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ENERGY
Randomised phase III study testing nivolumab and ipilimumab versus a carboplatin based doublet in first line treatment of PS 2 or elderly (more than 70 years old)
patients with advanced non-small cell lung cancer.  
Sponsor CHU de Rennes - 2, rue Henri le Guilloux, 35033 Rennes cedex 9 Coordinating investigator Dr Herve LENA, Service de Pneumologie - CHU de Rennes - Hôpital de Pontchaillou - 2, rue Henri le Guilloux 35033 Rennes cedex 9.  
Pharmacovigilance Catherine Mouchel, Service de Pharmacologie et Centre d'Investigation Clinique - INSERM 1414 - CHU de Rennes –
Hôpital de Pontchaillou - 2, rue Henri le Guilloux 35033 Rennes cedex 9.  
Pharmacy Dr Catherine Hamon, Pharmacie - CHU de Rennes - Hôpital de Pontchaillou - 2, rue Henri le Guilloux 35033 Rennes cedex 9
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methodology and data management centre

Dr David Pérol Unité de Biostatistique et d'Evaluation des Thérapeutiques, Direction de la Recherche et de l'Innovation - Centre Léon Bérard - 28, rue Laënnec - 69373 Lyon cedex 08 Biostatistician:
Sylvie Chabaud, Unité de Biostatistique et d'Evaluation des Thérapeutiques, Direction de la Recherche et de l'Innovation - Centre Léon Bérard - 28, rue Laënnec - 69373 Lyon cedex 08 Coordination and monitoring of study Direction de la Recherche et de l'Innovation, CHU de Rennes - 2, rue Henri le Guilloux, 35033 Rennes cedex 9 Groupe Français de Pneumo-Cancérologie  
| Version submitted to the authorities: Version 1.0 du 03/07/2017 Version accepted to the authorities: Version 2.0 du 06/11/2017   |
|----------------------------------------------------------------------------------------------------------------------------------|  
  
| ENERGY                                                                                                          | Trial Code Sponsor 35RC16_9734 / GFPC 08-2015 / BMS CA209-449                                                                 |            |    |       |     |         |               |    |
|-----------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------|------------|----|-------|-----|---------|---------------|----|
| SPONSOR :                                                                                                       | CHU Rennes (Rennes University Hospital Centre)                                                                                |            |    |       |     |         |               |    |
| TRIAL CODE :                                                                                                    | SPONSOR 35RC16_9734 GFPC 08-2015 BMS CA209-449                                                                                |            |    |       |     |         |               |    |
| EudraCT no. :                                                                                                   | 2017-002842-60                                                                                                                |            |    |       |     |         |               |    |
| PRODUCT/COMPOUND                                                                                                | Nivolumab / Ipilimumab                                                                                                        |            |    |       |     |         |               |    |
| COMPLETE TITLE                                                                                                  | Etude                                                                                                                         | randomisée | de | phase | III | testant | l'association | du |
| nivolumab et de l'ipilimumab versus un doublet à base de  carboplatine dans le traitement de première ligne du CBNPC  chez des patients PS 2 ou de plus de 70 ans. Randomised phase III study testing nivolumab and ipilimumab versus a carboplatin based doublet in first line treatment of PS 2  or elderly (more than 70 years old) patients with advanced nonsmall cell lung cancer.                                                                                                                 |                                                                                                                               |            |    |       |     |         |               |    |
| CLINICAL PHASE                                                                                                  | III                                                                                                                           |            |    |       |     |         |               |    |
| INDICATION(S) (TARGET)                                                                                          | Advanced non small cell lung cancer                                                                                           |            |    |       |     |         |               |    |
| COORDINATING INVESTIGATOR                                                                                       | Dr Herve Lena Service de pneumologie CHU of Rennes - Hôpital Pontchaillou 2 rue Henri Le Guilloux 35033 Rennes Cedex 9 France |            |    |       |     |         |               |    |
| PROTOCOL VERSION NO.                                                                                            | 2.0                                                                                                                           |            |    |       |     |         |               |    |
| DATE OF PROTOCOL                                                                                                | 06/11/2017                                                                                                                    |            |    |       |     |         |               |    |
| CPP                                                                                                             | Approved on 28/09/2017 By the Committee for the Protection of Persons SOOM IV of Limoges                                      |            |    |       |     |         |               |    |
| ANSM                                                                                                            | Date of authorisation: 12/09/2017 Authorisation no.: 170472A-12                                                               |            |    |       |     |         |               |    |
| THIS CONFIDENTIAL DOCUMENT IS THE PROPERTY OF CHU RENNES. NO UNPUBLISHED                                        |                                                                                                                               |            |    |       |     |         |               |    |
| INFORMATION CONTAINED IN THIS DOCUMENT CAN BE DISCLOSED WITHOUT THE PRIOR  WRITTEN AUTHORISATION OF CHU RENNES. |                                                                                                                               |            |    |       |     |         |               |    |
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table of contents

| TABLE OF CONTENTS                                                                                                  |                                                                 |
|--------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|
| GENERAL INFORMATION                                                                                                |                                                                 |
| 1                                                                                                                  | 1.1. Title .                                                    |
| 1.2.                                                                                                               | Sponsor                                                         |
| 1.3.                                                                                                               | Coordination and monitoring of study                            |
| 1.4.                                                                                                               | Investigators                                                   |
| 1.5.                                                                                                               | Pharmacy                                                        |
| 1.6.                                                                                                               | Pharmacovigilance                                               |
| 1.7.                                                                                                               | Methodologist - biostatistician                                 |
| 1.10.                                                                                                              | Efficacy evaluation committee                                   |
| DATA monitoring committee                                                                                          |                                                                 |
| 1.11.                                                                                                              |                                                                 |
| SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF STUDY ....................................... 19                   |                                                                 |
| 2                                                                                                                  | 2.1. Name and description of investigational medicinal products |
| 2. Summary of results of non-clinical trials and clinical trials available and relevant regarding the              |                                                                 |
| research involving the human person study concerned                                                                |                                                                 |
| 2.3 Summary of benefits and of foreseeable and known risks for the person who is a Patient in the research         |                                                                 |
| study                                                                                                              | ..                                                              |
| 25                                                                                                                 |                                                                 |
| 2.3.1.1 Individual benefits                                                                                        |                                                                 |
| 2.3.1.2 Collective benefit .                                                                                       |                                                                 |
| 2.3.2 Risks                                                                                                        |                                                                 |
| Individual risks                                                                                                   |                                                                 |
| 2.4. Description and rationale for route of administration, dosage, administration regimen and duration of         |                                                                 |
| treatment                                                                                                          |                                                                 |
| 2.5. Statement indicating that the study will be conducted in compliance with the protocol as well as with         |                                                                 |
| good clinical practices and legislative and regulatory conditions in force .                                       |                                                                 |
| 26                                                                                                                 |                                                                 |
| 2.7. References to the scientific literature and to relevant data used as a reference for the study                |                                                                 |
| 3                                                                                                                  | STUDY OBJECTIVES                                                |
| 3.1. Primary objective .                                                                                           |                                                                 |
| 3.2. Secondary objectives                                                                                          |                                                                 |
| 4                                                                                                                  | STUDY DESIGN                                                    |
| 4.1 Evaluation criteria                                                                                            |                                                                 |
| 4.1.1 Primary evaluation criteria                                                                                  |                                                                 |
| 4.1.2. Secondary evaluation criteria                                                                               |                                                                 |
| 4.2. Description of study methodology                                                                              |                                                                 |
| 4.2.1. Experimental design                                                                                         |                                                                 |
| 4.2. Conduct of study                                                                                              |                                                                 |
| 4.2.2.1. Inclusion Assessments and Procedures                                                                      |                                                                 |
| 4.2.2.2. On-Study Assessments and Procedures .                                                                     |                                                                 |
| 4.2.2.3 Post progression Assessments and Procedures                                                                |                                                                 |
| 4.2.2.4 Study Flow-chart                                                                                           |                                                                 |
| 4.3. Description of the measures taken to reduce and prevent bias                                                  |                                                                 |
| 4.3.1. Randomisation .                                                                                             |                                                                 |
| 4.3.2. Methods of blinding .                                                                                       |                                                                 |
| 4. Description of dosage and methods of administration of the investigational medicinal products.                  |                                                                 |
| Description of dose unit form, packaging and labelling of the investigational medicinal product(s) ............ 34 |                                                                 |
| 4.5. Expected duration of participation of persons and description of chronology and of duration of all            |                                                                 |
| study periods including monitoring .                                                                               |                                                                 |  
| ENERGY                                                                                                                                             | Trial Code Sponsor 35RC16_9734 / GFPC 08-2015  / BMS CA209-449        |
|----------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------|
| 4.6. Description of rules for permanent or temporary discontinuation .                                                                             |                                                                       |
| 4.6.1. Discontinuation of participation of a person in study .                                                                                     |                                                                       |
| 4.6.2. Discontinuation of part or of the entire study                                                                                              |                                                                       |
| SCREENING AND EXCLUSION OF PERSONS FROM THE STUDY ....................................................35                                           |                                                                       |
| 5                                                                                                                                                  | 5.1. Inclusion criteria for persons who are Patients in the study     |
| 5.2. Non-inclusion criteria for persons who are patients in the study.                                                                             |                                                                       |
| 5.3. Methods of recruitment                                                                                                                        |                                                                       |
| TREATMENTS ADMINISTERED TO PERSONS WHO ARE PATIENTS IN THE STUDY......37                                                                           |                                                                       |
| 6                                                                                                                                                  | 6.1. Description of the treatments necessary for conduct of the study |
| 6.1.1. Nivolumab - Ipilimumab                                                                                                                      |                                                                       |
| 6.1.1.1 Description                                                                                                                                |                                                                       |
| 6.1.1.2 Dosing schedule and Administration .                                                                                                       |                                                                       |
| 6.1.1.3 Dosage adjustment                                                                                                                          |                                                                       |
| 6.1.2. Comparator                                                                                                                                  |                                                                       |
| 6.1.2.1 Dose Reductions for Investigator's Choice Chemotherapy .                                                                                   |                                                                       |
| Carboplatin/pemetrexed .                                                                                                                           |                                                                       |
| Carboplatin-paclitaxel                                                                                                                             |                                                                       |
| 6.2. Packaging and labelling .                                                                                                                     |                                                                       |
| 6.3 Drug ordering and accountability .                                                                                                             |                                                                       |
| 6.4 Authorised and unauthorised medicinal products and treatments in the setting of the protocol,                                                  |                                                                       |
| including emergency medicinal products .                                                                                                           |                                                                       |
| 6.4.1. Authorised treatments .                                                                                                                     |                                                                       |
| 6.4.2. Unauthorised treatments                                                                                                                     |                                                                       |
| 6.4.3. Interaction with other medicinal products .                                                                                                 |                                                                       |
| 6.4.4. Emergency treatment .                                                                                                                       |                                                                       |
| 6.5. Conditions for storage of the investigational medicinal product ...........................................................................45 |                                                                       |
| 6.6. Management of Nivolumab and Ipilumumab, resupply and dispensing of Nivolumab and Ipilumumab. 46                                               |                                                                       |
| 6.6.1 Initial Orders .                                                                                                                             |                                                                       |
| 6.6.2 Re-Supply                                                                                                                                    |                                                                       |
| 6.6.3 Drug Excursions                                                                                                                              |                                                                       |
| 6.6.4 Handling and Dispensing                                                                                                                      |                                                                       |
| 6.6.5 Destruction                                                                                                                                  |                                                                       |
| 7                                                                                                                                                  | EVALUATION OF SAFETY .                                                |
| 7.1 Definitions                                                                                                                                    |                                                                       |
| 7.1.1 Adverse event (AE)                                                                                                                           |                                                                       |
| 7.1.2 Adverse reaction of an investigational medicinal product (AR)                                                                                |                                                                       |
| 7.1.3 Serious adverse event or serious adverse reaction (SAE/SAR)                                                                                  |                                                                       |
| 7.2 Investigator's role                                                                                                                            |                                                                       |
| 7.2.1 Adverse Events to be immediately notified to the sponsor .                                                                                   |                                                                       |
| 7.2.1.1 Serious Adverse Events .                                                                                                                   |                                                                       |
| 7.2.1.2. Potential Drug Induced Liver Injury (DILI)                                                                                                |                                                                       |
| 7.2.1.3 Suspected transmission of an infectious agent                                                                                              |                                                                       |
| 7.2.1.4 Non serious adverse event but critical to safety evaluation ................................................................. 48           |                                                                       |
| 7.2.2 Notification to the sponsor and time frame reporting .                                                                                       |                                                                       |
| 7.2.2.1 Events not to be notified immediately to the sponsor .                                                                                     |                                                                       |
| .                                                                                                                                                  | Specific hospitalizations                                             |
| Specific events related to non-small cell lung cancer progression ............................................................ 49                  |                                                                       |
| Non serious adverse events                                                                                                                         |                                                                       |
| 7.3 Sponsor's role .                                                                                                                               |                                                                       |
| 7.3.1 Analysis of serious adverse events .                                                                                                         |                                                                       |  
Trial Code Sponsor 35RC16 9734 / GFPC 08-2015 / BMS CA209-449  
| 7.3.2 Method of relationship assessment                         |                                          |
|-----------------------------------------------------------------|------------------------------------------|
| 7.3.3 Declaration of unexpected serious adverse events .        |                                          |
| 7.3.4 Transmission of annual safety reports                     |                                          |
| 7.3.5 Declaration of other safety data .                        |                                          |
| 7.4 Expected adverse reactions specific to the present study .  |                                          |
| 7.4.1 Adverse reactions related to Nivolumab or Ipilimumab .    |                                          |
| 7.2 Adverse reactions related to Carboplatin .                  |                                          |
| 7.4.3 Adverse reactions related to Pemetrexed                   |                                          |
| 7.4.4 Adverse reactions related to Paclitaxel                   |                                          |
| STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION               |                                          |
| 8                                                               | Sample size consideration                |
| Definition of population                                        |                                          |
| Endpoints                                                       |                                          |
| RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS .                  |                                          |
| 9                                                               | 9.1. Access to data                      |
| 9.2. Source documents                                           |                                          |
| 9.3. Confidentiality of data .                                  |                                          |
| 10                                                              | QUALITY CONTROL AND ASSURANCE            |
| 11                                                              | ETHICAL CONSIDERATIONS                   |
| 1.1. Regulatory and institutional review .                      |                                          |
| 1.2. Substantial changes .                                      |                                          |
| 1.3. Information for patients and written informed consent form |                                          |
| DATA PROCESSING AND RETENTION OF DOCUMENTS AND DATA             |                                          |
| 12                                                              | 12.1. Case report forms and data entry . |
| 12.2. CNIL .                                                    |                                          |
| 12.3. Archiving                                                 |                                          |
| 13                                                              | INSURANCE                                |
| 14                                                              | STUDY FEASIBILITY                        |
| RULES PERTAINING TO PUBLICATION                                 |                                          |
| 15                                                              |                                          |
| 16                                                              | LIST OF APPENDIX .                       |
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signatures investigator's signature

I have read all pages of this clinical trial protocol for which the CHU of Rennes is the sponsor. I
confirm that it contains all information necessary for the correct conduct of the study. I agree to conduct the study in compliance with the protocol and terms of conditions which are defined in it. I agree to conduct the study while complying with the conditions of:  
- Principles of the "Declaration of Helsinki",
- The rules and recommendations of international good clinical practice ((ICH-E6) and French good clinical practice (rules of good clinical practice for biomedical research studies of medicinal products for human use - decisions of 24 November 2006),
- National legislation and regulations pertaining to clinical trials, - Compliance with the Clinical Trials Directive of the EU [2001/20/EC].
I also agree that investigators and other qualified members of my team may have access to copies of this protocol and documents pertaining to the correct conduct of the study enabling them to work in compliance with conditions contained in these documents.
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sponsor's signature sponsor chu de

NAME : Monsieur Pascal Gaudron Signature : Date : 6 novembre 2017  
  
| SYNOPSIS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                     |
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| eNERGY Nivolumab Ipilimumab EldeRly GFPC 08-2015 Etude randomisée de phase III étudiant l'association du nivolumab et de l'ipilimumab  versus un doublet à base de carboplatinedans le traitement de première ligne du  CBNPC avancé chez des patients PS 2 ou de plus de 70 ans. Randomized phase III study testing nivolumab and ipilimumab versus a carboplatin  based doublet in 1st line treatment of PS 2 patients or elderly (more than 70 years old)  with advanced non-small cell lung cancer. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                     |
| SPONSOR                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 | CHU of Rennes                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                     |
| TITLE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   | Dr Hervé Lena Service de pneumologie CHU de Rennes - Hôpital Pontchaillou 2 rue Henri Le Guilloux 35033 Rennes Cedex 9 France                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                     |
| PROTOCOL VERSION                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | 2.0                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                     |
| COORDINATING  INVESTIGATOR                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Lung cancer is the most common cancer in the world and the leading cause of cancerrelated deaths in Western countries (1). Unfortunately, at the time of diagnosis, the  majority of patients already have metastatic disease and a systemic, palliative  treatment is the primary therapeutic option.  Guidelines for PS 2 patients or older than 75 years old patients at the time of diagnosis  recommend for fit patients a carboplatin doublet chemotherapy. Nivolumab has proven efficacy in 3rd line squamous cell lung carcinoma and is  superior to chemotherapy in 2nd line treatment of squamous and non-squamous lung  cancer in term of overall survival.  In 1st line, nivolumab failed to show superiority compared to a platin based doublet in  terms of progression free survival and overall survival in tumors ≥ 5% PD-L1  expression. The association Nivolumab plus Ipilimumab showed encouraging results  in first line setting in phase 1 study. We think that with regard to the manageable toxicity of nivolumab in lung cancer  population and the possibility to obtain long responses, this association could be a  valid option for this population of elderly and/or PS2 patients in term of overall  survival.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                     |
| ORIGINALITY AND                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         | It will be the first trial to test the efficacy of the association nivolumab and ipilimumab                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                     |
| INNOVATIVE ASPECTS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | in PS2 and elderly in advanced NSCLC patients.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                     |
| PRIMARY OBJECTIVE                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | To compare overall survival of patients in experimental arm versus chemotherapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                     |
| RATIONALE / CONTEXT                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     | To evaluate :   survival at one year of patients treated with nivolumab and ipilimumab versus  patients treated with chemotherapy,  the objective response rate,  the progression free survival,  the safety and the tolerability of nivolumab and ipilimumab versus  chemotherapy,  the QOL,  the prognostic impact of PD-L1 expression by immunochemistery (IHC) on  OS and PFS,  the predictive impact of a geriatric mini data set on OS, PFS and toxicity and  its evolution under treatment, this analysis will be restricted to patients ≥70  years old. |                                                                     |
| PRIMARY EVALUATION  CRITERION                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Overall survival                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                     |
| SECONDARY EVALUATION  CRITERIA                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Percentage of patients alive one year after inclusion in the trial, |
| SECONDARY OBJECTIVES                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |                                                                     |
| Protocole                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Version 2.0 du 06/11/2017                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Page 7/60                                                           |  
| ENERGY                              | Trial Code Sponsor 35RC16_9734 / GFPC 08-2015 / BMS CA209-449                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |
|-------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                    | Objective response rate according to Recist 1.1,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
|                                    | Progression free survival time,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
|                                    | Safety tolerability according to CTCAE 4.0,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
|                                    | QOL evaluated by EQ5D and EORTC QLQ-ELD14 every 6 weeks,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |
|                                    | PD-L1 testing by immunochemistery assessed by a central laboratory,                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
|                                    | Geriatric mini data set (restricted to patients ≥70 years old)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| METHODOLOGY / STUDY  SCHEDULE       | Open label Phase III randomized study   Signed written informed consent  Cytologically or histologically proven NSCLC (adenocarcinoma, squamous  cell carcinoma, large-cell carcinoma)  Stage IV or non-treatable by radiotherapy or surgery stage III (7th  classification)  No previous systemic chemotherapy for lung cancer, except in case of relapse  after adjuvant treatment for localized disease with 6 months or more between  end of previous chemotherapy and relapse  Patients less than 70 years old and PS 2 or 70 years older PS 0 to 2  Judged fit enough to receive a carboplatin based doublet according to ESMO  guidelines  Presence of at least one measurable target lesion (RECIST 1.1 rules) in a nonirradiated region and analysable by CT  Life expectancy >12 weeks  Prior radiation therapy is authorized if it involved less than 25% of the total  bone marrow volume and finished 14 days before D1 of planned treatment  Screening laboratory values must meet the following criteria and should be  obtained within 14 days prior to randomization/registration  WBC ≥ 2000/μL  Neutrophils ≥ 1500/μL  Platelets ≥ 100 x103 /μL  Hemoglobin > 10.0 g/dL  Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl)  ≥ 45 mL/min (if using the Cockcroft-Gault formula below): Female CrCl = [(140 - age in years) x weight in kg x 0.85] /  [72 x serum creatinine in mg/dL] Male CrCl = [(140 - age in years) x weight in kg x 1.00] / [72  x serum creatinine in mg/dL]  AST/ALT ≤ 3 x ULN   Total Bilirubin ≤ 1.5 x ULN (except Patients with Gilbert  Syndrome, who can have total bilirubin < 3.0 mg/dL)   Availability of adequate FFPE tumor-derived material (tumor blocks or slides)  from a biopsy, surgery or fine needle aspirate for analysis of PD-L1 testing by  IHC                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| CRITERIA FOR INCLUSION  OF PATIENTS | Age and Reproductive Status  Women of childbearing potential (WOCBP) must use appropriate method(s)  of contraception during treatment. WOCBP should use an adequate method to avoid pregnancy : o For 23 weeks (30 days plus the time required for nivolumab to  undergo five half-lives) after the last dose of nivolumab + ipilimumab, o For 4 weeks after the last dose of carboplatine + pemetrexed, o For 5 weeks after the last dose of carboplatine + paclitaxel.  Women of childbearing potential must have a negative serum or urine  pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) |  
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| within 24 hours prior to the start of treatment                                                              |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |        |         |         |           |        |          |             |
|--------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------|---------|---------|-----------|--------|----------|-------------|
|                                                                                                             | Women must not be breastfeeding                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |        |         |         |           |        |          |             |
|                                                                                                             | Men who are sexually active with WOCBP must use any contraceptive  method with a failure rate of less than 1% per year during treatment Men will be instructed to adhere to contraception for a period of 31 weeks  after the last dose of nivolumab + ipilimumab and with carboplatine +pemetrexed or carboplatine + paclitaxel up to 6 months thereafter.                                                                                                                                                                                                                                             |        |         |         |           |        |          |             |
|                                                                                                             | Patients with other severe concurrent disorders that occurred during the prior  six months before enrollment (myocardial infection, severe or unstable angor,  coronarian or peripheric arterial bypass operation, NYHA class 3 or 4  congestive heart failure, transient or constituted cerebral ischemic attack, at  least grade 2 peripheral neuropathy, psychiatric or neurological disorders  preventing the patient from understanding the trial, uncontrolled infections)  are not eligible.                                                                                                     |        |         |         |           |        |          |             |
|                                                                                                             | Serious or uncontrolled systemic disease judged as incompatible with the  protocol by the investigator                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |        |         |         |           |        |          |             |
|                                                                                                             | Another previous or concomitant cancer, except for basocellular cancer of the  skin or treated cervical cancer in situ, or appropriately treated localized lowgrade prostate cancer (Gleason score < 6), unless the initial tumor was  diagnosed and definitively treated more than 5 years previously, with no  evidence of relapse.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |        |         |         |           |        |          |             |
|                                                                                                             | Known activating mutation of EGFR (del LREA exon 19, mutation L858R or  L861X of exon 21, mutation G719A/S in exon 18) or EML4-ALK or ROS-1 translocation                                                                                                                                                                                                                                                                                                                                                                                                                                               |        |         |         |           |        |          |             |
|                                                                                                             | Superior caval syndrome                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |        |         |         |           |        |          |             |
|                                                                                                             | Uncontrolled infectious status                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          |        |         |         |           |        |          |             |
|                                                                                                             | All concurrent radiotherapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |        |         |         |           |        |          |             |
|                                                                                                             | Concurrent administration of one or several other anti-tumor therapies.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |        |         |         |           |        |          |             |
|                                                                                                             | Psychological, familial, social or geographic difficulties preventing follow-up  as defined by the protocol.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |        |         |         |           |        |          |             |
|                                                                                                             | Protected                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | person | (adults | legally | protected | (under | judicial | protection, |
| guardianship or supervision), person deprived of their liberty, pregnant  woman, lactating woman and minor), |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |        |         |         |           |        |          |             |
|                                                                                                             | Concurrent participation in another clinical trial                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |        |         |         |           |        |          |             |
|                                                                                                             | Patients are excluded if they have active brain metastases or leptomeningeal  metastases. Patients with brain metastases are eligible if metastases have been  treated and there is no magnetic resonance imaging (MRI) evidence of  progression for [lowest minimum is 4 weeks or more] after treatment is  complete and within 28 days prior to the first dose of nivolumab and  ipilimumab administration. There must also be no requirement for  immunosuppressive doses of systemic corticosteroids (> 10 mg/day  prednisone equivalents) for at least 2 weeks prior to study drug administration. |        |         |         |           |        |          |             |
|                                                                                                             | Patients should be excluded if they have an active, known or suspected  autoimmune disease. Patients are permitted to enroll if they have vitiligo, type  I diabetes mellitus, residual hypothyroidism due to autoimmune condition  only requiring hormone replacement, psoriasis not requiring systemic  treatment, or conditions not expected to recur in the absence of an external  trigger                                                                                                                                                                                                         |        |         |         |           |        |          |             |
|                                                                                                             | Patients should be excluded if they have a condition requiring systemic  treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or  other immunosuppressive medications within 14 days of study drug  administration. Inhaled or topical steroids and adrenal replacement doses > 10  mg daily prednisone equivalents are permitted in the absence of active  autoimmune disease.                                                                                                                                                                                                 |        |         |         |           |        |          |             |
| NON-INCLUSION CRITERIA  OF PATIENTS                                                                          |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |        |         |         |           |        |          |             |  
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|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Patients should be excluded if they are positive test for hepatitis B virus  surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV  antibody) indicating acute or chronic infection                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Patients should be excluded if they have known history of testing positive for  human immunodeficiency virus (HIV) or known acquired immunodeficiency  syndrome (AIDS)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Patients should be excluded if they have a lung disease that is symptomatic or  may interfere with the detection or management of suspected drug-related  pulmonary toxicity                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Allergies and Adverse Drug Reaction                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | History of allergy to study drug components                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
|                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        | Severe spinal hypoplasia and / or hemorrhagic tumors                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |
| The investigator will declare before randomization the treatment in control arm (ie the  choice of the second drug associated to carboplatin).  Patients will be randomized 1:1 into one of the two treatment arms and stratified by  age (70 years old versus less than 70 years old), by PS (PS 0/1 versus PS2) and by  histology (squamous versus non-squamous). Experimental arm:  Nivolumab (BMS-936558) dosed intravenously over 30 minutes at 240 mg  every 2 weeks combined with Ipilimumab dosed intravenously over 30 minutes at 1  mg/kg every 6 weeks until disease progression, unacceptable toxicity, or other reasons  specified in the protocol. Nivolumab and Ipilimumab can be continued beyond  progression according to RECIST 1.1 if the investigator assesses a clinical benefit  (defined paragraph) Control arm : the investigator will declare before randomization the treatment among: Doublet of chemotherapy according to standard of care carboplatin (AUC 5)  with a dose that will be capped to 700 mg and pemetrexed (500 mg/m²) over 4 to 6  hours every three weeks (restricted to non-squamous histology) or carboplatin (AUC  6) with a dose that will be capped to 700 mg and paclitaxel (90 mg/m²) D1 D8 D15 over 4 to 6 hours every 4 weeks, with a maximum of 4 cycles of carboplatin based  doublet, and the possibility to use maintenance with pemetrexed.   Follow up will be done over 30 minutes every 6 weeks in both arms, until progression. Patients treated by the association nivolumab plus ipilimumab in experimental arm  and who did not discontinue for progression or toxicity will be treated up to 2 years. In  case of subsequent progression a rechallenge with additional one year of treatment by  the association nivolumab plus ipilimumab will be proposed. For patients treated by chemotherapy in control arm, after progression, a second line  therapy will be proposed according to standard of care.  OS will be followed continuously while patients are on the study drug and every 3  months via in-person or phone contact after patients discontinue the study drug. All  randomized patients will be evaluated. Subsequent therapies will be recorded during  one year after inclusion. |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |
| TREATMENTS/STRATEGIES/ PROCEDURES                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | The primary endpoint of the phase III is overall survival. The study is calibrated to  detect a treatment effect hazard ratio (HR) of 0.65, translating in an improvement of 1- year OS rate from 40% (control arm) to 55% (Nivolumab and Ipilimumab arm). A total of 199 events observed at the time of the final analysis would have 85% power  to show statistically significant log-rank test at a 2-sided alpha level of 5%.  Considering a recruitment duration of 24 months and a18 months follow-up for the  last included patient (estimated total duration of the study: 42 months), 242 patients will be randomized in the study (121 by arm). |
| NUMBER OF PATIENTS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           |  
Randomization ratio 1:1 will be stratified according to Age (< 70 vs. ≥ 70 years),ECOG-PS status (0/1 vs. 2) and histology status (squamous vs non-squamous).  
Interim analysesDuring the trial, one interim analysis for futility will be performed, permitting to early stop the trial, if no sufficient efficacy is shown. This analysis will be performed after that 33% of the expected events have occurred. Using planned enrollment rate, this analysis should be performed after inclusion of 171 patients (17 months after first included patient). No adjustment of type I error was required. Stopping boundaries were defined according to Lan-DeMets spending function to control type II error. Table 1 shows the futility boundaries. An independent Data Safety Monitoring Board will be organized to discuss the conduct of the study after analysis performed.  
Sample size calculation and interim analysis planning were performed using East® software (Cytel Inc. 1994-2014), version 6.3.1 Table1: Futility boundaries  
  
| Look                                                                                                                                                                  | Fraction                     | of                                               | Cumulative   | P value   | HR futility bound   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------|--------------------------------------------------|--------------|-----------|---------------------|
| information                                                                                                                                                           |                              |                                                  |              |           |                     |
| 1                                                                                                                                                                     | 0.33                         | 0.012                                            | 0.698        | 1.137     |                     |
| 2                                                                                                                                                                     | 1                            | 0.15                                             | 0.0025       |           |                     |
| Recruitment period : 24 months Duration of patient monitoring : 18 months or until end of study treatment in both  arms Estimated total duration of study : 42 months |                              |                                                  |              |           |                     |
| EXPECTED FINDINGS AND                                                                                                                                                 | Superiority of nivolumab and | ipilimumab versus a carboplatin based-doublet in |              |           |                     |
| specific populations of elderly or PS2 NSCLC                                                                                                                          |                              |                                                  |              |           |                     |
| IMPACT  DURATION OF STUDY                                                                                                                                             |                              |                                                  |              |           |                     |  
| LIST OF ABBREVIATIONS   |                                                                                                           |
|-------------------------|-----------------------------------------------------------------------------------------------------------|
| Term                    | Definition                                                                                                |
| 21CFR50                 | United States Code of Federal Regulations, Title 21, Part 50                                              |
| ANC                     | absolute neutrophil count                                                                                 |
| AIDS                    | acquired immunodeficiency syndrome                                                                        |
| aPTT                    | activated partial thromboplastin time                                                                     |
| AE                      | adverse event                                                                                             |
| ALT                     | alanine aminotransferase                                                                                  |
| AT                      | aminotransaminases                                                                                        |
| ANOVA                   | analysis of variance                                                                                      |
| ADA                     | Anti-drug antibody                                                                                        |
| APC                     | Antigen Presenting Cell                                                                                   |
| AUC                     | area under the concentration-time curve                                                                   |
| AUC(INF)                | area under the concentration-time curve from time zero extrapolated to infinite time                      |
| AUC(0-T)                | area under the concentration-time curve from time zero to the time of the last quantifiable concentration |
| AUC(TAU)                | area under the concentration-time curve in one dosinginterval                                             |
| AST                     | aspartate aminotransferase                                                                                |
| A-V                     | atrioventricular                                                                                          |
| TR_AUC(0-T)             | AUC(0-T) treatment ratio                                                                                  |
| TR_AUC(INF)             | AUC(INF) treatment ratio                                                                                  |
| Cavg                    | average concentration                                                                                     |
| BLQ                     | below limit of quantification                                                                             |
| BOR                     | best overall response                                                                                     |
| b-HCG                   | beta-human chorionic gonadotrophin                                                                        |
| HCO3-                   | bicarbonate                                                                                               |
| BA/BE                   | bioavailability/bioequivalence                                                                            |
| BID, bid                | bis in die, twice daily                                                                                   |
| BP                      | blood pressure                                                                                            |
| BUN                     | blood urea nitrogen                                                                                       |
| BMI                     | body massindex                                                                                            |
| BMS                     | Bristol-Myers Squibb                                                                                      |
| Ca++                    | calcium                                                                                                   |
| CBNPC                   | cancer bronchique non-à-petites cellules                                                                  |
| CRF                     | Case Report Form, paper or electronic                                                                     |
| C                       | celcius                                                                                                   |
| cm                      | centimeter                                                                                                |
| CNS                     | central nervoussystem                                                                                     |  
| Cl-            | chloride                                                                                                                                                             |
|----------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| CL             | clearance                                                                                                                                                            |
| CRC            | clinical research center                                                                                                                                             |
| TR_Cmax        | cmax treatment ratio                                                                                                                                                 |
| CFR            | code of federal regulations                                                                                                                                          |
| CV             | coefficient of variation                                                                                                                                             |
| CTCAE v4       | common terminology criteria for adverse events version 4                                                                                                             |
| CBC            | complete blood count                                                                                                                                                 |
| CR             | complete response                                                                                                                                                    |
| CT             | computed tomography                                                                                                                                                  |
| Ctau           | concentration in a dosing interval (eg, concentration at 24 hours, concentration at 12 hours, etc.)                                                                  |
| CI             | confidence interval                                                                                                                                                  |
| CrCl           | creatinine clearance                                                                                                                                                 |
| C              | cycle                                                                                                                                                                |
| CMV            | cytomegalovirus                                                                                                                                                      |
| CTLA-4         | cytotoxic t lymphocyte-associated antigen 4                                                                                                                          |
| D              | day                                                                                                                                                                  |
| dL             | deciliter                                                                                                                                                            |
| D/C            | discontinue                                                                                                                                                          |
| ECOG           | eastern cooperative oncology group                                                                                                                                   |
| T-HALFeff_AUC  | effective elimination half life that explains the degree of auc accumulation observed                                                                                |
| T-HALFeff_Cmax | effective elimination half life that explains the degree of cmax accumulation observed)                                                                              |
| ECG            | electrocardiogram                                                                                                                                                    |
| eCRF           | electronic case report form                                                                                                                                          |
| EDC            | electronic data capture                                                                                                                                              |
| EP             | endpoint                                                                                                                                                             |
| EGFR           | epidermal growth factorreceptor                                                                                                                                      |
| q              | every                                                                                                                                                                |
| eg             | exempli gratia (for example)                                                                                                                                         |
| Ct             | expected concentration at a certain time, usually at the end of an expected future dosing  interval (eg, concentration at 24 hours, concentration at 12 hours, etc.) |
| ESR            | expedited safety report                                                                                                                                              |
| FISH           | fluorescent in situ hybridization                                                                                                                                    |
| FSH            | follicle stimulating hormone                                                                                                                                         |
| FDA            | food and drug administration                                                                                                                                         |
| FFPET          | formalin fixed paraffin embedded tissue                                                                                                                              |
| FFPE           | formalin fixed paraffin-embedded                                                                                                                                     |
| GGT            | gamma-glutamyl transferase                                                                                                                                           |  
Page 13/60  
| ENERGY   | Trial Code Sponsor 35RC16_9734 / GFPC 08-2015 / BMS CA209-449   |
|----------|-----------------------------------------------------------------|
| GFPC     | groupe français de pneumo-cancérologie                          |
| GFR      | glomerular filtration rate                                      |
| GCP      | good clinical practice                                          |
| g        | gram                                                            |
| T-HALF   | half life                                                       |
| HR       | hazard ratio                                                    |
| HIPAA    | health information portability and accountability act           |
| HR       | heart rate                                                      |
| HBsAg    | hepatitis b surface antigen                                     |
| HBV      | hepatitis b virus                                               |
| HCV AB   | hepatitis c antibody                                            |
| HCV RNA  | hepatitis c rna                                                 |
| HCV      | hepatitis c virus                                               |
| HRT      | hormone replacement therapy                                     |
| h        | hour                                                            |
| HCG      | human chorionic gonadotropin                                    |
| HIV      | human immunodeficiency virus                                    |
| ie       | id est (that is)                                                |
| IHC      | immunohistochemistry                                            |
| IEC      | independent ethics committee                                    |
| IRRC     | independent radiology review committee                          |
| ICF      | informed consent form                                           |
| IRB      | institutional review board                                      |
| IVRS     | interactive voice response system                               |
| ICH      | international conference on harmonisation                       |
| IU       | international unit                                              |
| IU/L     | international unit perliter                                     |
| IU/mL    | international unit per milliliter                               |
| IV       | intravenous                                                     |
| IMP      | investigational medicinalproducts                               |
| IND      | investigational new drug exemption                              |
| IB       | investigator brochure                                           |
| KM       | kaplan-meier                                                    |
| kg       | kilogram                                                        |
| LDH      | lactate dehydrogenase                                           |
| L        | liter                                                           |
| LCSS     | lung cancer symptom scale                                       |
| Mg++     | magnesium                                                       |  
Page 14/60  
| MRI        | magnetic resonance maging                       |
|------------|-------------------------------------------------|
| Cmax, CMAX | maximum observed concentration                  |
| MTD        | maximum tolerated dose                          |
| mCRPC      | metastatic castration-resistant prostate cancer |
| m          | meter                                           |
| mcg        | microgram                                       |
| miRNA      | microrna (micro ribonucleic acid)               |
| mg         | milligram                                       |
| mL         | milliliter                                      |
| mL/min     | milliliters per minute                          |
| mm         | millimeter                                      |
| mmHg       | millimeters of mercury                          |
| MIC        | minimum inhibitory concentration                |
| min        | minute                                          |
| mo         | month                                           |
| MDSC       | myeloid derived suppressor cells                |
| NIMP       | non-investigational medicinal products          |
| NSCLC      | non-small cell lung cancer                      |
| NSAID      | nonsteroidal anti-inflammatory drug             |
| N/A        | not applicable                                  |
| NE         | not evaluable                                   |
| N          | number of patients orobservations               |
| ORR        | overall response rate                           |
| OS         | overallsurvival                                 |
| PR         | partial response                                |
| PRO        | patient reported outcomes                       |
| PBMC       | peripheral blood mononuclear cells              |
| PD         | pharmacodynamics                                |
| PK         | pharmacokinetics                                |
| PPK        | population pharmacokinetic                      |
| K+         | potassium                                       |
| K3EDTA     | potassium ethylenediaminetetraacetic acid       |
| PD-1       | programmed death-1                              |
| PD-L1      | programmed death-ligand 1                       |
| PD-L2      | programmed death-ligand 2                       |
| PFS        | progression free survival                       |
| PD         | progressive disease                             |
| PS         | performance status                              |  
| ENERGY     | Trial Code Sponsor 35RC16_9734 / GFPC 08-2015 / BMS CA209-449    |
|------------|------------------------------------------------------------------|
| QC         | quality control                                                  |
| QOL        | Quality of life                                                  |
| QPCR       | quantitative polymerase chain reaction                           |
| QD, qd     | quaque die, once daily                                           |
| RBC        | red blood cell                                                   |
| RCC        | renal cell carcinoma                                             |
| CLR        | renal clearance                                                  |
| RECIST 1.1 | response evaluation criteria in solid tumors version 1.1         |
| SAE        | serious adverse event                                            |
| SNP        | single nucleotide polymorphism                                   |
| Na+        | sodium                                                           |
| SD         | stable disease                                                   |
| SD         | standard deviation                                               |
| SOP        | standard operating procedures                                    |
| SmPC       | summary of product characteristics                               |
| t          | temperature                                                      |
| TID, tid   | ter in die, three times a day                                    |
| TSH        | thyroid stimulating hormone                                      |
| T          | time                                                             |
| Tmax, TMAX | time of maximum observedconcentration                            |
| TAO        | trial access online, the bms implementation of an edc capability |
| Cmin, CMIN | trough observed concentration                                    |
| TILs       | tumor infiltrating lymphocytes                                   |
| UV         | ultraviolet                                                      |
| ULN        | upper limit of normal                                            |
| VAS        | visual analog scale                                              |
| WBC        | white blood cell                                                 |
| WOCBP      | women of childbearing potential                                  |
| WHO        | world health organization                                        |
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1 general information 1.1. title

Etude randomisée de phase III testant l'association du nivolumab et l'ipilimumab versus un doublet à base de platine dans le traitement de première ligne du CBNPC chez des patients PS 2 ou de plus de 70 ans.  
Randomised phase III study testing nivolumab and ipilimumab versus a carboplatin based doublet in first line treatment of PS 2 or elderly (more than 70 years old) patients with advanced non-small cell lung cancer.  
1.2.Sponsor Identification CHU of Rennes 2, rue Henri le Guilloux 35033 Rennes cedex 9 Signature of protocol on behalf of the sponsor Pascal Gaudron, Director of Research CHU of Rennes 2, rue Henri le Guilloux 35033 Rennes cedex 9 Person responsible for study on the side of the sponsor Pascal Gaudron, Director of Research CHU of Rennes 2, rue Henri le Guilloux 35033 Rennes cedex 9 1.3.Coordination and monitoring of study Direction of Research CHU of Rennes 2, rue Henri le Guilloux 35033 Rennes cedex 9 1.4.Investigators Coordinating investigator Dr Hervé Léna Service de pneumologie CHU of Rennes- Hôpital de Pontchaillou 2 rue Henri Le Guillou 35033 Rennes Cedex 9 Associated investigators (see appendix 1)
1.5.Pharmacy Dr Catherine Hamon Pharmacie CHU of Rennes - Hôpital de Pontchaillou 2 rue Henri le Guilloux 35033 Rennes cedex 9 1.6.Pharmacovigilance Dr Catherine Mouchel Service de Pharmacologie et Centre d'Investigation Clinique - INSERM 0203 CHU of Rennes - Hôpital de Pontchaillou 2 rue Henri le Guilloux 35033 Rennes cedex 9
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1.7.methodologist - biostatistician

- **Methodologist :**
Dr David Pérol Unité de Biostatistique et d'Evaluation des Thérapeutiques Direction de la Recherche et de l'Innovation Centre Léon Bérard 28, rue Laënnec - 69373 Lyon Cedex 08
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- biostatistician

Sylvie Chabaud Biostatisticienne - Responsable pôle statistique Unité de Biostatistique et d'Evaluation des Thérapeutiques Direction de la Recherche et de l'Innovation Centre Léon Bérard 28, rue Laënnec - 69373 Lyon Cedex 08 1.8.Referent for geriatric analysis based on mini data set assessment Pr Elena Paillaud Département de gériatrie CHU Henri Mondor 51 Avenue du Maréchal de Lattre de Tassigny 94010 Créteil Cedex 1.9.Referent for PD-L1 testing by immunochemistery (IHC) assessed by the central laboratory Pr Diane Damotte Service d'anatomie et cytologie pathologiques HU-PARIS OUEST SITE G.POMPIDOU APHP 20 Rue Leblanc 75015 Paris 1.10. **Efficacy evaluation committee**
The efficacy evaluation committee will review all available tumor assessment scans to determine response (RECIST 1.1).  
The determined response will be used in the analyses of ORR and PFS.  
The members are: Dr Gilles Robinet, service d'oncologie thoracique, CHU Brest Dr Maurice Pérol, service d'oncologie médicale, Centre Léon Bérard Lyon Pr Christos Chouaid, service de pneumologie Centre Hospitalier Intercommunal Créteil Pr Alain Vergnenègre, service de pneumologie, CHU Limoges Dr Hervé Léna, service de pneumologie, CHU Rennes This committee will meet three times a year to follow inclusion rates, primary and secondary endpoints of the study. Conference call will be organized if necessary.
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1.11. data monitoring committee

A Data Monitoring Committee (DMC) will be established to provide oversight of safety and efficacy considerations in protocol Energy, and to provide advice to the Sponsor regarding actions the committee deems necessary for the continuing protection of patients enrolled in the trial. The DMC will monitor patient safety and evaluate the available efficacy data for the study. The group will be responsible for promptly reviewing the DMC recommendations, for providing guidance regarding the continuation or termination of the study, and for determining whether amendments to the protocol or changes in study conduct are required. After meeting, the DMC will notify the clinical study leadership group that it has met and will provide recommendations about the study by telephone or email. Any recommendation by  
the DMC regarding study modification will be submitted to the clinical study leadership team within pre-specified business days of the DMC meeting.  
Members of the DMC are:
Thoracic oncologists :
Pr A Cortot, Service de pneumologie, CHU Lille Dr B Mennecier, Service de pneumologie, CHU Strasbourg Pharmacovigilance : Dr Sophie Duranton, Direction de la Recherche, CHU Poitiers Méthodologist :
Bruno Giraudeau, CIC Inserm 1415, CHU Tours
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2 scientific rationale and general

Nivolumab (BMS-936558) is a fully human, IgG4 (kappa) isotype mAb that binds PD-1 on activated immune cells and disrupts engagement of the receptor with its ligands PD-L1 (B7-H1/CD274) and PD-L2 (B7-DC/CD273), thereby abrogating inhibitory signals and augmenting the host antitumor response. Ipilimumab is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen expressed on a subset of T cells from human and nonhuman primates. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, including the activation and proliferation of tumor infiltrating Teffector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including the anti-tumor response.
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2.2. summary of results of

Chemotherapy is feasible and beneficial for elderly NSCLC patients with advanced/metastatic disease [1–4]. On the other hand, it should be noted that elderly had higher rates of adverse events during chemotherapy compared with patients younger than 55 years and this observation was independent of comorbidity [5]. This could be the reason for the significant under-treatment of elderly patients in clinical practice.  
Prospective trials support the use of carboplatin-based doublets in fit elderly patients [6-7]. For less fit patients, singleagent treatment (gemcitabine, vinorelbine, taxanes) represents a valid option according to ESMO guidelines published in 2014 [8]. There are no data to support any single agent offering an OS benefit, very limited data are available for octogenarians and, therefore, no specific recommendations can be made for this group. Performance status, comorbidities, life expectancy and patient's preference should be taken into account when developing a treatment strategy. For patients PS 2 with advanced NSCLC, the updated systematic review performed by the ASCO clinical practice guideline update and published in oct 2015 [9] identified two small trials specifically comparing single agent versus combination chemotherapy in patients with PS 2. The first trial which included 205 participants, compared carboplatin plus pemetrexed with pemetrexed alone[10]. In the results, OS and PFS were statistically significantly longer with the combination. Adverse events were slightly more frequent with the combination, but the results were not statistically significant. One trial with 56 participants compared cisplatin plus gemcitabine with gemcitabine and found that OS and QoL was also higher; however, the study was stopped early and had few participants [11]. The Cochrane systematic review on chemotherapy and supportive care, updated in 2012, continued to show that chemotherapy and best supportive care versus supportive care alone benefit patients, including those who have PS 2 [12]. PFS were statistically significantly longer with the combination.  
Trials limited to patients with PS 2 have typically not reported the cause for designation of PS 2 (ie, cancer-related symptoms secondary to large tumor burden v poor PS designation because of multiple chronic conditions). That's why ASCO guidelines concluded in 2015, that the data informing chemotherapy decisions for patients with PS 2 are insufficient to make a strong recommendation favoring combination chemotherapy. Patients and clinicians should discuss the risks and benefits of combination chemotherapy. Some patients may choose single-agent chemotherapy if their perception of risk outweighs perceived benefits of combination therapy. There is no effective tool to determine which patients will tolerate doublet therapy and experience an improvement in PS with a reduction of symptoms and which patients will experience an acceleration of their decline with treatment [9].
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experimental arm

Immunotherapeutic approaches recently have demonstrated clinical efficacy in several cancer types, including melanoma and hormone-refractory prostate cancer [13]. Tumors may modulate and evade the host immune response through a number of mechanisms, including down regulation of tumor-specific antigen expression and presentation, secretion of anti-inflammatory cytokines, and upregulation of inhibitory ligands. T cell checkpoint regulators such as CTLA-4 and programmed death-1 (PD-1, CD279) are cell surface molecules that, when engaged by their cognate ligands, induce signaling cascades down-regulating T cell activation and proliferation. One proposed model by which therapeutic T cell checkpoint inhibitors derive antitumor activity is through breaking of immune tolerance to tumor cell antigens. Nivolumab is now approved in Europe to treat patients with metastatic squamous cell NSCLC with progression on or after platinum-based chemotherapy. The approval was based on the results of CA209017 [14], a randomized trial of nivolumab versus docetaxel. The median overall survival (OS) for Patients in the nivolumab arm was 9.2 months versus 6 months for those in the docetaxel arm (HR = 0.59). Improvement in survival was observed for nivolumab regardless of PD-L1 expression, though there was a trend for better efficacy for those with PD-L1 expressing tumors. A single arm trial (CA209063) of 117 Patients with metastatic squamous cell NSCLC, with progression after platinum-based chemotherapy and at least one additional systemic regimen, showed a 15% overall response rate (ORR), of whom 59% had response durations of 6 months or longer [15].  
A second phase 3 study, CA209057 [16], stopped at a preplanned interim analysis by the independent Data Monitoring Committee (DMC), met its primary endpoint of superior overall survival of nivolumab versus docetaxel in Patients with previously-treated non-squamous NSCLC. Patients in the nivolumab arm had a 27% reduction in risk of death (HR = 0.73; P = 0.0015). Interaction p-values, reported for PD-L1 expression subgroups by each of the predefined expression levels, suggested a clinically important signal of a predictive association. Nivolumab also significantly improved ORR vs docetaxel (P=0.0246), with ORR as high as 36% in Patients with PD-L1 expressing tumors. OS approximately doubled with nivolumab vs docetaxel across the PD-L1 expression continuum. In contrast, no difference in OS was seen between nivolumab and docetaxel when PD-L1 was not expressed in the tumor. Nivolumab monotherapy has also been evaluated in first-line NSCLC, where it showed promising activity regardless of histology. As in pretreated NSCLC, activity with nivolumab monotherapy is pronounced in PD-L1 expressing NSCLC. The recruitment of the trial comparing nivolumab to chemotherapy in 1st line at the investigator's choice is closed to inclusions. In general, nivolumab also has been well tolerated to date, with a favorable safety profile relative to anticipated toxicities based on an immunostimulatory mechanism of action.  
Nivolumab monotherapy has also been evaluated in first-line NSCLC, where it showed promising activity regardless of histology [17]. But study Checkmate 026 failed to demonstrate a PFS nor OS benefit in favor of Nivolumab versus a platin-based doublet in first line treatment of stage IV NSCLC ≥ 5% PD-L1 expression [18].  
Preclinical data indicate that the combination of PD-1 and CTLA-4 receptor blockade may improve antitumor activity. In vitro combinations of nivolumab plus ipilimumab increase IFN-ɤ production 2- to 7-fold over either agent alone in a mixed lymphocyte reaction. Increased antitumor activity of the combination was also observed in 3 of 5 syngeneic murine cancer models. In a murine melanoma vaccine model, blockade with either CTLA-4 or PD-1 antibodiesincreased the proportion of CTLA-4 and PD-1-expressing CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor infiltration of T effector cells and decreased intratumoral T regulatory cells, as compared to either agent alone [19].  
The combination of nivolumab and ipilimumab was evaluated in CA209004 (MDX1106-04), a phase 1b multiple ascending dose study in Patients with treatment-naive and previously treated advanced melanoma. Results showed promising activity, with higher, but tolerable toxicity than ipilimumab alone [20]. Based on these data, CA209069, a phase 2 study, compared the combination to ipilimumab alone in treatment-naïve patients with advanced melanoma:
nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 weeks x4 followed by nivolumab 3 mg/kg every 2 weeks versus ipilimumab 3 mg/kg every 3 weeks x 4 [21]. In patients with BRAF wild type tumors, the ORR was 61% (44/72),
including 22% (16/72) complete responses (CR) in the group treated with the combination, compared to 11% (4/37) with 0 CRs in those treated with ipilimumab alone. The median PFS was not reached in the combination versus 4.4 months for ipilimumab alone (HR=0.4). It should be noted that in the combination group, the ORR was independent of PD-L1 expression. In this group, ORR was 58% among patients with PD-L1+ tumors and 55% among those with PD-L1- tumors. In contrast, in the ipilimumab alone group, the ORR was numerically higher among patients with PD-L1+ tumors (18%) compared to those with PD-L1- tumors (4%). Grade 3-4 treatment-related AEs were reported in 54% of patients receiving the combination compared to 24% for ipilimumab alone. Ipilimumab has been shown to have activity in lung cancer. A Phase 2 study (CA184041) in Patients with NSCLC or small cell lung cancer (SCLC) investigated the addition of ipilimumab to carboplatin and paclitaxel using 2 different schedules (concurrent and phased). The phased schedule demonstrated a significant improvement of immune-related progression-free survival as well as progression-free survival by modified WHO criteria compared to chemotherapy alone, in both NSCLC and SCLC [22]. Based on the initial data in melanoma, and the activity observed with nivolumab and ipilimumab in lung cancer, the nivolumab plus ipilimumab combination has been also evaluated as first-line therapy in patients with advanced NSCLC. In CA209012, early combination cohorts evaluated 2 dosing schedules that were studied in the CA209004 study in melanoma: - nivolumab 1 mg/kg + ipilimumab 3 mg/kg, q 3 weeks x4, followed by nivolumab 3 mg/kg q 2 weeks (arms G and H, n=24); -nivolumab 3 mg/kg + ipilimumab 1 mg/kg, q 3 weeks x4, followed by nivolumab 3 mg/kg q 2 weeks (arms I and J,
n=25)
These regimens resulted in significant toxicity, with 39% of patients discontinuing treatment due to a treatment-related adverse event.  
Thus, additional combination cohorts were initiated, using lower doses of both nivolumab and ipilimumab, or less frequent dosing of ipilimumab. Data from these cohorts demonstrate that both nivolumab 1 mg/kg + ipilimumab 1 mg/kg q 3 weeks with nivolumab maintenance 3 mg/kg q2w (arm N in study CA209012), as well as ipilimumab at 1 mg/kg q6w is tolerable, when given with nivolumab 3 mg/kg q2w (arm Q in study CA209012). Overall, the safety data are not dissimilar to what has been observed in the nivolumab arm (arm F in CA209012). Of particular note, the rate of discontinuation due to drug-related AEs was 13% in arm N and 11% in arm Q compared to 10% in the nivolumab monotherapy arm (arm F) [17].  
Table1: Treatment-related immune adverse events from selected cohorts in C209012 [17].  
Table 5.5.1.1-2:  
| Grade - CA209012             | Arm O              |                     |                    |           |             |           |           |           |
|------------------------------|--------------------|---------------------|--------------------|-----------|-------------|-----------|-----------|-----------|
| Arm N                        | Arm P              | Arm Q               |                    |           |             |           |           |           |
| Nivo 1 mg/kg + Ipi           | Nivo 1 mg/kg Q2W + | Nivo 3 mg/kg Q2TV + | Nivo 3 mg/kg Q2W + |           |             |           |           |           |
| Ipi 1 mg/kg Q12W             |                    |                     |                    |           |             |           |           |           |
| l mg/kg Q3W                  | Ipi 1 mg/kg Q6W.   | Ipi 1 mg/kg Q6M     |                    |           |             |           |           |           |
| N = 40                       | N = 39             | N = 39              |                    |           |             |           |           |           |
| N = 31 a                     | n (%)              | n (%)               | n(%)               |           |             |           |           |           |
| Category                     | n (%)              |                     |                    |           |             |           |           |           |
| Crade 3-4                    | Crade 3-4          | Crade 3-4           |                    |           |             |           |           |           |
| Preferred Term               | Any Crade          | Any Crade           | Crade 3-4          | Any Crade | Any Crade   |           |           |           |
| AEs                          | 31 (100.0)         | 16 (51.6)           | 37 (92.5)          | 24 (60.0) | 37 ( 97.4 ) | 15 (39.5) | 36 (92.3) | 18 (46.2) |
| Drug-related AEs             | 26 (83.9)          | 9 (29.0)            | 29 (72.5)          | 16 (40.0) | 31 (81.6)   | 14 (36.8) | 28 (71.8) | 13 (33.3) |
| Drug-related AEs in ≥ 10% of |                    |                     |                    |           |             |           |           |           |
| Subjects                     |                    |                     |                    |           |             |           |           |           |
| Fatigue                      | 9 (29.0)           | 0                   | 9 (22.5)           | 1 (2.5)   | 6 (15.8)    | 1 (2.6)   | 9 (23.1)  | 1 (2.6)   |
| Rash                         | 9 (29.0)           | 4 (12.9)            | 10 (25.0)          | 2 (5.0)   | 6 (15.8)    | 1 (2.6)   | 4 (10.3)  | 1 (2.6)   |
| Diarrhea                     | 6 (19.4)           | 10 (25.0)           | 8 (21.1)           | 8 (20.5)  |             |           |           |           |
| 0                            | 2 (5.0)            | 1 (2.6)             | 0                  |           |             |           |           |           |
| Pruntus                      | 6 (19.4)           | 0                   | 4 (10.0)           | o         | 9 (23.7)    | 0         | 5 (12.8)  | 0         |
| Lipase Increased             | 4 (12.9)           | 2 (6.5)             | 3 (7.5)            | 1 (2.5)   | 6 (15.8)    | 3 (7.9)   | 0         | o         |
| Arthralgia                   | 4 (12.9)           | o                   | 2 (5.0)            | o         | 4 (10.5)    | o         | 0         | 0         |
| 6 (15.4)                     |                    |                     |                    |           |             |           |           |           |
| Nausea                       | 4 (12.9)           | 0                   | 3 (7.5)            | 0         | 6 (15.8)    | 10        | l (2.6)   |           |
| Pneumonitis                  | 3 (9.7)            | 1(3.2)              | 3 (7.5)            | 0         | 4 (10.5)    | 2 (5.3)   | 2 (5.1)   | l (2.6)   |
| Amylase Increased            | 3 (9.7)            | 2 (6.5)             | 2 (5.0)            | 0         | 6 (15.8)    | 1 (2.6)   | 0         | o         |
| 4 (10.3)                     | 1 (2.6)            |                     |                    |           |             |           |           |           |
| Rash Maculo-papular          | 3 (9.7)            | o                   | 1 (2.5)            | 0         | 5 (13.2)    | o         |           |           |
| Adrenal Insufficiency        | 2 (6.5)            | 2 (6.5)             | 3 (7.5)            | 2 (5.0)   | 1 (2.6)     | l (2.6)   | 5 (12.8)  | 2 (5.1)   |
| Decreased Appetite           | 2 (6.5)            | o                   | 3 (7.5)            | o         | 4 (10.5)    | 0         | 5 (12.8)  | o         |
| Hypothyroidism               | 2 (6.5)            | 6 (15.0)            | 2 (5.3)            |           |             |           |           |           |
| 0                            | 0                  | 0                   | 1 (2.6)            | 0         |             |           |           |           |
| ALT Increased                | 2 (6.5)            | 1 ( 3.2 )           | 8 (20.0)           | 4 (10.0)  | 1 (2.6)     | 0         | 1 (2.6)   | 1 (2.6)   |
| AST Increased                | 2 (6.5)            | 1 ( 3.2)            | S (20.0)           | 5 (12.5)  | 1 (2.6)     | 0         | 1 (2.6)   | 1 (2.6)   |
| Hyperthyroidism              | 2 (6.5)            | o                   | 3 (7.5)            | o         | o           | o         | 4 (10.3)  | o         |
| Pyrexia                      | 2 (6.5)            | 0                   | 1 (2.5)            | o         | 5 (13.2)    | 0         | 2 (5.1)   | o         |
| Dry mouth                    | 2 (6.5)            | 0                   | 4 (10.0)           | 0         | 2 (5.3)     | 10        | 1 (2.6)   | 10        |
| Rash generalized             | 0                  | 2 (5.0)             | 0                  | 0         | 0           | 4 (10.3)  | o         |           |
| 0                            |                    |                     |                    |           |             |           |           |           |
| Transaminases Increased      | 1 (3.2)            | 0                   | o                  | 0         | 0           | o         | 1 (2.6)   | l (2.6)   |  
| Table 5.5.1.1-2:                                                                                                                       | Summary of Safety in Subjects Treated with Nivolumab + Ipilimumab (New Cohorts) by Worst CTC   |                    |                 |           |           |           |           |           |
|----------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------|--------------------|-----------------|-----------|-----------|-----------|-----------|-----------|
| Grade - CA209012                                                                                                                       |                                                                                                |                    |                 |           |           |           |           |           |
| Arm N                                                                                                                                  | Arm O                                                                                          | Arm P              | Arm Q           |           |           |           |           |           |
| Nivo 3 mg/kg Q2W +                                                                                                                     |                                                                                                |                    |                 |           |           |           |           |           |
| Nivo 1 mg/kg ÷ Ipi                                                                                                                     | Nivo 1 mg/kg Q2W +                                                                             | Nivo 3 mg/kg Q2W + |                 |           |           |           |           |           |
| l mg/kg Q3W                                                                                                                            | Ipi 1 mg/kg Q6W.                                                                               | Ipi 1 mg/kg Q12W   | Ipi 1 mg/kg Q6W |           |           |           |           |           |
| N = 31                                                                                                                                 | N = 40                                                                                         | N = 39             | N = 39          |           |           |           |           |           |
| n(%)                                                                                                                                   | n(%)                                                                                           | n(%)               | n(%)            |           |           |           |           |           |
| Category                                                                                                                               |                                                                                                |                    |                 |           |           |           |           |           |
| Preferred Term                                                                                                                         | Any Crade                                                                                      | Grade 3-4          | Any Crade       | Grade 3-4 | Any Crade | Crade 3-4 | Any Crade | Crade 3-4 |
| SAEs                                                                                                                                   | 13 (41.9)                                                                                      | 1 (35.5)           | 26 (65.0)       | 18 (45.0) | 23 (60.5) | 12 (31.6) | 24 (61.5) | 14 (35.9) |
| Drug-related SAEs                                                                                                                      | 6 (19.4)                                                                                       | 5 (16.1)           | 15 (37.5)       | 1 (27.5)  | 12 (31.6) | 9 (23.7)  | 1 (28.2)  | 9 (23.1)  |
| Drug-related SAEs in                                                                                                                   |                                                                                                |                    |                 |           |           |           |           |           |
| > 1 Subject                                                                                                                            | 2 (6.5)                                                                                        | 2 (6.5)            | 3 (7.5)         | 2 (5.0)   | 1 (2.6)   | 2 (5.1)   | 2 (5.1)   |           |
| Adrenal Insufficiency                                                                                                                  | 1 (2.6)                                                                                        |                    |                 |           |           |           |           |           |
| Hypophysitis                                                                                                                           | 2 (6.5)                                                                                        | 2 (6.5)            | 1 (2.5)         | 0         | 10        | 10        | 0         | 10        |
| Pneumonitis                                                                                                                            | 2 (6.5)                                                                                        | 1 (3.2)            | 2 (5.0)         | o         | 2 (5.3)   | 2 (5.3)   | 1 (2.6)   | 1 (2.6)   |
| 1 (3.2)                                                                                                                                | 3 (7.5)                                                                                        | 3 (7.5)            |                 |           |           |           |           |           |
| Autoimmune hepatitis                                                                                                                   | 1 (3.2)                                                                                        | 10                 | 0               | 0         | 10        |           |           |           |
| Colitis                                                                                                                                | 10                                                                                             | 0                  | 1 (2.5)         | 1 (2.5)   | 1 (2.6)   | 1 (2.6)   | 3 (7.7)   | 2 (5.1)   |
| Diarrhea                                                                                                                               | 1 (3.2)                                                                                        | o                  | 2 (5.0)         | 2 (5.0)   | 2 (5.3)   | 1 (2.6)   | 0         | 0         |
| Acute kidney injury                                                                                                                    | 0                                                                                              | 1 (2.5)            | 2 (5.3)         | 1 (2.6)   | 0         | 0         |           |           |
| 0                                                                                                                                      | 0                                                                                              |                    |                 |           |           |           |           |           |
| AEs Leading to Discontinuation                                                                                                         | 4 (12.9)                                                                                       | 3 (9.7)            | 5 (12.5)        | 5 (12.5)  | 8 (21.1)  | 4 (10.5)  | 7 (17.9)  | 3 (7.7)   |
| Drug-related AEs Leading to                                                                                                            | 4 (12.9)                                                                                       | 3 (9.7)            | 3 (7.5)         | 3 (7.5)   | 4 (10.5)  | 2 (5.3)   | 5 (12.8)  | 3 (7.7)   |
| Discontinuation                                                                                                                        |                                                                                                |                    |                 |           |           |           |           |           |
| Drug-related AEs Leading to                                                                                                            |                                                                                                |                    |                 |           |           |           |           |           |
| Discontinuation in > 1 Subject                                                                                                         |                                                                                                |                    |                 |           |           |           |           |           |
| Pneumonitis                                                                                                                            | 1 (3.2)                                                                                        | 1 (3.2)            | 10              | 0         | 2 (5.3)   | 1 (2.6)   | 2 (5.1)   | 1 (2.6)   |
| Autoimmune hepatitis                                                                                                                   | 2 (5.0)                                                                                        | 2 (5.0)            | 0               | 10        |           |           |           |           |
| Analysis of safety in the nivolumab monotherapy group focused on the initial cohort ( N = 20) whose safety data is sufficiently mature |                                                                                                |                    |                 |           |           |           |           |           |
| Source: Preliminary data for CA209012, database lock date, 18-Feb-2016.                                                                |                                                                                                |                    |                 |           |           |           |           |           |  
Note: Safety events were reported between the first dose and 100 days after the last dose of study drug. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; Nivo = nivolumab; Ipi = ipilimumab The toxicity rate was higher with the combination compare to nivolumab alone. Nevertheless it was a majority of grade 12 toxicities.  
| Nivo 3 Q2W                               | Nivo 3 Q2W      | Nivo 3 Q2W
(n = 52)                 |                 |
|------------------------------------------|-----------------|-----------------|-----------------|
| p 1 012W
(n = 38)                                          | (n = 39)        |                 |                 |
| Confirmed ORR, % (95% CI)                | 47              | 39              | 23              |
| (31, 64)                                 | (23, 55)        | (13, 37)        |                 |
| Median duration of response, mo (95% Cl) | NR (11.3, NR)   | NR (8.4, NR)    | NR (5.7, NR)    |
| Median length of follow-up,  mo (range)  | 12.9 (0.9–18.0) | 1.8 (1.1–18.2)  | 14.3 (0.2–30.1) |
| Best overall response, %                 |                 |                 |                 |
| Complete response                        | 0               | 0               | 8               |
| Partial response                         | 47              | 39              | 15              |
| Stable disease                           | 32              | 18              | 27              |
| Progressive disease                      | 13              | 28              | 38              |
| Unable to determine                      | 8               | 15              | 12              |
| Median PFS, mo (95% CI)                  | 8.1 (5.6, 13.6) | 3.9 (2.6, 13.2) | 3.6 (2.3, 6.6)  |
| 1-year OS rate, % (95% CI)               | NC              | 69 (52, 81)     | 73 (59, 83)     |  
Table 2: Clinical activity of nivolumab/ipilimumab combination and nivolumab alone[17].  
Table 3: Clinical activity of nivolumab/ipilimumab combination compared to nivolumab alone by PD-L1 status, using 1% cutoff [ 17 ].  
  
Flat dose regimens of nivolumab The safety and efficacy of 240 mg Q2W flat dose of nivolumab is expected to be similar to3 mg/kg Q2W dosing regimen.  
A flat dose of nivolumab 240 mg Q2W was selected since it is identical to a dose of 3 mg/kg for patients weighing 80 kg, the observed median body weight in nivolumab treated cancer patients. Using a PPK model, the overall distributions of nivolumab exposures (Cavgss, Cminss, Cmaxss, and Cmin1) are comparable after treatment with either 3 mg/kg or 240 mg nivolumab. The predicted range of nivolumab exposures (median and 90% prediction intervals) resulting from a 240 mg flat dose across the 35 to 160 kg weight range is maintained well below the corresponding exposures observed with the well tolerated 10 mg/kg nivolumab Q2W dosage. Across the various tumor types in the clinical program, nivolumab has been shown to be safe and well tolerated up to a dose level of 10 mg/kg, and the relationship between nivolumab exposure produced by 3 mg/kg and efficacy and safety has been found to be relatively flat. Given the similarity of nivolumab PK across tumor types and the similar exposures predicted following administration of 240 mg flat dose compared to 3 mg/kg Q2W regimen, it is expected that the safety and efficacy profile of 240 mg Q2W nivolumab will be similar to that of 3 mg/kg nivolumab. Hence, a flat dose of 240 mg nivolumab is under investigation.
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shorter infusion duration

Establishing that nivolumab can be safely administered using a shorter infusion time (30 minutes) is under investigation. Previous clinical studies of nivolumab monotherapy have used a 60-minute infusion duration wherein, nivolumab has been safely administered up to 10 mg/kg over long treatment periods. Infusion reactions including high-grade hypersensitivity reactions have been uncommon across nivolumab clinical program. In CA209010, a dose association was observed for infusion site reactions and hypersensitivity reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were Grade 1-2 and were manageable. An infusion duration of 30 minutes for 3 mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to present any safety concerns compared to the prior experience at 10 mg/kg nivolumab dose infused over a 60-minute duration. The safety of nivolumab 3 mg/kg administered as a 30-min infusion was assessed in CA209153 in patients (n=322) with previously treated advanced NSCLC. Overall, there were no clinically meaningful differences in the frequency of hypersensitivity/infusion-related reactions (of any cause or treatment-related) in patients administered nivolumab over a 30 min infusion compared with that reported for patients with the 60 min infusion. Thus, it was shown that nivolumab can be safely infused over 30 min.  
Based on these data, the following schedule will be evaluated in Inergy:
- Nivolumab (3 mg/kg every 2 weeks) + ipilimumab (1 mg/kg every 6 weeks) will be evaluated in both PD-L1+ and PDL1- patients.  
Of note, all patients included in the trials with nivolumab and ipilimumab were in good general status PS 0 to 1 (inclusion criteria). Number of elderly patients included in CA209 057 and CA 209 017 was very low even if there was no limitation of age in inclusion criteria. Median age for example in 057 study was 61 years old with only 7% older than 75.  
Energy is planned to compare the efficacy and safety of nivolumab and ipilimumab versus carboplatin-based doublet in advanced NSCLC in first line in patients ≥70 years old or PS2.
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2.3 summary of benefits and

2.3.1.1 Individual benefits Regard to the low toxicity of nivolumab and ipilimumab in lung cancer population, the possibility to obtain long responses, nivolumab and ipilimumab could be a valid option for this frail population of patients. 2.3.1.2 Collective benefit Evaluation of new treatments in these specific populations of frail or elderly lung cancer patients will potentially increase the therapeutic possibilities for these specific populations.
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2.3.2 risks individual risks

Physical risks and constraints The main risk in this frail population could be the delay to cytotoxic chemotherapy. First evaluation will be done at 6 weeks, allowing a rapid crossover in case of progression under nivolumab and ipilimumab. In case of clinical progression, a rapid evaluation will be asked to confirm progression and beginning of chemotherapy. The association of nivolumab and ipilimumabincrease toxicity compared to nivolumab alone but at the doses of nivolumab plus ipilimumab that will be used in this study we don't expect to observe a higher rate of discontinuation due to drug-related AEs than with nivolumab alone. This association appears tolerable even for a frail population.  
Psychological risks and constraints Not applicable. Cancer patients benefit of specific support according to plans cancers 1 to 3. All research sites have an agreement for treatment of advanced cancer patients and psychological support is part of this agreement.  
Socio-economic risks and constraints Nivolumab and ipilimumab will be supplied by BMS. All other drugs are registered and used in this indication and are included in national and international recommendations.
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2.4. description and rationale for

Patients will receive treatment with nivolumab as a 30 minutes infusion at 240 mg every 2 weeks and ipilimumab as a 30 minutes infusion at 1 mg/kg every 6 weeks, starting on Day 1, until disease progression, unacceptable toxicity, or other reasons specified in the protocol section 4.6. All decisions to continue treatment beyond initial progression documented in the study record, discussed and agreed to by the study coordinator. Patients should be re-consented with an ICF describing any reasonably foreseeable risks or discomforts. Accumulating evidence indicates a minority of Patients treated with immunotherapy may derive clinical benefit despite initial evidence of PD.  
Patients will be permitted to continue treatment beyond initial RECIST 1.1 defined PD as long as they meet the following criteria determined by the investigator: - Investigator-assessed clinical benefit and Patient is tolerating study drug. - Tolerance of study drug - Stable performance status The assessment of clinical benefit should take into account whether the Patient is clinically deteriorating and unlikely to receive further benefit from continued treatment.  
Treatment beyond progression will not delay an imminent intervention to prevent serious complications of disease progression (eg, CNS metastases).  
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-assessed progression to determine whether there has been a decrease in the tumor size or continued PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the patient is clinically deteriorating and unlikely to receive any benefit from continued treatment with nivolumab + ipilimumab.  
For the patients who continue nivolumab + ipilimumab study therapy beyond progression, further progression is defined as an additional 10% increase in tumor burden from time of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions compared to the time of initial PD. Nivolumab+ ipilimumab treatment should be discontinued permanently upon documentation of further progression. New lesions are considered measureable at the time of initial progression if the longest diameter is at least 10 mm (except for pathological lymph nodes which must have a short axis of at least15 mm). Any new lesion considered nonmeasureable at the time of initial progression may become measureable and therefore included in the tumor burden if the longest diameter increases to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 mm). In situations where the relative increase in total tumor burden by 10% is solely due to inclusion of new lesions which become measurable, these new lesions must demonstrate an absolute increase of at least 5 mm.  
For statistical analyses, this will need to be described in patient population information. E.g. Patients who continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be considered to have investigatorassessed progressive disease at the time of the initial progression event.
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control arm

Patients will receive according to standard practice and local guidelines:
- carboplatine AUC 5 with a dose that will be capped to 700 mg I.V D1 and pemetrexed (500 mg/m²) I.V D1 over 4 to 6 hours every 3 weeks for 4 cycles (restricted to non-squamous histology)
- or carboplatine AUC 6 with a dose that will be capped to 700 mg I.V D1 and paclitaxel (90 mg/m²) I.V D1 D8 D15 over 4 to 6 hours every 4 weeks for 4 cycles (allowed in squamous and non-squamous histologies).  
Premedication (steroids for pemetrexed and paclitaxel, folic acid and vitamin B12 for pemetrexed) and emesis prevention therapy are required and will be used as standard practice. Treatment will be given for 4 cycles except in case of progression or toxicity. See chapter 6 for more detailed description. In cases of patient with a body surface area≥2m², all the chemotherapies doses will be capped at 2m² of body surface area. 2.5. Statement indicating that the study will be conducted in compliance with the protocol as well as with good clinical practices and legislative and regulatory conditions in force The sponsor and the investigator also agree that this study will be conducted:
in compliance with the protocol, in compliance with local and international good clinical practice currently in force, in compliance with legislative and regulatory conditions currently in force in participating countries.
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2.6. description of the studied

Patients with untreated non-small cell lung cancer, patients less than 70 years old with PS2 or older than 70 years old with PS 0, 1 or 2 or at diagnosis. The selection procedures are described in chapter 5.
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2.7. references to the scientific

1. Gridelli C, Brodowicz T, Langer CJ et al. Pemetrexed therapy in elderly patients with good performance status:
analysis of two phase III trials of patients with nonsquamous non-small-cell lung cancer. Clin Lung Cancer 2012; 13: 340–346. 2. Kawaguchi T, Tamiya A, Tamura A et al. Chemotherapy is beneficial for elderly patients with advanced non-small-cell lung cancer: analysis of patients aged 70–74, 75-79, and 80 or older in Japan. Clin Lung Cancer 2012; 13: 442–447. 3. Davidoff AJ, Tang M, Seal B et al. Chemotherapy and survival benefit in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 2191–2197.  
4. Zhu J, Sharma DB, Chen AB et al. Comparative effectiveness of three platinumdoublet chemotherapy regimens in elderly patients with advanced non-small cell lung cancer. Cancer 2013; 119: 2048–2060.  
5. Chrischilles EA, Pendergast JF, Kahn KL et al. Adverse events among the elderly receiving chemotherapy for advanced non-small-cell lung cancer. J Clin Oncol 2010; 28: 620–627. 6- Quoix E, Zalcman G, Oster JP et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet 2011; 378: 1079–1088.  
7- Socinski MA, Langer CJ, Okamoto I et al. Safety and efficacy of weekly nab(R)- paclitaxel in combination with carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 314– 321. 8- Pallis AG, Gridelli C, Wedding U, *et al.* Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Ann Oncol Off J Eur Soc Med Oncol ESMO 2014; 25: 1270–83. 9- Masters GA, Temin S, Azzoli CG, Giaccone G, Baker S Jr, Brahmer JR, Ellis PM, Gajra A, Rackear N, Schiller JH,
Smith TJ, Strawn JR, Trent D, Johnson DH; American Society of Clinical Oncology Clinical Practice. Systemic Therapy for Stage IV Non-Small-Cell Lung Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J
Clin Oncol. 2015 Oct 20;33(30):3488-515. 10- Zukin M, Barrios CH, Pereira JR, et al: Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non–small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol 31:2849-2853, 2013. 11- Morabito A, Gebbia V, Di Maio M, et al: Randomized phase III trial of gemcitabine and cisplatin vs. gemcitabine alone in patients with advanced non-small cell lung cancer and a performance status of 2: The CAPPA-2 study. Lung Cancer 81:77-83, 2013 12- Non-Small Cell Lung Cancer Collaborative Group: Chemotherapy and supportive care versus supportive care alone for advanced non-small cell lung cancer. Cochrane Database Syst Rev 5:CD007309, 2010 13- Mellman I, Coukos G & Dranoff G. Cancer immunotherapy comes of age. Nature 2011 Dec 22;29 4 8 0:480-89.  
14- Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE,
Holgado E, Waterhouse D, Ready N, Gainor J, Arén Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M,
Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. 15- Rizvi NA, Mazières J, Planchard D, Stinchcombe TE, Dy GK, Antonia SJ, Horn L, Lena H, Minenza E, Mennecier B, Otterson GA, Campos LT, Gandara DR, Levy BP, Nair SG, Zalcman G, Wolf J, Souquet PJ, Baldini E, Cappuzzo F, Chouaid C, Dowlati A, Sanborn R, Lopez-Chavez A, Grohe C, Huber RM, Harbison CT, Baudelet C, Lestini BJ, Ramalingam SS. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial.Lancet Oncol. 2015 Mar;16(3):257-65.  
16- Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhäufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crinò L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. 17- Hellmann MD et al. CheckMate 012: Safety and efficacy of first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin Oncol 34, 2016 (suppl; abstr 3001). 18- Socinski M. CheckMate 026: A Phase 3 Trial of Nivolumab vs Investigator's Choice (IC) of Platinum-Based Doublet Chemotherapy (PT-DC) as First-Line Therapy for Stage IV/Recurrent Programmed Death Ligand 1 (PD-L1) − Positive NSCLC' Abstract LBA7_PR, ESMO2016.  
19- Curran MA, Montalvo W, Yagita H, et al. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. PNAS 2010; 107: 4275-80. 20- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. New Engl J Med 2013; 369: 122-33. 21- Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015; 372:2006-2017. 22- Ipilimumab (BMS-734016) Investigator Brochure, version 17, 2014.
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3 study objectives

3.1. Primary objective To compare overall survival of patients treated with nivolumab + ipilimumab versus patients treated with chemotherapy.
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3.2. secondary objectives

To compare:
survival rate at one year of patients treated with nivolumab + ipilimumab versus patients treated with chemotherapy, the objective response rate, the Progression free survival, the safety and the tolerability of nivolumab + ipilimumab versus chemotherapy, the QOL,
the prognostic impact of PD-L1 expression by immunochemistery (IHC) on OS and PFS,
the prognostic impact of a geriatric mini data set on OS, PFS and toxicity and its evolution under treatment restricted to patients ≥70 years old.
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4 study design 4.1 evaluation

4.1.1 **Primary evaluation criteria** Overall survival 4.1.2. Secondary evaluation criteria Survival rate at one year, Objective response rate according to RECIST 1.1, Progression free survival, Safety tolerability according to CTCAE version 4.0, Quality of life according to EQ-5D and EORTC QLQ-ELD14 questionnaires every 6 weeks, PD-L1 expression by immunochemistery (IHC) as a predictive factor of OS and PFS,
Geriatric mini data set restricted to patients ≥70 years old.
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4.2. description of study methodology

4.2.2. Conduct of study  
  
  
4.2.2.1. Inclusion Assessments and Procedures Within 28 days before treatment:
Informed consent must be obtained prior to any specific procedure to the trial Checking inclusion/ exclusion criteria A complete medical history and concomitant medications Physical measurements including height, and weight (calculated BMI, calculated BSA for Patients randomized to treatment Arm B). Focused physical examination may be performed as clinically indicated ECOG performance status Vital signs (including heart rate, blood pressure) within 72 hours of dosing Oxygen saturation by pulse oximetry at rest, (also monitor amount of supplemental O2 if applicable) within 72 hour of dosing A serum or urine pregnancy testing for WOCBP will be collected within 24 hours prior to start of study therapy Laboratory tests include (performed within 7 days prior to randomization unless otherwise specified)
Blood for complete blood count (CBC) with differential, including neutrophil and lymphocyte count Serum chemistry tests : urea level, serum creatinine, sodium, potassium, calcium, phosphate, chloride, glucose, LDH)
AST, ALT, albumin, total bilirubin, alkaline phosphatase TSH, free T3 and free T4 (within 28 days of randomization) Hepatitis B surface antigen (HBV sAG), Hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV
RNA),HIV and CMV serology testing within 28 days prior to randomization Signs and symptoms present prior to randomization (regardless of relationship to disease) will be recorded.  
Additionally, record any concomitant medications taken within 14 days of randomization.  
Disease evaluation (chest abdomen CT scan, PET scan or bone scan if suspicion of bone disease, brain or MRI if clinically indicated)
QOL evaluated with EQ5D and EORTC QLQ-ELD14 Geriatric mini data set only for patients ≥70 years old (appendix 9)
Electrocardiogram Availability of adequate FFPE tumor-derived material (tumor blocks or slides) from a biopsy, surgery or fine needle aspirate for analysis of PD-L1 testing by IHC. The tumor blocks or slides will be secondary sent to Pr Diane Damotte, service d'anatomie et cytologie pathologiques Hôpital Européen Georges-Pompidou H.E.G.P. 20 Rue Leblanc (Paris 15 - Vaugirard) 75015 Paris.  
4.2.2.2. On-Study Assessments andProcedures Before every infusion of treatment (experimental and control arm):
Adverse Events and Serious Adverse Events Concomitant medications taken through course of study should be recorded Blood for CBC with differential, including WBC, lymphocyte count, ANC, hemoglobin, hematocrit, and platelet count (results to be obtained within 72 hours prior to dosing on infusion days).  
Serum chemistry tests: urea level, serum creatinine, albumin, sodium, potassium, calcium, phosphate, chloride, glucose, and LDH.  
Liver function tests including AST, ALT, total bilirubin, and alkaline phosphatase Vital signs (heart rate, blood pressure)
Physical measurements including weight (and calculated BSA for Patients randomized to treatment Arm B), and ECOG performance status For nivolumab + ipilimumab arm, oxygen saturation by pulse oximetry at rest (obtained within 72 hours of dosing and at any time a Patient has any new or worsening respiratory symptoms. also monitor amount of supplemental oxygen if applicable) If a Patient shows changes on pulse oximetry or other pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, fever) consistent with possible pulmonary adverse events, the patient should be immediately evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity management algorithm contained within the Investigator's Brochure.