subject to review by the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC), and/or to inspection by appropriate regulatory authorities. It is important 
that the investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process. 
9.2. Ethics  
9.2.1. Medical Research and Ethics Committee (MREC)/ Local Ethics Committee (LEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements, if applicable, from the MREC/LEC. All correspondence with the 
MREC/LEC should be retained in the ISF. 
The only circumstance in which an amendment may be initiated prior to MREC/LEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the patients. In that 
event, the investigator must notify the MREC/LEC and Sponsor-PI immediately after 
implementation. Otherwise, any amendments submitted to the MREC/LEC shall await approval 
before implementation.  
9.2.2. Data Privacy and Confidentiality 
All information obtained in this study will be kept and handled in a confidential manner, in 
accordance with applicable laws and/or regulations. When publishing or presenting the study 
results, the patient identity will not be revealed without expressed consent by the patient.  
Instead of the study subject’s name, patient clinical or medical record number at the hospital will 
be used and will be coded with a unique study identification number for the clinical trial. The study 
identification number instead of patient personal identifiers will be used on subject data sheets. 
Only the study investigator and limited study staff will have access to the coded list of study 
identification numbers. 
9.2.3. Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator agrees to keep 
records, including the identity of all participating patients (sufficient information to link records, 
e.g. CRFs and hospital records), all original signed informed consent documents, copies of all 
CRFs, safety reporting forms, source documents, and detailed records of treatment disposition, 
and adequate documentation of relevant correspondence (e.g. letters, meeting minutes, telephone 

50 
 
 
 
calls reports). The records should be retained by the investigator according to the International 
Conference on Harmonization (ICH), local regulations, or as specified in the Clinical Study 
Agreement (CSA), whichever is longer. 
On completion of study, all data entered in the EDC will be exported to a password protected 
computer and will be copied to CDs. Once copied, the data in the computer will be erased. CDs 
and all other hardcopy records should be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. The data will 
be destroyed after that period of storage. Subjects will not be allowed to view their personal study 
data, as the data will be consolidated into a database. 
9.3. Study Insurance  
Trial insurance will be purchased by Sponsor-PI from a reliable insurance company using CRMY 
funds for the entire duration of the trial to support any approved expenses, claims and events 
related to the clinical trial protocol and product.  
9.4. Publications  
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all the following: posting of a synopsis online, abstract and/or presentation at a scientific 
conference, or publication of a full manuscript. The Sponsor-PI will work with the authors to 
submit a manuscript describing trial results within 12 months after the last data becomes 
available, which may take up to several months after the last subject visit in some cases.  
Authorship credit should be based on 1) substantial contributions to conception and design or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors must meet conditions 1, 2 and 3. Significant contributions to trial execution may also be 
considered to determine authorship if contributions have also been made to all three of the 
preceding authorship criteria. Although publication planning may begin before conducting the 
trial, final decisions on authorship and the order of authors’ names will be made based on 
participation and actual contributions to the trial and writing, as discussed above. The first author 
is responsible for defending the integrity of the data, method(s) of data analysis and the scientific 
content of the manuscript. 
The Sponsor-PI must have the opportunity to review all proposed abstracts, manuscripts, or 
presentations regarding this trial 45 days prior to submission for publication/presentation. When 

51 
 
 
 
publishing or presenting the study results, the patient identity will not be revealed without 
expressed consent by the patient. Any information identified by the Sponsor-PI as confidential 
must be deleted prior to submission; this confidentiality does not include efficacy and safety 
results. Permission for any type of publication/presentation will be first obtained from the 
Director General of Health. 
 
 
 
 

52 
 
 
 
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Gogishvili M, Melkadze T, Makharadze T, Giorgadze D, Dvorkin M, Penkov K, Laktionov K, 
Nemsadze G, Nechaeva M, Rozhkova I, Kalinka E, Gessner C, Moreno-Jaime B, Passalacqua R, 
Li S, McGuire K, Kaul M, Paccaly A, Quek RGW, Gao B, Seebach F, Weinreich DM, 
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Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart 
M, Garon EB: Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced 
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of immune checkpoint inhibitors in cancer to allow global access. Nat Med. 2022 
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55 
 
 
 
11.0   APPENDIX 
Appendix 1: Schedule of Activities 
Study Period 
Screening/ 
Baselinea 
Treatment Period (6-Weekly Cycles) 
End of 
Treatment 
Post-Treatment 
Visit Number 
  
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
Safety Follow 
Up 
Follow Up 
Visitsu 
Survival 
Follow 
Upv 
Treatment 
Cycle 
  
  
C1 
C2 
C3 
C4 
C5 
C6 
C7 
onwards 
Discontinuation 
90 Days Post 
Discontinuation 
Every 6 Weeks 
Post 
Discontinuation 
Every 
12 
Weeks 
 
D1 
D8 
D1 
D8 
D1 
D8 
D1 
D8 
D1 
D8 
D1 
D8 
D1 
At time of 
Discontinuation 
 
Treatment 
Day 
-28 
to -
1 
-7 to 
-1  
1 
8 
21 
28 
42 
49 
63 
70 
84 
91 
105 
112 
126 
 
Visit Window 
(Days)e 
  
  
0 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±7 
 
Administrative Proceduresb 
 
Informed 
Consentf 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Inclusion/ 
Exclusion 
Criteria 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Demography 
and Baseline 
Characteristics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Medical/ 
Surgical 
History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 

56 
 
 
 
Prior and 
Concomitant 
Medication 
Reviewg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
 
Prior 
Treatment for 
NSCLC 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Post-Study 
Anticancer 
Therapy Status 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X 
 
Chemotherapyd 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
[X] 
  
  
  
  
 
Trial Treatment 
Administrationc 
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
X 
  
  
  
  
 
Clinical Procedures/ Assessmentsb 
 
Adverse Event/ 
Serious 
Adverse Event 
Reviewh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
Vital Signs 
(heart rate, 
blood 
pressure), 
Weight and 
Heighti 
X 
[X]a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
 
Full Physical 
Examination 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
 

57 
 
 
 
Directed 
Physical 
Examination 
  
[X]a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Laboratory Procedures/ Assessmentsb 
 
Hematologyj 
X 
[X]a 
[X] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Serum 
Chemistryk 
X 
[X]a 
[X] 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
 
Coagulation/ 
Urinalysisl 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Calculated 
Creatinine 
Clearancem 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Serum 
Pregnancy 
Testn 
X 
  
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
  
  
  
 
Urine 
Pregnancy 
Testn 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
X 
  
  
  
 
T3, FT4, TSHo 
X 
  
X 
  
  
  
  
  
  
  
X 
  
  
  
X 
X 
  
  
  
 
12-Lead ECGp 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
[X] 
  
  
  
 
Efficacy Assessmentb 
 
CT TAPq 
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
  
X 
  
 
CT Brainr 
X 
  
  
  
  
  
[X] 
  
  
  
[X] 
  
  
  
[X] 
[X] 
  
[X] 
  
 
Central Laboratoryb 
 

58 
 
 
 
Archival or 
New Obtained 
Tissue or 
FNAC Sample 
for EGFR, 
ALK, ROS1 
and PDL1s 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
[X] 
  
  
  
 
Blood for PD1 
Receptor 
Occupancy 
(Arm1)t  
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
 
 
Blood  
and Stool 
Sample for 
Future 
Biomarker 
Research 
(Arm1 & 
Arm2)t 
X 
  
  
  
  
  
X 
  
  
  
X 
  
  
  
X 
X 
  
  
  
 
Tissue 
Collection and 
Pleural 
Effusion Fluidw 
for Future 
Biomarker 
Research  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Xx 
  
  
  
 
 
[X] denotes as an optional test  
Abbreviations: NSCLC, non-small cell lung carcinoma; ECOG, Eastern Cooperative Oncology Group; T3, triiodothyronine; FT4, free thyroxine; TSH, thyroid stimulating 
hormone; ECG, electrocardiogram; CT, computed tomography; TAP, thorax, abdomen, pelvis; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, 
proto-oncogene 1 receptor tyrosine kinase; PDL1, programmed cell death ligand 1 
a The Screening visit must occur within 28 days before treatment allocation, and the baseline visit must occur within 7 days before treatment allocation. If Screening is performed 
within 7 days before treatment allocation, physical examination, vital signs, and clinical laboratory assessments do not need to be repeated at baseline. Screening and baseline 
procedures may be performed on the same day as long as it is within 7 days before treatment allocation.  
b All assessments/ procedures will be performed on Day 1 before dosing except as indicated. 

59 
 
 
 
c For patients enrolled in arm 1, 40mg Nivolumab will be administered on day 1 of every 6-weekly cycle up to 35 cycles (C1D1, C3D1, C5D1, C7D1, C9D1, C11D1, C13D1, 
C15D1, C17D1, C19D1, C21D1, C23D1, C25D1, C27D1, C29D1, C31D1, C33D1, C35D1). Dose interruption is permitted due to toxicity or other reasons not related to study 
therapy, but no dose reduction is allowed. If there is dose interruption, all assessments/ procedures except imaging should be performed based on new dosing schedule.  
d For both patients in arm 1 and 2, chemotherapy (Cisplatin or Carboplatin AND Pemetrexed or Gemcitabine or Docetaxel or Paclitaxel) will be administered as per local practice. 
Administration will be 3-weekly basis, up to 4 to 6 cycles based on investigator’s discretion. The use of Pemetrexed in patients with adenocarcinoma who showed response to the 
initial 4 to 6 cycles of chemotherapy can be continued as maintenance dose. 
e In general, the window for each visit is ± 3 days unless otherwise noted. 
f Written consent must be obtained prior to performing any protocol specified procedures. Results of a test performed prior to the participant signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment). Screening 
number will be assigned when the study informed consent is signed. Signing the informed consent for future biomedical research (FBR) sample is optional.  
g All concomitant medications or therapies, including herbal supplements, taken from 28 days before treatment allocation to 30 days after the last dose will be recorded.  
h After written informed consent but before study drug initiation, only SAEs associated with protocol-imposed interventions will be recorded. After the first dose of study drug, all 
SAEs and AEs will be recorded until 90 days after the last dose of study drug or before initiation of a new antineoplastic therapy, whichever occurs first. SAEs, AEs and pregnancies 
ongoing at the End of Treatment visit will be followed until resolution or until the condition is considered stable by the Investigator. 
i Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. If g10% change in body weight occurs, weight-based therapy should be adjusted. Height is 
to be measured at screening/baseline visit only. 
j Hematology: hemoglobin, hematocrit, platelet count, red blood cell (RBC), white blood cell (WBC) count, absolute neutrophil count (ANC), and WBC differential (absolute 
and/or percent). Hematology assessments scheduled for the day of the dosing must be available and assessed for abnormalities before dosing. The sampling for the hematology 
assessment can be drawn within 72 hours prior to dosing. If the screening/ baseline hematology assessment is performed 72 hours prior to enrolment, then the assessment need not 
to be repeated during Day 1 of Cycle 1. 
k Serum chemistry: total bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase (LDH), total protein, albumin, 
sodium, potassium, chloride, carbon dioxide (or bicarbonate), calcium, phosphorus, magnesium, blood urea nitrogen (BUN; also called urea), creatinine, uric acid, glucose. Serum 
Chemistry assessments scheduled for the day of the dosing must be available and assessed for abnormalities before dosing. The sampling for the hematology assessment can be 
drawn within 72 hours prior to dosing. If the screening/ baseline hematology assessment is performed 72 hours prior to enrolment, then the assessment need not to be repeated 
during Day 1 of Cycle 1. 
l Coagulation: activated partial thromboplastin time (aPTT) and prothrombin time (PT)/international normalized ratio 
(INR); Urinalysis will be assessed only at baseline. 
m Calculated creatinine clearance to be performed at screening. Use local laboratory results or calculate by Cockcroft-Gault formula. 
n For women of child-bearing potential, urine or serum (as per local regulations/ practice) pregnancy test should be performed at Day 1 of each cycle, prior to administration of 
study medication; if a urine pregnancy test is positive, study drug must be interrupted and a serum pregnancy test performed. Additional pregnancy testing may be performed 
throughout the study as clinically indicated. A serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  
o T3, FT4 and TSH tests will be at screening and every 12-weekly (± 7 days) until End of Treatment.  
p Baseline 12–lead ECG; End of Treatment, if clinically indicated. 

60 
 
 
 
q CT TAP to be performed at screening and every 6-weekly (± 7 days) for the first three months (C3D1, C5D1) from the date of treatment assigned. Subsequent imaging to be 
performed at 9-weekly (± 7 days) intervals for the first year (C8D1, C11D1, C14D1, C17D1) and 12-weekly (± 7 days) thereafter (C21D1, C25D1, C29D1, C33D1), regardless of 
any dose interruptions or dose delays. Tumor assessments can occur as clinically indicated anytime during the study, and at the time of clinical suspicion of disease progression. 
Clinical disease progression should be verified by radiographic imaging; study treatment should continue until radiographic progression has occurred. In participants who 
discontinue study therapy without confirmed disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation (i.e., date of discontinue ± 
4-week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t mandatory. If treatment 
discontinuation is due to documented disease progression as per investigator’s discretion, this is the final required tumor imaging.  
r Brain CT to be performed at screening and if clinically indicated. 
s Tumor tissue from an archival tissue sample or newly obtained core or excisional biopsy (EB) or fine needle aspirate cell (FNAC) block from participants is required for EGFR, 
ALK, ROS1 and PDL1 biomarker analysis. A newly obtained tissue from a core or excisional biopsy or FNAC is preferred, but an archival sample of up to 3 years is also acceptable. 
If the participant signs the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for FBR. 
t For treatment 1, ~24mL of blood will be used to evaluate PD1 receptor occupancy, while for treatment arm 2, it will be stored for FBR with patient consent. An additional ~16mL 
of blood will be collected from treatment arm 1 patients who consent to FBR. Blood and stool collection will occur at screening, every 6 weekly before dosing until radiographic 
confirmed disease progression and up to 3 consecutive imaging timepoints or post discontinuation of the treatment or end of treatment (EOT). If the screening imaging was 
performed as a routine scan prior to giving consent in participation of this trial, the blood and stool samples for FBR will be taken within 28 days prior to treatment allocation. 
u In participants who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) disease progression, (3) death, or (4) the end of the study, whichever occurs first. 
v After the start of new anti-cancer treatment or documented disease progression, the participant should be contacted by telephone every 12 weeks to assess for survival status. 
w If a FBR-consented patient has any pleural effusion fluid drained throughout the study, the fluid may be collected and stored for FBR.  
x If a FBR-consented patient has any tissue collected post-progressive disease confirmation, the tissue may be archived for FBR.  
 
 
 
 
 
 
 
 
 
 
 
 

61 
 
 
 
Appendix 2: Sample Size Calculation Method for Complete Analysis  
 
 
 
By Schoenfeld -  Schoenfeld D. Sample-Size Formula for the Proportional-Hazards Regression-Model. Biometrics. 1983;39(2):499-503 
 
111 with 10% attrition = 111/0.9 = 123 

62 
 
 
 
Appendix 3: Sample Size Calculation Method for Interim Analysis  
 
 
 
 

63 
 
 
 
Appendix 4: Imaging and Treatment After First Radiologic Evidence of Progressive Disease 
 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of disease 
progression by 
RECIST 1.1 per 
investigator 
assessment  
Repeat imaging at 4 to 8 
weeks to confirm disease 
progression  
May continue study 
treatment at the assessment 
of the investigator and after 
the participant’s consent  
Repeat imaging at 4 to 8 weeks to 
confirm disease progression per 
investigator’s discretion only.  
Discontinue treatment  
First radiologic 
evidence of disease 
progression by 
RECIST 1.1   
Repeat imaging at 4 to 8 
weeks to confirm disease 
progression.  
May continue study 
intervention at the 
investigator’s discretion 
while awaiting confirmatory 
tumor imaging by site by 
iRECIST.  
Repeat imaging at 4 to 8 weeks to 
confirm disease progression per 
investigator’s discretion only.  
Discontinue treatment  
Repeat tumor imaging 
confirms disease 
progression (iCPD) 
by iRECIST per 
investigator 
assessment.  
No additional imaging 
required.  
Discontinue treatment 
(exception is possible upon 
consultation with Sponsor).  
No additional imaging required.  
Not applicable  
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator 
assessment.  
Repeat imaging at 4 to 8 
weeks to confirm disease 
progression. May occur at 
next regularly scheduled 
imaging visit.  
Continue study intervention 
at the investigator’s 
discretion.  
Repeat imaging at 4 to 8 weeks to 
confirm disease progression per 
investigator’s discretion only.  
Discontinue treatment  

64 
 
 
 
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.  
Continue regularly 
scheduled imaging 
assessments.  
Continue study intervention 
at the investigator’s 
discretion.  
Continue regularly scheduled 
imaging assessments.  
May restart study intervention 
if condition has improved 
and/or clinically stable per 
investigator’s discretion. Next 
tumor imaging should occur 
according to the regular 
imaging schedule.  
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response Evaluation Criteria in Solid 
Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; RECIST 
1.1=Response Evaluation Criteria in Solid Tumors 1.1; VOP=verification of progression