Clinical trial NCT02654587
Conditions: Non Small Cell Lung Cancer
Keywords: Advanced Non-Small-Cell Lung Cancer Therapeutic Cancer Vaccine Resistance to Immunotherapy Quality of Life
Sponsor: OSE Immunotherapeutics
Start date: 2016-02-12; Completion date: 2021-01-15
Enrollment: 219 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this clinical trial was to determine if the therapeutic cancer vaccine OSE2101 (TEDOPI) was more effective than standard chemotherapy (docetaxel or pemetrexed) in treating HLA-A2 positive patients with metastatic NSCLC who progressed after sequential or concurrent chemotherapy and immune checkpoint inhibitor given in first or second-line treatment.

The main questions were to compare the survival, the tolerance to treatment and the quality of life of patients between the two arms of treatment (OSE2101 versus standard chemotherapy)

Detailed description:
The study was a two-step randomized (2:1) study. Patients were stratified by histology (non-squamous versus squamous), best response to first-line treatment \[complete response or partial response versus stable disease or progressive disease\] and line of treatment with prior ICI (first-line ICI when combined with platinum-based chemotherapy versus second-line ICI when administered as sequential treatment). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of the interim analysis, a decision was taken to early stop the accrual due to COVID-19 after 219 out of 363 patients were randomized. It led to a decrease of the study power from 80% to 62%. At the time of the interim analysis, a subgroup of patients was identified from stratification factor based on a clinical and biological rationale: those who received ICI second line and having received at least 12 weeks ICI. This subgroup was defined as ICI secondary resistance. The final analysis was carried out in the subgroup of patients with ICI secondary resistance and in all patients (ICI primary and secondary resistance).

Arms: arm 1: OSE2101 was administered as a 1 mL-subcutaneous injection on Day 1 every three weeks for six cycles, then every eight weeks for the remainder of year one and finally every twelve weeks beyond year one until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. Should pseudo progression or delayed response to treatment suspected in arm A, investigator may continue treatment beyond the time of RECIST-defined progression, if the patient is perceived to be experiencing clinical benefit of OSE2101. OSE2101 dose was 5 mg of peptides (0.5 mg for each peptide). arm 2: Patients receiving docetaxel: Docetaxel 75 mg/m2 will be administered by intravenous infusion over 1 hour on Day 1 of a 21-day cycle.

Patients receiving pemetrexed: Pemetrexed, 500 mg/m2, will be administered by intravenous infusion over 10 minutes on Day 1 of a 21-day cycle.

Docetaxel and pemetrexed will be continued until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal.
Interventions: intervention 1: OSE2101 intervention 2: Docetaxel intervention 3: Pemetrexed
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 


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Signature page 
 
Sponsor 
 
  
 
Signature 
 
 
 
Date 
Coordinating investigators – Co-Chairs of the Steering Committee 
 
 
 
 
 
 
 
Date 
 
 
Signature 
 
 
 
Date 
Principal Investigator 
 
 
Signature 
 
Date 
As an investigator, I have read and approve this protocol. My signature, in conjunction with the signature of 
the sponsor, confirms the agreement of both parties that this clinical study will be conducted in accordance 
with the protocol and all related documents, and in accordance with all applicable laws and regulations 
including but not limited to the Guideline for Good Clinical Practice (GCP), the Code of Federal 
Regulations (CFR), Directive 2001/20/EC, the ethical principles of the Declaration of Helsinki and its 
amendments. 
Nothing in this document is intended to limit the authority of a physician to provide emergency medical 
care under applicable regulations. 




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Revision History 
 
Study protocol 
version 
Summary of main changes 
Version 1.0 on 
27-Jul-2015 
Initial version submitted to Authorities (not applicable in countries) 
Version 1.2 on 
02-Oct-2015 
Exclusion criteria n°9 added to exclude patients treated with corticosteroids within 3-weeks 
before inclusion (except if low dose) 
Version 2.0 on 
30-Nov-2015 
Exclusion criteria n°1 modified to exclude patients with Large Cell Carcinoma; Inclusion 
criterion n°5 clarified to authorize patients as 2nd line after failure of prior platinum-based 
chemotherapy or as 3rd line after failure of platinum-based chemotherapy then immune 
checkpoint inhibitor (ICI) 
Version 3.0 on 
14-Feb-2017 
Inclusion criterion n°5 modified to authorize patients as 2nd line or 3rd line after failure of 
platinum-based chemotherapy and/or failure of ICI (sequential or combined with chemo) as ICIs 
may be used either as 1st or 2nd line therapy; PDL-1 expression on tumor biopsy not further 
mandatory for inclusion; clarification on inclusion criteria n°9 to authorize only patients with 
asymptomatic brain metastases 
Version 4.0 on 
21-Dec-2017 and 
Version 4.1 on 
28-Feb-2018 
Inclusion criterion n°5 modified to only authorize the subgroup of patients previously treated 
with ICI and who have progressed after ICI (as 2nd line after ICI + chemotherapy first line or 
as 3rd line after platinum-based chemotherapy in first line then ICI in second line);  Study design 
modified for a Phase II (Step 1) / Phase III (Step 2) design with a first step Fleming non 
comparative Phase II design; First secondary criterion modified for disease control rate instead of 
progression-free survival; Clarification on population for analysis for Step 1 and Step 2 (in 
version 4.1 per request after the  voluntary harmonized procedure (VHP) in the European 
Union); Per IDMC request, the recruitment was temporarily halted from June 2017 to November 
2017 before the decision to restart the recruitment only in the subgroup of patients who 
progressed after ICI was taken based on the IDMC independent analysis of data (safety and 
death events) reported in the first 131 patients randomized until June 2017; This analysis was 
blinded from the investigators and the Sponsor. 
Version 5.0 on 
29-Mar-2019 
Implementation of the 8th edition of TNM instead of 7th edition leading to modify the study title 
with no modification of the target study population; Inclusion criterion n°7 modified to authorize 
patient with progression during or within 12 months after the end of ICI as sequential or 
concomitant platinum-based chemotherapy ± radiation for locally advanced disease (stage III); 
Study design modified to remove the possibility of a sample size reassessment of Step 2 based on 
the Step 1 Phase II results,  to continue with the 2:1 randomization ratio in Step 2 and, as a 
consequence, to increase the number of events in Step 2 from 250 to 278 and to increase 
accordingly the number of patients, also to not consider for the final analysis the 38 patients with 
previous ICI treatment randomized before the recruitment hold; Implementation of NCI CTCAE 
version 5.0 instead of CTCAE version 4.0 leading to clarifying the definition of cytokine release 
syndrome (CRS) as well as the management of CRS still per Lee recommendation; A 
translational study has been added for patients/sites who agreed, in order to assess 
immunogenicity before and under treatment. 
Version 6.0 on 
02-Feb-2022 
To notify the decision to early stop the recruitment in April 2020 per the IDMC recommendation 
due to the impact of the COVID-19 pandemic on the primary endpoint of the study (OS) and the 
risk on data integrity, and to harmonize the study protocol with the final Statistical Analysis Plan 
(SAP) completed on 23-jul-21 before database lock.  


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Main changes of the analysis plan compared to protocol v5.0 were to reorder the secondary 
endpoints and to add Post-Progression Survival (PPS) and Time to worsening of ECOG PS as 
first secondary endpoints to better reflect the efficacy of a cancer vaccine, to consider a 
Population of Interest (PoI) identified during Step-1 as the main population for the final analysis, 
and to estimate the study power considering that half of patients have been finally included due 
to the early study discontinuation. Additional analysis of COVID-19 impact, and quality of life 
based on EORTC and FDA guidance’s were added. 


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Protocol Summary 
 
Title 
A randomized parallel group Phase III trial of OSE2101 as 2nd or 3rd 
line compared with standard treatment (docetaxel or pemetrexed) in HLA-A2 
positive patients with advanced Non-Small-Cell Lung Cancer with progressive 
disease after last treatment with immune checkpoint inhibitors (ICI) 
(OSE2101C301) 
Objectives 
Step 1 (Phase II) 2:1 randomized non-comparative one stage Fleming Phase II 
Primary objective 
• To evaluate the overall survival (OS) rate at 12 months in HLA-A2 positive 
patients with advanced NSCLC as 2nd or 3rd line therapy after failure of 
checkpoint-inhibitor regimens 
Secondary objectives 
• To describe secondary measures of clinical efficacy including OS (median), 
disease control rate (DCR) at 6 and 12 months, Health-related Quality of life 
(QoL), progression free survival (PFS), objective response rate (ORR) and 
evaluate duration of response (DR) 
• To assess the safety and tolerability 
• To describe patient reported outcomes (PRO) disease/treatment-related 
symptoms of lung cancer 
 
Step 2 (conditional Phase III) 2:1 comparative randomized Phase III 
Primary objective 
• To demonstrate that OSE2101 is superior to control treatment with respect to 
OS in HLA-A2 positive patients with advanced NSCLC as 2nd or 3rd line 
therapy after failure of checkpoint-inhibitor regimens; primary population 
will be the Population of Interest (PoI) defined as patients with secondary 
resistance to ICI monotherapy with ICI given 2nd line; sensitivity analysis 
will be done in all patients 
Secondary objectives 
• To compare secondary measures of clinical efficacy including Post 
progression Survival (PPS), Time to worsening of ECOG PS, Health-related 
QoL, DCR at 6 and 12 months, and PFS 
• To assess the safety and tolerability of OSE2101 compared to the control 
treatment 
Exploratory objectives 
• To compare other efficacy criteria (ORR, DR), other QoL criteria, time to 
next lung cancer therapy and COVID-19 impact in both treatment arms.  
Design  
Open-label, multicenter, controlled, randomized, parallel group, 2-step Phase 
II/III study; Randomization 2:1 in experimental Arm A OSE2101 or Arm B 
Standard of Care (SoC) docetaxel or pemetrexed using the following 
stratification factors: histology (squamous vs. non squamous), best response to 
first line treatment (objective response vs. no objective response), line rank of 


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previous treatment with ICI (ICI first line vs. ICI second line)  
Study  
planned 
duration 
First subject 
First visit 
 
Q1 2016 
Last subject 
Last visit (Step 1) 
Last visit (Step 2) 
 
≈Q1 2020  
Q1 2021  
Centers / 
Country 
Approximately 80 to 125 centers in the European Union, North America and 
other countries. The study includes IND and non-IND centers (21 CFR 312.120 
compliant). 
Subjects / 
Groups 
Step 1 (Phase II) 
A total of 38 patients with previous ICI treatment have been recruited before 
protocol version 4.0. After implementation of protocol version 4.0, 108 new 
patients are to be randomized with a 2:1 randomization ratio in order to reach a 
total of 84 patients in arm A (OSE2101) evaluable at 12 months (death observed 
within 12 months or follow-up time of 12 months or more). 
Step 2 (Phase III) 
After end of randomization in Step 1, the same 2:1 randomization ratio will be 
continued for patients entering Step 2 until a cumulated total of new 363 patients 
or a cumulated total of 278 deaths (both counts excluding the 38 patients 
enrolled before protocol 4.0) is reached. 
Step-1 analysis was reviewed by the independent data monitoring committee 
(IDMC) in March 2020. Step-1 data showed that the predefined thresholds of 12 
months-OS rate in OSE2101 arm was achieved. At this time, the IDMC was 
concerned about the impact of the COVID-19 pandemic on the primary endpoint 
of the study (OS), on the risk on data integrity and recommended to stop accrual 
early.  
The Sponsor decided to stop the accrual in April 2020. At that date, 219 patients 
have been enrolled and planned to be followed for survival up to mid-January 
2021. From Step-1 analysis, a population of interest (PoI) consisting of patients 
from the 2d line ICI stratification factor with secondary resistance to ICI 
(duration of ICI ≥ 12 weeks) was identified as having a benefit over SoC and 
being proposed as the main population for final analysis (Kluger et al., 2020). 
 
N.B.: All patients included in the study will be monitored until death-events or 
termination of the study or decision to withdraw from the study, even after a 
change in therapy for progression, as the main criterion is OS and as all patients 
included in the post-ICI stratum will be kept for the final analysis. 
Patients included within the subgroup "no previous treatment with ICI" before 
recruitment hold in this subgroup will continue treatment as planned. They will 
be described separately in the final analysis.  


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Study periods 
The total study duration for an individual subject will depend on the survival of 
the subject, including the following periods: 
• Pre-screening: HLA-A2 testing (using PCR methods) can be done at any 
time before inclusion (a specific consent form is available). 
• Screening: 1 to 35 days before treatment administration. 
• Randomization: treatment allocation and baseline for OS calculations. 
• Treatment:  
− For OSE2101 (Arm A): Day 1 each 21-day cycle for 6 cycles, then 
every 8 weeks for the remainder of year one and, finally every 
12 weeks beyond year one (see Figure 2: Schedule of OSE2101 
administration) 
− For docetaxel or pemetrexed (Arm B): Day 1 each 21-day cycle (i.e. 
every 3 weeks) 
− In both arms, treatment cycles will be repeated until unequivocal 
RECIST 1.1-defined disease progression as determined by the 
investigator, unacceptable toxicity, or consent withdrawal. Should 
pseudo progression or delayed response to treatment be suspected in 
arm A, investigator may continue treatment beyond the time of 
RECIST-defined progression, if the patient is perceived to be 
experiencing clinical benefit. 
• End of treatment: 4 weeks after the final treatment administration to obtain 
assessments from the 4 previous weeks. 
• Post-treatment follow-up: every 2 months after discontinuation of 
treatment for the post-treatment survival status. 
Inclusion 
criteria 
Protection of study subjects and compliance 
1. Signed and dated informed consent document indicating that the patient has 
been informed of all the pertinent aspects of the trial prior to enrollment 
2. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests, and other study procedures 
Demography 
3. Female or male, 18 years of age or older 
Cancer Diagnosis and treatment  
4. Histologically or cytologically proven diagnosis of NSCLC that is locally 
advanced (stage III) unsuitable for radiotherapy or metastatic (stage IV) 
according to the 8th edition of tumor, node, metastasis (TNM) in Lung 
Cancer published by the International Union Against Cancer and the 
American Joint Committee on Cancer 
5. Subjects with disease recurrence or progression after therapy with an 
immune checkpoint inhibitor and platinum-based chemotherapy:  


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• either 1st line chemotherapy followed by 2nd line checkpoint inhibitor 
• or 1st line combination of checkpoint inhibitor and chemotherapy 
Patients with progression during or within 12 months after the end of ICI as 
sequential or concomitant platinum-based chemotherapy ± radiation for 
locally advanced disease (stage III) are eligible 
6. Subjects with measurable or non-measurable lesions 
7. Subjects must express HLA-A2 phenotype as assessed serologically 
8. Subjects must be considered suitable for chemotherapy with either single-
agent pemetrexed or docetaxel 
9. Subjects with brain metastases are eligible if treated (whole brain 
radiotherapy, stereotaxic radiotherapy, surgery) at least 3 weeks prior to 
initiation of study treatment and have no symptoms related to brain 
metastases for at least 2 weeks before initiation of study treatment and are 
not taking any forbidden medications (see Section 4.3.5 of the protocol) 
10. Any prior chemotherapy, immunotherapy, hormonal therapy, radiation 
therapy or surgeries must have been completed at least 3 weeks prior to 
initiation of study treatment 
11. Any toxicity from prior therapy must have recovered to ≤ Grade 1 (except 
alopecia) 
Clinical status 
12. ECOG performance status 0-1 
13. Adequate organ function as defined by all the following criteria: 
• Albuminemia > 25 g/L 
• Serum aspartate transaminase (AST) and serum alanine transaminase 
(ALT) 1.5 x upper limit of normal (ULN) with alkaline 
phosphatase  2.5 x ULN, or AST and ALT  5 x ULN if liver 
function abnormalities are due to liver metastases 
• Total serum bilirubin  1.5 x ULN  
• Absolute neutrophil count (ANC)  1500/L  
• Platelets  100000/L 
• Hemoglobin  9.0 g/dL (in the absence of transfusion within 2 weeks 
before randomization) 
• Creatinine clearance (based on modified Cockcroft-Gault formula) 
≥ 45 ml/min 
Exclusion 
criteria 
 Cancer Diagnosis and treatment 
1. Small-cell lung cancer/mixed NSCLC with small cell component or other 
neuroendocrine lung cancers (typical and atypical carcinoids, large-cell 
neuroendocrine carcinomas) 


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2. Patients with squamous cell carcinoma histology, and who had docetaxel as 
part of his prior chemotherapy will not be eligible to the trial 
3. Current or previous treatment with investigational therapy in another 
therapeutic clinical trial (interrupted less than 4 weeks before study treatment 
initiation) 
4. Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to 
TKI (EGFR exon 18-21) or ALK rearrangement 
5. Ongoing immunotherapy (checkpoint inhibition, antigen immunotherapy 
that would be scheduled to continue concomitantly to the study) 
6. Spinal cord compression (unless treated with the patient attaining good pain 
control and stable or recovered neurologic function), carcinomatous 
meningitis, or leptomeningeal disease 
7. Patients with squamous cell histology or non-squamous cell histology 
previously treated by pemetrexed, with a contraindication for docetaxel with 
grade ≥ 2 neuropathy or hypersensitivity reaction to medications formulated 
with polysorbate 80 (Tween 80) as they could be randomly assigned to 
Arm B 
Medical history and clinical status 
8. Patients with a condition requiring systemic treatment with either 
corticosteroids or other immunosuppressive medications 
9. Treatment with corticosteroids in the last 3-week period before inclusion, c 
corticosteroids with minimal systemic absorption (e.g. with a dose ≤ 500 
microgram beclomethasone equivalent for inhaled steroids), or steroid doses 
≤ 10 mg daily prednisone equivalent which are permitted 
10. A 
recognized 
immunodeficiency 
disease 
including 
human 
immunodeficiency 
virus 
(HIV) 
infection 
and 
other 
cellular 
immunodeficiencies, hypogammaglobulinemia or dysgammaglobulinemia; 
subjects who have hereditary, congenital or acquired immunodeficiencies 
11. Patients with auto-immune disease, with the exception of type I diabetes or 
treated hypothyroidism 
12. Patients with interstitial lung disease 
13. Patients with active B or C hepatitis 
14. Other malignancy: patients will not be eligible if they have evidence of other 
active invasive cancer(s) (other than NSCLC) within 5 years prior to 
screening (except appropriately treated non-melanoma skin cancer or 
localized cervical cancer, or other local tumors considered cured (e.g. 
localized and presumed cured prostate cancer) 
15. Other severe acute or chronic medical or psychiatric conditions, or 


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laboratory abnormalities that would impart, in the judgment of the 
investigator and/or sponsor, excess risk associated with study participation 
or study drug administration, and which would, therefore, make the patient 
inappropriate for entry into this study 
16. Female patients must be surgically sterile or be postmenopausal, or must 
agree to use effective contraception during the period of the trial and for at 
least 90 days after completion of treatment (See Appendix 4: Guidance on 
Contraception) 
17. Male patients sexually active with a woman of childbearing potential must 
be surgically sterile or must agree to use effective contraception during the 
period of the trial and for at least 90 days after completion of treatment. The 
decision of effective contraception will be based on the judgment of the 
principal investigator (See Appendix 4: Guidance on Contraception) 
18. Breastfeeding women 
19. Women with a positive pregnancy test 
Investigational 
drug 
OSE2101 is combination of 10 synthetic peptides targeting 5 tumor–associated 
antigens. It is a T-cell specific immunotherapy. 
  
OSE2101 will be administered as a 1 mL-subcutaneous injection on Day 1 every 
three weeks for six cycles, then every eight weeks for the remainder of year one 
and finally every twelve weeks beyond year one until unequivocal RECIST 1.1-
defined disease progression as determined by the investigator, unacceptable 
toxicity, or consent withdrawal. Should pseudo progression or delayed response 
to treatment suspected in arm A, investigator may continue treatment beyond the 
time of RECIST-defined progression, if the patient is perceived to be 
experiencing clinical benefit. 
 
OSE2101 dose will be 5 mg of peptide (0.5 mg for each peptide). 
Control 
treatment 
Docetaxel, 75 mg/m2, will be administered by intravenous infusion over 1 hour 
on Day 1 of a 21-day cycle to patients with squamous cancer or to patients with 
non-squamous cancer who had previously been treated with pemetrexed.  
Pemetrexed, 500 mg/m2, will be administered by intravenous infusion over 
10 minutes on Day 1 of a 21-day cycle to patients with non-squamous cancer 
and who have not previously received pemetrexed.  
Docetaxel and pemetrexed will be continued until unequivocal RECIST 1.1-
defined disease progression as determined by the investigator, unacceptable 
toxicity, or consent withdrawal.  
Concomitant 
therapies 
• Mandatory concomitant therapies (premedication) for patients in Arm B 
(Docetaxel / Pemetrexed) are detailed in Section 4.3.5 of the protocol. 
• 
and authorized and prohibited therapies for patients in Arm A and B are 
detailed in Section 4.3.5 of the protocol. 


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Efficacy 
endpoints 
Primary efficacy endpoint:  
• Overall survival (OS):  
o In Step 1: OS rate at 12 months in experimental Arm A 
(OSE2101) in 84 evaluable patients exposed to OSE2101 
o In Step 2: comparison of OS between experimental Arm A 
(OSE2101) and control Arm B (docetaxel or pemetrexed) when 
278 events observed; due to early study discontinuation (219 
patients included instead of 363 patients), statistical hypothesis 
was revised with a comparison of OS between experimental Arm 
A and control Arm B in the PoI (refer statistical methodology 
section) 
Secondary efficacy endpoints (in Steps 1 & 2):  
• Disease control rate (DCR) at 6 and 12 months based on RECIST1.1 
• QLQ-C30 (EORTC QLQ questionnaire): “Global health status/QoL” 
score based on questions 29 (How would you rate your overall health 
during the past week?) and 30 (How would you rate your overall quality 
of life during the past week?)  
• QLQ-LC13 (lung cancer module from EORTC QLQ questionnaire): 
time to 1st ≥ 10-point deterioration in chest pain (question 40), dyspnea 
(questions 33, 34, 35) or cough (question 31) (in Step-1 only) 
• Post Progression Survival  
• Time to worsening of ECOG PS  
• QLQ-C30 Global health status score change from baseline (in Step 2 
only) 
• QLQ-C30 Functional scores change from baseline (in Step 2 only) 
• QLQ-C30 Symptom scores change from baseline (in Step 2 only) 
• QLQ-LC13 Symptom scores change from baseline (in Step 2 only) 
• Progression free survival based on RECIST1.1 
• Objective Response Rate (ORR) (in Step 1 only) 
• Duration of Response (DR) (in Step 1 only) 
Exploratory 
endpoints 
In Step 2 only: 
• ORR 
• DR 
• All the other scores of QoL 
• COVID-19 impact 
In Steps 1: 
• Time to deterioration (TTD) in patient reported chest pain 
• TTD in patient reported dyspnea 
• TTD in patient reported cough 
In Steps 1 & 2: 
• Time to next lung cancer therapy 
Tolerability / 
Safety 
• Incidence, severity, seriousness and relationship to study treatments of 
adverse events (AE), immune-related adverse events (irAE) and any 


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endpoints 
laboratory abnormalities 
Translational 
study  
Patient can agree to participate in all or some parts of the translational study. 
Patient can refuse to participate in the translational study without compromising 
his/her participation in the main study.  
The main objectives are to explore biomarkers and pharmacodynamic 
parameters before and after the start of study treatment (OSE2101 or 
chemotherapy) in a population of NSCLC patients who progressed after ICI 
treatment.  
Blood samples: 
• Pre-, on-treatment and after treatment collection of peripheric blood 
mononuclear cells (PBMCs) for: 
o Immunophenotyping 
o OSE2101 vaccine antigen-specific T-cell frequency 
• Pre-, on-treatment and after treatment collection of liquid biopsies (e.g. 
cell free DNA (cfDNA)): 
o Tumor Mutational Burden (TMB) and/or other mutation of 
interest (e.g. gene profiling of OSE2101 vaccine TAA) 
Blood samples will be taken at baseline, then every 6 weeks until Cycle 7 (e.g. 
Day 1 of Cycles 3, 5 and 7), then every 12 weeks (e.g. at time of CT scan) until 
end of treatment and/or progression in all arms.  
 
Tumor samples: 
• Specimens from archiving tumor biopsies (at first diagnosis and/or at any 
time before study entry) will be collected.  
• If possible, a new tumor biopsy will be collected within 35 days prior to 
the first study treatment administration (during the screening period). An 
archiving tumor biopsy collected before the screening period is 
acceptable, should the biopsy be collected after the end of ICI treatment. 
A second tumor biopsy (e.g. in the same tumor site) will be undertaken 
between cycle 3 and cycle 6 and/or at time of the disease progression. Of 
note, a blood sample will be collected for Whole-Exome sequencing 
(WES) for: 
o Determination of HLA class I expression in tumor (e.g. HLA-A2 
and Beta-2 microglobulin) 
o Tumor and tumor microenvironment (TME) characterization by 
multiplex IHC and gene profiling (i.e. CD8 exhausted T cells, 
TIL infiltration, …) 
All blood and tumor samples will be stored in certified biobanks before being 
submitted to central laboratories for analysis.  
If the patient agrees, remaining specimens after analysis will be biobanked for 
future biomarker research and drug development projects, e.g. to identify 
patients that are more likely to benefit from a treatment or experience an 
adverse event (AE), or to gain a mechanistic or genetic understanding of drug 
effects and thereby. 


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Statistical 
methodology 
Step 1 – Phase II sample size 
The primary objective of Step 1 is to evaluate the overall survival rate after 
12 months in OSE2101 arm. The following statistical hypotheses are considered: 
- 
H0 (null): 25% of overall survival rate at 12 months (uninteresting to 
pursue any further investigation) 
- 
H1 (alternative): 40% of overall survival rate at 12 months (clinically 
relevant to discuss the interest of further investigation in a Phase III 
comparative trial). 
According to the previous hypotheses and a Fleming one step Phase II design 
with a 2.5% one-sided type I error and a power of 80%, 84 evaluable patients 
have to be enrolled in the arm A. 
 
Fleming decision rules  
Amongst the first 84 evaluable patients: 
To reject H0 we have to observe at least 30 (35.7%) patients alive at 12 months 
then it will be interesting to run the next step of Phase III comparative trial.  
If less than 30 patients are alive at 12 months, H0 will not be rejected and it will 
be considered uninteresting to pursue any further investigation. 
The probability to conclude for inefficacy whereas the true rate is 40% is 
β=18.1%. 
The probability to conclude for efficacy whereas the true rate is 25% is α=1.9%. 
In order to limit the total number of patients needed in Step 1, a 2:1 
randomization ratio to receive OSE2101 (Arm A) or pemetrexed or docetaxel 
(Arm B) has been used for new patients recruited since version 4.0 of the 
protocol came into effect. A total of 38 patients with previous ICI treatment 
have been recruited before protocol version 4.0, from whom 18 patients 
randomized in arm A (OSE2101), thus 84 – 18 = 66 new evaluable patients need 
to be recruited in arm A (OSE2101). Based on a 2:1 randomization ratio, 66/2 = 
33 
 
new patients need to be randomized in arm B, leading to a total of 99 new 
evaluable patients. With an expected 7% rate of patients not evaluable at 12 
months or withdrawn, a total of 108 new patients will be randomized for Step 1. 
 
Step 2 – Phase III sample size 
For Step 2, the same 2:1 randomization ratio will be continued. All the 38 
patients randomized before protocol version 4.0 in the subgroup of patients with 
previous ICI treatment and all new patients included in Step 1 / Phase II will be 
followed during Step 2 /Phase III. However, the final analysis of Phase II/Phase 
III will exclude the 38 patients with previous ICI treatment randomized before 
the recruitment hold. 
In order to reach a power of 80% for the two-sided log rank test at the 5% 
significance level when assuming a median OS of 7 months for the control and 
10 months for the experimental arm, a total of 278 events is required. If the new 
patients are uniformly included over an accrual period of 36 months followed by 


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a follow-up of 6 months after the last inclusion, observing 278 events would 
require a total of 363 new patients. The actual number of new patients may be 
reduced if the 278 events are observed earlier (this is an event-driven study). 
Both counts exclude the 38 patients enrolled before protocol 4.0. 
Due to early study discontinuation due to COVID-19 (219 patients included 
instead of 363 patients), the power decreased to 62% with the same hypotheses 
(HR=0.70). 
Considering Step 1 results in the PoI, the following hypotheses have been 
proposed for final analysis: 
Assuming a HR of 0.55 observed in PoI in Step-1 and a median OS of 7 
months in SoC (unchanged as initially planned), a total of 90 events in 
the PoI will provide a power of 80% and a 2-sided logrank test at a 5% 
two-sided level, if the patients are included over an accrual period of 48 
months followed by a follow-up of 6 months after the last inclusion. 
Steering 
Committee 
A Steering Committee including representatives from the investigators, the 
Sponsor and other experts will be responsible of the study supervision.  
Independent 
Data 
Monitoring 
Committee 
An independent Data Monitoring Committee (IDMC) will review the safety and 
tolerability data and assess the risk/benefit ratio of the investigational drug on a 
regular basis. The IDMC membership, role and responsibilities will be detailed 
in a specific IDMC charter. 
 


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Table 1: Visits and assessments schedule (Arm A: OSE2101) 
Period 
Pre-screening 
Screening 
Treatment 
End of treatment 
Visit 
 
Screening and 
randomization 
Cycle 1 
(3 week-cycle) 
Cycles 2 to 6 
(3 week-cycle) 
Cycles 7 to 9 
(8 week-cycle) 
Cycles ≥ 10 or 
EOT 
(12-week cycle) 
End of 
treatment1 
Post-
treatment 
Follow-up2 
Cycle day 
 
-35 Day/ -1 Day 
Day 1 (±2) 
Day 15 (±2) 
Day 1 (±2) 
Day 1 (±4) 
Day 1 (±8) 
Informed consent for HLA-A2 
determination and biobanking 
X 
 
 
 
 
 
 
 
 
HLA-A2 determination3 
X 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
Medical/ Oncological history 
 
X 
 
 
 
 
 
 
 
Previous medications 
 
X 
 
 
 
 
 
 
 
EGFR/ALK alterations, PD-L14 
 
X 
 
 
 
 
 
 
 
Body height 
 
X 
 
 
 
 
 
 
 
Body weight 
 
X 
X 
 
X 
X 
X 
X 
 
Physical examination 
 
X 
X 
 
X 
X 
X 
X 
 
Vital signs (Body temperature, 
BP/PR, oxygen saturation) 
 
X 
X 
 
X 
X 
X 
X 
 
12-lead ECG 
 
X 
 
 
X 
X 
X 
X 
 
ECOG Performance status 
 
X 
X 
 
X 
X 
X 
X 
 
Hematology/ Biochemistry5 
 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation/ HIV test6 
 
X 
 
 
 
 
 
 
 
Pregnancy test (as appropriate) 
 
X 
 
 
 
 
 
X 
 
Tumor assessments (including 
scans) 
 
X 
every 6 (± 1) weeks until documented RECIST 1.1 progression7 
(X)8  
Randomization 
 
X 
 
 
 
 
 
 
 
OSE2101 administration9 
 
 
X 
 
X 
X 
X 
 
 
EORTC QLQ-C30, QLQ-LC13 
 
 
X 
 
X 
X 
X 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
Serious Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
 
Hospitalizations 
 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent for translational 
study and biobanking (optional)10 
 
X 
 
 
 
 
 
 
 
Blood samples for biomarkers 
(optional)11 
 
X 
 
 
every 6 (± 3) 
weeks (e.g. at D1 
of Cycles 3, 5 & 7) 
every 12 (± 3) weeks (e.g. at time of imaging) until EOT 
and/or progression 
 
Tumor samples for biomarkers 
(optional)12 
 
X 
 
 
X (e.g. between 
Cycles 3 & 6) 
 
 
X (e.g. at 
tumor 
progression) 
 


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1 
End of treatment: visit to obtain last assessments after the study drug stop from the 4 previous weeks. 
2 
Post-treatment follow-up: data collection on survival status and any subsequent cancer therapy (if any) every 2 months after study drug discontinuation until death. 
3 
HLA-A2 testing can be done at any time during patient management before inclusion. A pre-screening consent is available to test patients for instance during 1st or 2nd 
line therapy. 
4 
EGFR/ALK alterations and PD-L1 expression on tumor tissue: if these results are not available, they have to be done in local or central laboratories during the screening 
period. EGFR/ALK alterations is mandatory before randomization in patients with non-squamous cancer or never/light smokers with squamous cancer. If PD-L1 
expression is not documented and no tumor tissue available to perform the testing, then the PD-L1 status can be omitted. 
5 
Hematology and biochemistry tests: to be done at Day 1 Cycle 1 only if screening assessment done more than 7 days before. Thereafter at Day 1 of each subsequent 
cycle, local laboratory tests will be done every 3 weeks (less than 72 hours (3 days) before study treatment administration) until Cycle 6, then every 8 weeks (less than 4 
days before study administration) until Cycle 9, then every 12 weeks (less than 8 days before each subsequent administration. 
6 
HIV test: to be done for all eligible patients with HIV status unknown. 
7 
Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be done every 6 weeks (± 1-week allowance) after Day 1 Cycle 1, meaning it could be 
between 2 treatment visits; CT scan of the pelvis will be performed only upon request according to clinical suspicion. In case of clinical suspicion of bone metastasis out 
of the area reported by CT scan, imaging test will be performed under discretion of the investigator and will be repeated every 12 weeks. For Germany, with respect to 
brain metastases, MRI should be the privileged imaging technic and CT should only be considered when there are contra-indications to MRI. 
8 
Tumor assessments should be continued until documented RECIST 1.1 disease progression for patients who have not progressed during the treatment period. 
9 
OSE2101 treatment will continue until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable toxicity, or consent 
withdrawal. Should pseudo progression or delayed response to treatment suspected in arm A, investigator may continue treatment beyond the time of RECIST-defined 
progression, if the patient is perceived to be experiencing clinical benefit. 
10 Separate informed consent (optional) will be obtained from the patient who agreed to participate in a translational study and authorizing the bio banking of the remaining 
samples to be used for future biomarker research and drug development projects. Patient can agree to participate in all and/or some parts of the translational study. 
Patient can refuse to participate in the translational study without compromising his/her participation in the main study. 
11 Blood samples for biomarkers will be taken at baseline (during the screening period), then every 6 (± 3) weeks until Cycle 7 (e.g. at D1 of Cycles 3, 5 and 7), then every 
12 (± 3) weeks (e.g. at time of imaging) until end of treatment and/or progression. 
12 Specimens from archiving tumor biopsies (at first diagnosis and/or at any time during previous treatment) will be collected. As possible, a new tumor biopsy will be 
collected within 35 days prior to the first study treatment administration (during the screening period). An archiving tumor biopsy collected before the screening period is 
acceptable, should the biopsy be collected after the end of ICI treatment. A second tumor biopsy (e.g. in the same tumor site) will be undertaken between Cycle 3 and 
Cycle 6 and/or at time of the disease progression. A blood sample will be collected for Whole-Exome sequencing (WES) at screening. 
 
 


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Table 2: Visits and assessments schedule (Arm B: Docetaxel or Pemetrexed) 
Period 
Pre-screening 
Screening 
Treatment 
End of treatment 
Visit 
 
Screening and 
randomization 
Cycle 1 
(3 week-cycle) 
Cycle 2 
(3 week-cycle) 
Cycles ≥3 
(3 week-cycle) 
End of treatment1 
Post-treatment 
Follow-up2 
Study day 
 
-35 Day/ -1 Day 
Day 1 (±2) 
Day 15 (±2) 
Day 1 (±2) 
Day 1 (±2) 
Informed consent for HLA-A2 
determination and biobanking 
X 
 
 
 
 
 
 
 
HLA-A2 determination3 
X 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
Medical/ Oncological history 
 
X 
 
 
 
 
 
 
Previous medications 
 
X 
 
 
 
 
 
 
EGFR/ALK alterations, PD-L14 
 
X 
 
 
 
 
 
 
Body height 
 
X 
 
 
 
 
 
 
Body weight 
 
X 
X 
 
X 
X 
X 
 
Physical examination 
 
X 
X 
 
X 
X 
X 
 
Vital signs (Body temperature, BP/PR, 
oxygen saturation) 
 
X 
X 
 
X 
X 
X 
 
12-lead ECG 
 
X 
 
 
X 
X 
X 
 
ECOG Performance status 
 
X 
X 
 
X 
X 
X 
 
Hematology/ Biochemistry5 
 
X 
X 
X 
X 
X 
X 
 
Coagulation/ HIV test6 
 
X 
 
 
 
 
 
 
Pregnancy test (as appropriate) 
 
X 
 
 
 
 
X 
 
Tumor assessments (including scans) 
 
X 
every 6 (± 1) weeks until documented RECIST 1.1 progression7 
(X)8 
Randomization 
 
X 
 
 
 
 
 
 
Docetaxel or Pemetrexed9 
 
 
X 
 
X 
X 
 
 
EORTC QLQ-C30, QLQ-LC13 
 
 
X 
 
X 
X 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
X 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
 
Serious Adverse Events 
 
X 
X 
X 
X 
X 
X 
 
Hospitalizations 
 
X 
X 
X 
X 
X 
X 
 
Informed consent for translational study 
and biobanking (optional)10 
 
X 
 
 
 
 
 
 
Blood samples for biomarkers (optional)11 
 
X 
 
every 6 (± 3) weeks (e.g. at D1 of Cycles 3, 5 & 7), then every 12 (± 3) weeks 
(e.g. at time of imaging) until EOT and/or progression 
 
Tumor samples for biomarkers (optional)12 
 
X 
 
 
 
X (e.g. between 
Cycles 3 & 6) 
X (e.g. at tumor 
progression) 
 


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1 
End of treatment: visit to obtain last assessments after the study drug stop from the 4 previous weeks. 
2 
Post treatment follow-up: data collection on survival status and any subsequent cancer therapy (if any) every 2 months after study drug discontinuation until death. 
3 
HLA-A2 testing can be done at any time during patient management before inclusion. A pre-screening consent is available to test patients for instance during 1st or 
2nd line therapy. 
4 
EGFR/ALK alterations and PD-L1 expression on tumor tissue: if these results are not available, they have to be done in local or central laboratories during the 
screening period. EGFR/ALK alterations is mandatory before randomization in patients with non-squamous cancer or never/light smokers with squamous cancer. If 
PD-L1 expression is not documented and no tumor tissue available to perform the testing, then the PD-L1 status can be omitted. 
5 
Hematology and biochemistry tests: to be done at Day 1 Cycle 1 only if screening assessment done more than 7 days before. Thereafter at Day 1 of each subsequent 
cycle, local laboratory tests will be done every 3 weeks (less than 72 hours (3 days) before study treatment administration) until Cycle 6, then every 8 weeks (less 
than 4 days before study administration) until Cycle 9, then every 12 weeks (less than 8 days before each subsequent administration. 
6 
HIV test: to be done for all eligible patients with HIV status unknown. 
7 
Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be done every 6 weeks (± 1-week allowance) after Day 1 Cycle 1 meaning it could 
be between 2 treatment visits; CT scan of the pelvis will be performed only upon request according to clinical suspicion. In case of clinical suspicion of bone 
metastasis out of the area reported by CT scan, imaging test will be performed under discretion of the investigator and will be repeated every 12 weeks. For 
Germany, with respect to brain metastases, MRI should be the privileged imaging technic and CT should only be considered when there are contra-indications to 
MRI. 
8 
Tumor assessments should be continued until documented RECIST 1.1 disease progression for patients who have not progressed during the treatment period. 
9 
Docetaxel and pemetrexed treatment will continue until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable 
toxicity, or consent withdrawal. Premedication is required with docetaxel and pemetrexed. Premedication will occur before Day 1 (i.e. Day 1 of each cycle will be 
injection day for chemotherapy). 
10 
Separate informed consent (optional) will be obtained from the patient who agreed participating in a translational study and authorizing the bio banking of the 
remaining samples to be used for future biomarker research and drug development projects. Patient can agree to participate in all and/or some parts of the 
translational study. Patient can refuse to participate in the translational study without compromising his/her participation in the main study. 
11 
Blood samples will be taken at baseline (during the screening period), then every 6 (± 3) weeks until Cycle 7 (i.e. at D1 of Cycles 3, 5 and 7), then every 12 (± 3) 
weeks (e.g. at time of CT imaging) until end of treatment and/or progression. 
12 
Specimens from archiving tumor biopsies (at first diagnosis and/or at any time during previous treatment) will be collected. As possible, a new tumor biopsy will be 
collected within 35 days prior to the first study treatment administration (during the screening period). An archiving tumor biopsy collected before the screening 
period is acceptable, should the biopsy be collected after the end of ICI treatment. A second tumor biopsy (e.g. in the same tumor site) will be undertaken between 
Cycle 3 and Cycle 6 and/or at time of the disease progression. A blood sample will be collected for Whole-Exome sequencing (WES) at screening. 
 


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TABLE OF CONTENTS 
1 
BACKGROUND AND RATIONALE .......................................................................26 
1.1 
Target indication........................................................................................26 
1.2 
OSE2101 ...................................................................................................31 
1.3 
Design considerations................................................................................35 
2 
STUDY OBJECTIVES ...............................................................................................37 
3 
ETHICAL CONSIDERATIONS ................................................................................38 
3.1 
Ethics and Good Clinical Practice .............................................................38 
3.2 
Ethics Committee/ Institutional Review Board .........................................39 
3.3 
Informed consent and subject information ................................................39 
3.4 
Governance of the study ............................................................................39 
4 
INVESTIGATIONAL PLAN .....................................................................................39 
4.1 
Overall Study Design and Plan .................................................................39 
4.2 
Study Population .......................................................................................41 
4.2.1 
Subject population .....................................................................................41 
4.2.2 
Inclusion criteria ........................................................................................41 
4.2.3 
Exclusion criteria .......................................................................................42 
4.3 
Study Drugs ...............................................................................................43 
4.3.1 
Description, packaging and labelling ........................................................43 
4.3.2 
Storage .......................................................................................................44 
4.3.3 
Study drug administration .........................................................................44 
4.3.4 
Treatment Exposure and Compliance .......................................................46 
4.3.5 
Concomitant medications ..........................................................................46 
4.3.6 
Study instructions, restrictions and exclusion period ................................48 
4.4 
Study premature discontinuation and withdrawal .....................................48 
4.4.1  
Premature discontinuation .........................................................................48 
4.4.2 
Lost to Follow Up......................................................................................49 
4.5 
Treatment Assignment ..............................................................................49 
4.5.1 
Identification of subjects ...........................................................................49 
4.5.2 
Randomization...........................................................................................49 
4.6 
Study Endpoints ........................................................................................49 
4.6.1 
Efficacy endpoints .....................................................................................49 
4.6.2 
Safety and tolerability endpoints ...............................................................50 
4.6.3 
Exploratory translational endpoints...........................................................51 
4.7 
Study Assessment Procedures ...................................................................52 
4.7.1  
Screening assessments ...............................................................................52 
4.7.2 
HLA-A2 testing .........................................................................................53 
4.7.3 
EGFR and ALK determination, PD-L1 expression at screening ..............54 
4.7.4 
Tumor assessments ....................................................................................54 
4.7.5 
Quality of life ............................................................................................55 


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4.7.6 
Safety laboratory assessments ...................................................................55 
4.7.7 
Vital signs ..................................................................................................55 
4.7.8 
Physical examination .................................................................................56 
4.7.9 
ECG ...........................................................................................................56 
4.7.10 
Day 1 of study treatment cycle assessments .............................................56 
4.7.11 
End of treatment / withdrawal assessments ...............................................56 
4.7.12 
Post treatment follow-up assessments .......................................................56 
4.8 
Post-study access to study treatment .........................................................56 
5 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................57 
5.1 
Reporting of adverse events ......................................................................57 
5.2 
Reporting period ........................................................................................57 
5.3 
Assessment of causality.............................................................................58 
5.4 
Definitions of Adverse Events ..................................................................58 
5.5 
Severity of adverse events .........................................................................59 
5.6 
Serious Adverse Events .............................................................................60 
5.6.1 
Definition...................................................................................................60 
5.6.2 
Hospitalization - Prolongation of existing hospitalization ........................61 
5.6.3 
Serious Adverse Events related to study-mandated procedures ................61 
5.7 
Reporting of serious and non-serious adverse events ...............................62 
5.7.1 
Reporting requirements .............................................................................62 
5.7.2 
Serious adverse event reporting requirements...........................................62 
5.8 
Management of adverse events, dosing adaptations and risk minimization 
strategy ......................................................................................................63 
6 
STATISTICAL METHODOLOGY AND ANALYSES ............................................68 
6.1 
Statistical Analysis Plan ............................................................................68 
6.2 
Analysis Sets .............................................................................................68 
6.3 
Sample size ................................................................................................69 
6.4 
Primary and secondary efficacy endpoints ................................................71 
6.5 
Exploratory efficacy endpoints .................................................................73 
6.6 
Safety and tolerability endpoints ...............................................................74 
6.7 
Interim analysis .........................................................................................74 
6.8 
Exposure to study drugs ............................................................................75 
6.9 
Baseline Parameters and Concomitant Medications .................................75 
7 
PROCEDURES AND QUALITY ASSURANCE ......................................................75 
7.1 
Procedures .................................................................................................75 
7.1.1 
Protocol amendments ................................................................................75 
7.1.2 
Monitoring .................................................................................................76 
7.1.3 
Data management ......................................................................................77 
7.1.3.1 
Data collection ...........................................................................................77 
7.1.4 
Recording of data and retention of documents ..........................................77 


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7.1.5 
Audit ..........................................................................................................78 
7.1.6 
Publication of study results .......................................................................78 
7.1.7 
Disclosure and confidentiality ...................................................................78 
7.1.8 
Premature termination or suspension of the study ....................................79 
7.2 
Insurance and Compensation to subjects and investigators ......................79 
8 
REFERENCES ............................................................................................................80 
9 
APPENDICES .............................................................................................................88 
APPENDIX 1: RECIST 1.1 CRITERIA .................................................................89 
APPENDIX 2: EORTC QOL QUESTIONNAIRES..............................................98 
APPENDIX 3: ECOG ...............................................................................................99 
APPENDIX 4: GUIDANCE ON CONTRACEPTION ........................................100 
 
LIST OF TABLES 
 
Table 1: Visits and assessments schedule (Arm A: OSE2101) .........................................16 
Table 2: Visits and assessments schedule (Arm B: Docetaxel or Pemetrexed) .................18 
Table 3: Dose Reduction for Pemetrexed – Hematologic Toxicities ................................66 
Table 4: Dose Reduction for Pemetrexed – Non-hematologic Toxicities .........................66 
Table 5: Dose Reduction for Pemetrexed - Neurotoxicity CTC Grade .............................67 
Table 6: Summary of the Overall Response Status ...........................................................94 
Table 7: Best overall response when confirmation of CR and PR required ......................95 
 
LIST OF FIGURES 
 
Figure 1: Control group treatment allocation.....................................................................36 
Figure 2: Schedule of OSE2101 administration ................................................................45 
Figure 3: Treatment algorithm for management of cytokine release syndrome (per Lee, 
2014) ..................................................................................................................................65 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase  
ATC 
Anatomic Therapeutic Chemical Classification 
BP 
Blood Pressure 
Bpm 
beats per minute 
CBC 
Complete blood count 
CEA 
Carcinoembryonic Antigen 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CR 
Complete response 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CT 
Chemotherapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Cytotoxic T-lymphocyte 
CYP3A4 
Cytochrome P450, family 3, subfamily A, polypeptide 4 
DCR 
Disease control rate 
DNA 
Desoxyribonucleic Acid 
DoR 
Duration of response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
ELISA 
Enzyme Linked Immunosorbent Assay 
ELISPOT 
Enzyme-Linked Immuno Spot 
EORTC QLQ 
European Organization for Research and Treatment of Cancer Quality of 
Life Questionnaire 
EOS 
End of Study 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose Positon Emission Tomography 
FFPE 
Formaldehyde Fixed-Paraffin Embedded 
FISH 
Fluorescence in situ hybridization 
G-CSF 
Granulocyte Colony Stimulating Factor 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HER-2/neu 
Human Epidermal Receptor-2/neurological 


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HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HR 
Hazard Ratio 
HRQoL 
Health Related Quality of Life 
HTL 
Helper T-lymphocyte 
ICH 
International Conference on Harmonization 
ICI 
Immune Checkpoint Inhibitor 
IDMC 
Independent Data Monitoring Committee 
IFN 
Interferon 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
irAE 
Immune-related Adverse Event 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IUD 
intrauterine device 
IV 
Intravenous or intravenously 
IVD 
In Vitro Diagnostics Device 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate Dehydrogenase 
LLT 
Low level terms 
MAGE 2/3 
Melanoma Antigens 2/3 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NE 
Not evaluable 
NSCLC 
Non Small Cell Lung Cancer 
ORR 
Objective response rate 
OS 
Overall survival 
p53 
A nuclear –regulatory protein 
PADRE 
Pan-DR-Epitope 
PBMCs 
Peripheral-blood mononuclear cells 
PCSA 
Potential clinically significant abnormality 
PD 
Pharmacodynamics 
PD 
Progressive disease 
PET 
Positon Emission Tomography 
PFS 
Progression free survival 
PR  
Partial response 
PR 
Pulse Rate 
PRO 
Patient reported outcomes 
PT 
Preferred Term 
QLQ-C30 and 
QLQ-LC13 
Lung cancer module in EORTC QLQ 
QoL 
Quality of life 
RANK-L 
Receptor Activator of Nuclear Factor Kappa B ligand 


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RECIST 
Response Evaluation Criteria in Solid Tumors 
rIL 
Recombinant Interleukin 
RNA 
Ribonucleic Acid 
ROS1 
c-ros oncogene 1, receptor tyrosine kinase 
SAE 
Serious Adverse Event 
SAP 
Statistical analysis plan  
SD 
Standard Deviation 
SD 
Stable disease 
SE 
Standard Error 
SOC 
System Organ Class 
TAA 
Tumor-associated antigen 
TKI 
Tyrosine-Kinase Inhibitor 
TSH 
Thyroid Stimulation Hormone 
TTD 
Time to deterioration 
ULN 
Upper limit of normal 
WES 
Whole-Exome sequencing 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
WT 
Wild type 
  
 


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1 
BACKGROUND AND RATIONALE  
1.1 
Target indication 
Worldwide, lung cancer has the highest incidence (2.09 million) and mortality (1.76 million) 
among all cancers (Globocan 2018; 30). It is the leading cause of cancer death among males in 
both more and less developed countries, and has surpassed breast cancer as the leading cause of 
cancer death among females in more developed countries (30). Cancer stage at diagnosis 
determines treatment options and has a strong influence on the length of survival. In the SEER 
database (39), 57% of patients are diagnosed with advanced stage (metastatic) disease, with a 5y-
overall survival (OS) of 4.2%. For the overall population 5y OS is 17.4%. Lung cancer is 
diagnosed at a median age of 70 years.  
Non-small-cell lung cancers (NSCLC) account for 85%–90% of lung cancers, while small-cell 
lung cancer (SCLC) has been decreasing in frequency in many countries over the last two 
decades (39).  
Tumor subtypes are considered in therapeutic decisions. Adenocarcinoma is the most common 
histologic subtype. Approximately 63% of advanced NSCLC are diagnosed as adenocarcinoma, 
17% as squamous, and 20% as not otherwise specified (37).  
 
Platinum-based doublet chemotherapy is the standard first-line treatment for non-selected 
patients with advanced NSCLC who have a good performance status. Platinum-based doublet 
chemotherapy prolongs survival and improves quality of life (QoL) in patients with PS 0–2. For 
most patients, four cycles of chemotherapy are recommended, notably when maintenance 
treatment is considered, with a maximum of six cycles. Several regimens of first-line treatment 
have shown comparable efficacy. Cisplatin compared to carboplatin globally has reported better 
response rate (RR) and in the subgroup of patients with non-squamous histology when cisplatin 
is added to third-generation regimens has reported better OS. There is no single platinum-based 
doublet standard chemotherapy. Pemetrexed use should be restricted to non-squamous NSCLC 
and bevacizumab combined with paclitaxel–carboplatin regimen improves OS in patients with 
non-squamous histology and PS 0– 1, and may be offered after exclusion of contraindications 
(65).  
 
Personalized treatment has changed the diagnostic and treatment approach in NSCLC and could 
have an impact on patients’ outcome (44) as 30% of advanced NSCLC have some kind of 
actionable oncogenic driver mutation. The most common are sensitizing EGFR mutation (around 
17% in non-Asian population), ALK-rearrangements (8%) and others such as ROS1-
rearrangements. These oncogenic drivers are almost always mutually exclusive in patients with 
NSCLC. Targeted agents currently approved for the treatment of NSCLC and include the first-
generation, reversible EGFR-targeted tyrosine-kinase inhibitors (TKIs) erlotinib and gefitinib; 
the second-generation irreversible EGFR-TKI, afatinib; and the ALK inhibitor, crizotinib. New 
treatments indicated for acquired resistance are being tested.   
 
Erlotinib, docetaxel and pemetrexed are approved second-line therapies for advanced NSCLC 
patients who progress after first-line treatment (65). The OS for these second line therapies 
ranged from 5.5 to 8.3 for chemotherapy and 5.3 to 6.7 for erlotinib (15, 24, 34, 73). Some 
differences exist among these therapies. Pemetrexed has shown a similar efficacy to docetaxel in 


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second-line setting but with a significantly better toxicity profile (34). Efficacy of pemetrexed 
compared to docetaxel according to histology has been reviewed (71) and this favored 
pemetrexed specifically in large cell carcinoma, although this histologic category has been 
revised subsequently (77). The TITAN trial reported that erlotinib was equivalent to pemetrexed 
or docetaxel in refractory patients (progression during first-line chemotherapy) unselected for 
EGFR status (15). In molecularly selected wild-type (wt) EGFR population, the TAILOR trial 
showed that docetaxel was superior to erlotinib as second-line therapy with respect to OS and 
progression free survival (PFS) (24). However, in the subset analysis of EGFR-wt tumors, the 
DELTA trial failed to demonstrate a gain in OS for docetaxel vs. erlotinib (42), reinforcing 
erlotinib as a potential second-line treatment option independently of EGFR status.  
Currently, the efficacy of approved drugs for second-line treatment in NSCLC or their response 
rate are limited and new treatment options are awaited.  
 
Tumor angiogenesis is critical for tumor progression. Recently two randomized Phase III trials 
have tested the efficacy of antiangiogenic therapies in second-line for advanced NSCLC. The 
LUME-lung 1 trial (64) was conducted in 1314 patients and demonstrated that docetaxel plus a 
multi-antiangiogenic (VEGFR, PDGFR, FGFR) angiokinase inhibitor, nintedanib, improved 
PFS, the primary endpoint of the trial (3.4 mo. Vs. 2.7 mo., HR 0.79, 95%CI 0.68-0.79, 
p=0.0019). Although an OS benefit was not noted in the study population (10.1 mo. Vs. 9.1 mo., 
HR 0.94, 95%CI 0.83-1.05, p=0.27), in the hierarchical analysis, nintedanib plus docetaxel 
significantly improved OS in the subgroup of adenocarcinomas (12.6 mo. Vs. 10.3 mo., HR 0.83, 
95%CI 0.7-0.99, p=0.0359), as well as in those adenocarcinoma tumors with a more aggressive 
behavior (defined progression within 9 months of starting prior first-line therapy; 10.9 mo. Vs. 
7.9 mo., HR 0.75, 95%CI 0.6-0.92, p=0.0073). Toxicity grade 3 or higher was more common in 
combination arm than monotherapy (31.3% vs. 26.7%, mainly diarrhea, and reversible increase 
in transaminases) (64), however, it did not have an impact on patient self-reported QoL (56). The 
OS benefit with nintedanib and docetaxel may have been optimized by the fact that the 
population included in the trial was highly selected (the study excluded patients with brain 
metastasis or radiological evidence of blood vessel involvement or cavitation or with hemoptysis 
or thrombosis; and median age was only 60). These results have led to the approval of nintedanib 
in Europe, not in the US (as of April 2015) as second-line treatment in combination with 
docetaxel in locally advanced or metastatic NSCLC patients.  
 
Another product, ramucirumab, a monoclonal antibody anti VEGFR-2 was tested in the REVEL 
trial (25, 61). A total of 1253 patients were included in this Phase III study and the addition of 
ramucirumab, to standard therapy with docetaxel improved OS, the primary endpoint of the trial, 
(10.5 mo. Vs. 9.1 mo., HR 0.86, 95%CI 0.75-0.98, p=0.023), PFS (4.5 mo. Vs. 3 mo., HR 0.76, 
95%CI 0.68-0.86, p<0.0001) and overall response rate (ORR: 23% vs. 14%, p <0.001), without 
detrimental effect on quality of life. Ramucirumab has been approved in this indication by FDA 
but not by EMA (as of April 2015). 
 
Immunotherapeutic approach has been tested in the treatment of NSCLC. Several Immune 
checkpoint inhibitors (ICIs) exist (such as CTLA-4 and programmed death 1 (PD-1) receptor) 
which dampen the T-cell immune response to antigens expressed by tumor cells. Checkpoint 


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inhibition with Ipilimumab, a monoclonal antibody against CTLA-4, has been tested in NSCLC 
and reported a significant improvement in immune-related PFS compared to placebo when 
administered concomitantly with chemotherapy (47). The PD-1 receptor is another checkpoint 
molecule expressed on activated T cells and engaged by ligands PD-L1 and PD-L2, which are 
expressed by tumor cells and infiltrating immune cells.  Tumor PD-L1 expression is prevalent in 
NSCLC, and the interaction of PD-1 with the PD-L1 and PD-L2 ligands inhibits T-cell activation 
and promotes tumor immune escape. In 2015, two randomized Phase III trials have reported the 
efficacy of nivolumab, a fully human IgG4 monoclonal antibody antiPD-1, in advanced NSCLC 
patients who had disease progression during or after first-line chemotherapy. In squamous 
NSCLC subtype, 272 patients were randomized to nivolumab (3 mg/kg every 2 weeks) or 
docetaxel (75 mg/m2 every 3 weeks). Nivolumab reported a significant improvement in OS over 
docetaxel (9.2 months vs. 6 months, p<0.001), with 1-y OS of 42% versus 24%, respectively. 
The response rates were also significantly improved with nivolumab compared with docetaxel, 
20% vs. 9%, respectively (p=0.008) (10). Nivolumab has been approved by FDA and EMA for 
2nd line treatment of stage IV squamous cell NSCLC following results of this trial. In the second 
Phase III trial, 582 non-squamous patients were randomized to nivolumab or docetaxel at the 
same schedule. Nivolumab significantly improved OS (12.2 months vs. 9.4 months, p= 0.0015), 
1-yOS (51% vs. 39%) and median duration of response (17.1 months vs. 5.6 months) compared 
to docetaxel, respectively (60). In both trials the toxicity profile was in favor of nivolumab. Of 
note, in squamous subtype, the expression PD-L1 was neither prognostic nor predictive of 
benefit with nivolumab. However, in non-squamous histology, PD-L1 expression was a 
predictive marker of efficacy of nivolumab. The full results of this trial (8) led to approval of 
Nivolumab by FDA in non-squamous NSCLC as well. These results reinforce immunotherapy as 
a new strategy in the treatment of NSCLC patients. 
 
Other ICIs have been tested in NSCLC. Pembrolizumab, an anti-PD1 inhibitor, has been tested 
in a phase I study in advanced NSCLC patients.  Pembrolizumab reported an objective response 
rate of 19.4% with a median duration of response of 12.5 months, with an acceptable toxicity 
profile. In those patients with high expression of PD-L1 (expression in at least 50% of tumor 
cells) the response rate was 45.2% with a median PFS of 6.3 months, suggesting that the 
expression of PD-L1 correlated with improved the efficacy of pembrolizumab (26). The updated 
results of this trial in 101 treatment-naïve PD-L1+ NSCLC patients reported an ORR of 24% and 
a median PFS of 6 months with no significant between-dose differences, with the greatest 
efficacy observed in patients with PD-L1 staging in ≥ 50% of tumor cells (70).  Preliminary 
results of pembrolizumab in a Phase II trial in 10 advanced NSCLC patients with untreated 
asymptomatic brain metastasis has reported a 44% and 34% of brain and systemic response rate, 
respectively (31). The results of the Keynote 010 trial led to approval of pembrolizumab in 
patients with NSCLC with PD-L1 expression on at least 1% of tumor cells as both doses tested 
improved OS over docetaxel with a favorable benefit risk ratio (36). 
 
Two anti-PD-L1 antibodies, atezolizumab (MPDL3280A) and durvalumab (MEDI4736), have 
been tested in NSCLC. Updated results of atezolizumab in a phase I trial with 88 advanced 
NSCLC patients, reported an ORR of 21%, with a median duration of response of 67 weeks and 
1-year OS of 82%.  PD-L1 expression in the tumor microenvironment appeared to be a 


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predictive biomarker for MPDL3280 clinical efficacy (38). In a single arm Phase II study in 205 
PD-L1 selected patients with NSCLC, atezolizumab have reported clinical efficacy in both 
chemo-naïve and previously treated patients (ORR 29% and 17%, respectively) and some 
evidence of clinical efficacy in previously treated patients with asymptomatic brain metastases 
(75). In a randomized Phase II trial (POLAR study) with 287 previously treated NSCLC patients, 
atezolizumab has been compared to docetaxel. Atezolizumab has reported a trend toward OS 
improvement (11.4 months vs. 9.5 months, HR 0.77; 95 CI 0.55-1,06, p=0.11) with an improved 
overall survival benefit observed with increasing PD-L1 expression (76). The complete results of 
the POPLAR study were published later by Fehrenbacher et al (19). 
 
Eventually the OAK Phase III study in 2nd or 3rd line therapy of advanced NSCLC showed 
improved median OS (13.8 vs 9.6 months) with atezolizumab compared to docetaxel (68). 
In 198 NSCLC patients, MEDI4736 administered at 10 mg/kg IV every 2 weeks until 
unacceptable toxicity, disease progression, or for up to 12 months, has reported an ORR of 16% 
(27% in PD-L1+ and 5% in PD-L1-), and DCR at 12 weeks of 42%. The ORR was higher in 
squamous (21%) than non-squamous (13%) patients. The duration of response ranged from 0.1 
to 54.4 weeks. Preliminary OS data suggests that PD-L1+ patients appear to have improved OS 
compared with patients with PD-L1- tumors (NA vs. 8.9 months) (69). 
 
All of these results suggest immunotherapy as an important therapeutic approach in NSCLC 
patients and thus our study will consider previous checkpoint inhibitor therapy as a stratification 
criterion for randomization.  
 
New results have been published and address the possible benefit of using immune checkpoint 
inhibitors in 1st line therapy of advanced NSCLC. These results are conflicting with very positive 
results for anti PD-1 therapy with pembrolizumab in patients with PD-L1 expression over 50% 
of tumor cells (66) but not with anti PD-1 therapy with nivolumab in patients included whatever 
was the level of PD-L1 expression (28). Yet, various combination therapies may be beneficial 
with reports by Hellmann et al (35) or Langer et al (45). Thus, it has been advised by the 
Steering Committee of our study during its December 13th 2015 session that there should be an 
amendment to the current protocol to allow for inclusion of patients treated with checkpoint 
inhibitors alone or in combination as 1st line therapy and that patient should anyhow be offered 
also platinum-based chemotherapy (1st or 2nd line) before entering the trial. This led to version 
3.0 of the protocol.  
 
Numerous studies evaluating ICIs as stand-alone and in combination are ongoing in early stage. 
In 2017, durvalumab as maintenance treatment for one year after radical treatment with 
concurrent chemo-radiotherapy in locally advanced unresectable NSCLC showed an 
improvement in median time to death or distant metastasis of 23.2 months in durvalumab arm vs. 
14.6 months in placebo arm (1). 
 
In 2019, immunotherapies play an important role in the treatment of NSCLC (62). Since 2015, 
four anti PD-(L)1 monoclonal antibodies (nivolumab, pembrolizumab, atezolizumab and 
durvalumab), alone and in combination with various compounds (i.e. ipilimumab, or 


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chemotherapy ± bevacizumab), have consistently demonstrated a superiority of overall survival 
in first and second-line treatment in advanced NSCLC and in locally advanced unresectable 
NSCLC.  Overall, in advanced NSCLC, a meaningful improvement of long-term OS rate at 3 
and 5 years of 25% is maintained with ICIs (62).  
 
This major improvement in therapy, albeit with limited response rate (10, 60) when ICI are used 
as monotherapy, led us to consider that, where available, checkpoint inhibition would be offered 
before moving to investigational therapy and thus that the current Phase II/III target should 
include 2nd or 3rd line therapy in patients with no therapeutic alternative after failure of platinum 
and immune checkpoint inhibition. In 2018, data of durvalumab + tremelimumab were reported 
in 78 immunotherapy-pretreated advanced NSCLC patients (27). 94% of patients received ≥ 2 
lines of prior therapy including PD-1 or PD-L1 inhibitors. 40 (51%) patients “relapsed” after ICI 
(defined as responders, then progression; prior median time to progression of 7 mo) and 38 
(49%) were “refractory” to previous ICI (defined as no response; prior median time to 
progression of 2.6 mo). The combination durvalumab + tremelimumab was manageable. Severe 
(Grade 3 and 4) related AEs occurred in 28% of patients, with diarrhea (6%) being most 
common. 5 patients (6%) discontinued due to a treatment-related AE. No treatment-related 
deaths were observed. Objective response rate was reported in 4 (5.1%) patients [2(5%) patients 
in relapsed group, 2(5.3%) patients in refractory group]. Median progression-free survival (PFS) 
was 1.8 mo (95% CI; 1.6-2.5) [2.5 mo (95% CI; 1.6-3.5) in relapsed group, 1.7 mo (95% CI; 1.6-
1.7) in refractory group]. Median overall survival (OS) was 8.4 mo (95% CI; 6.2-10.4) [8.5 mo 
(95% CI; 4.0-14.3) in relapsed group, 8.3 mo (95% CI; 6.0-10.4) in refractory group. OS rate at 
12 months was 34.1% (37.5% in relapsed group, 30.1% in refractory group). 
 
These limited data comfort our current statistical assumption that an OS-rate at 12 months of 
40% is a relevant efficacy target in this population. However, the continuation of the study in 
Step 2 which plans to demonstrate a better survival of OSE2101 over the control group (HR 0.7), 
will be discussed at the end of Step 1 between the steering  committee (SC) and the Sponsor 
based on the recommendations of the independent data monitoring committee (IDMC). Since the 
start of the study in 2015, there have been major forward advances in the management of 
NSCLC. The decision of continuing the study in Step 2 (Phase 3) will consider the expected 
benefit of OSE2101 as well the relevance of the specific design of the Phase 3 in regards of the 
state of the art in the management of advanced NSCLC known at time of the analysis (see 
Section 6.7).   
 
Moreover, different vaccines have been designed for specific peptide epitopes in NSCLC (79). In 
the adjuvant setting, the Phase III MAGRIT trial did not report improvement in disease free 
survival with the recMAGE-A3 + AS15 cancer immunotherapeutic (MAGE-A3 CI) as adjuvant 
therapy compared with placebo in patients with stage IB-IIIA completely resected MAGE-A3-
positive NSCLC, even in the population who did not receive adjuvant chemotherapy (78). In 
locally advanced disease, the Phase III START trial, randomly assigned 1,513 patients with 
unresectable stage IIIB NSCLC following definitive chemoradiation to L-BLP25 (liposomal 
vaccine) with best supportive care (BSC) or placebo plus BSC. The trial failed to meet its 
primary endpoint of improved OS with L-BLP25 (25.6 vs. 22.3 months for placebo; P=0.123) 


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(13). In advanced disease, different vaccines have been tested such as Belagenpumatucel-L (54), 
EGF vaccine (32), TG4010 vaccine (TIME trial) (63) or IDO vaccine (40). However, 
heterogeneity of tumor-associated antigen (TAA) expression, the potential for tumor associated 
antigen (TAA) loss, and variability of the human T-cell repertoire suggest that effective cancer 
T-specific immunotherapies require induction of a wide breadth of cytotoxic T lymphocytes 
(CTL) specificities. This can best be achieved with T-specific immunotherapies targeting 
multiple TAAs. 
1.2 
OSE2101  
The OSE2101 T-specific immunotherapy was designed to induce CTLs against five TAAs 
frequently overexpressed in NSCLC (i.e. carcinoembryonic antigen [CEA], p53, HER-2/neu, and 
melanoma antigens MAGE2 and 3). These TAAs have been used alone in previous studies 
involving NSCLC patients. OSE2101 is composed of 10 synthetic peptides from these TAAs, 
nine of the peptides representing CTL epitopes and one pan-DR epitope. Each CTL epitope is 
restricted by HLA-A2.1 and at least one other member of the HLA-A2 superfamily of major 
histocompatibility complex class I molecules. HLA-A2 phenotype is expressed by approximately 
45% of the general population as well as cancer patients. These epitopes being HLA-A2 
restricted means that they can bind only HLA-A2 molecules to be presented to the T-lymphocyte 
and thus, can only be effective in patients having HLA-A2 phenotype.  
 
The pan-DR epitope (PADRE) is a rationally designed helper T-lymphocyte (HTL) epitope 
included to augment the magnitude and duration of CTL responses (5). The innovation is to 
associate epitopes designed and modified chemically (analogs), of different tumor antigens in the 
same combination. Some of these analogs will increase the HLA-A2 binding and others will 
increase the T cell receptor binding. 
 
It was previously demonstrated that all of the epitopes selected were immunogenic. The utility of 
the analog peptides was further documented, as the CTLs generated were capable of recognizing 
wild-type epitopes expressed on tumor cell lines. Moreover, others have demonstrated 
measurable recall or post-vaccination CTL responses against most of the nine CTL epitopes 
(including the wild-type versions of analogs in the current product). The immunogenicity of 
OSE2101 after in vivo immunization was also demonstrated in HLA-A2.1/Kb transgenic mice, 
which express the human HLA-A2.1 molecule (refer to investigator brochure) 
 
OSE2101 clinical trials 
 
In two phase I trials in stage IIB-IIIA NSCLC (NCT00054899) and stage III colon cancer 
(NCT00054912) patients, subcutaneous OSE2101 was administered at 5 mg peptide/dose at 3-
week schedule for a total of 6 doses. The objectives were to evaluate the safety and 
immunogenicity of OSE2101 measured by IFN-γ ELISPOT assays. A total of 16 out of 24 
enrolled patients completed six injections over 18 weeks (6 out of 10 NSCLC patients, and 10 
out of 14 colon cancer patients). 
  
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OSE2101 was reaction at the site of injection (erythema, pain, granuloma, and induration). Other 
side effects were: fatigue, rigors, nausea, vomiting, arthralgia, myalgia, pain in the extremities 
and dyspnea. Only 1 out of 24 patients reported an immune-related adverse event with a cytokine 
release reaction (fever, chills, chest pain, nausea and apnea) that was resolved within 24 hours of 
hospitalization.  
A strong CTL response was observed in the majority of patients tested.  
Immune response was defined in the protocol as one (or more) epitope-specific response greater 
than two standard deviations above background values as assessed by the ELISPOT assay. 15 
out of 16 patients receiving 6 injections were responding (93%) indicating that the T-specific 
immunotherapy was immunogenic and effective at inducing strong and broad CTL responses in 
a high frequency of patients (only one patient out of the 16 failed to respond to the T-specific 
immunotherapy, the expression of a less cross-reactive subtype in the HLA-A2 supertype family, 
HLA-A*0207, most likely accounted for the lack of immunogenicity in this patient). With 
respect to breadth of responses, eight of the 15 patients generated CTL responses to over half 
(five or more) of the epitopes in OSE2101 and, on average, each patient induced CTL responses 
to approximately four epitopes. 
 
In NSCLC patients, HLA-A2 is expressed as in the general population (22, 74) and is thought to 
be between 40 and 50%. Interestingly, HLA-A2 positivity appears as being an independent 
negative prognostic factor in cancers (48) and also in NSCLC: the role of HLA-A2 measured by 
blood sampling has been established by different and independent teams in large series of 
patients. Serological HLA-A2 expression appears as an independent risk factor of lymph node 
involvement and distant metastasis (12, 51, 47). However, a more recent analysis has shown that 
the HLA-A2 status was not identified as a prognostic factor in a large advanced NSCLC 
population treated with platinum-based chemotherapy (84). 
 
A Phase II, open-label, multicenter, single dose-group, multiple administration study of 
OSE2101 in patients with HLA-A2 positive advanced NSCLC was performed (NCT00104780) 
(4, 53, 54). 
The study was designed to evaluate the safety, efficacy (response and survival), and 
immunogenicity of OSE2101 in patients with advanced NSCLC who were HLA-A2 positive. 
The T-specific immunotherapy was administered subcutaneously at a dose of 5 mg every 3 
weeks for the first 15 weeks, then every 2 months through year 1, then quarterly through year 2, 
for a total of 13 doses. 
Patients were to be followed at three months after the last injection. Survival status was then to 
be ascertained every three months through year three then annually until year five.  
Tumor assessment was performed at baseline with reassessment at weeks 9 and 18 and at months 
6, 9, and 12. Leukapheresis was performed before vaccination (at screening) and at weeks 9 and 
18 to obtain sufficient cells to conduct the immunogenicity assays. Hematology, electrolytes, 
liver, other organ functions, urinalysis, and antinuclear antibody titer were assessed. Toxicity 
was monitored and graded according to the National Cancer Institute Common Toxicity Criteria. 
All patients signed the protocol-specific local institutional review board approved informed 
consent form. Response Evaluation Criteria in Solid Tumors were used to evaluate response. 


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Eligible patients for this study were 18 years or older with histologic confirmation of stage IIIB 
or IV or recurrent NSCLC. Patients had to have an Eastern Cooperative Oncology Group 
performance status of 0 or 1, an absolute granulocyte count ≥ 1,500/µL, platelet count 
≥100,000/µL, hemoglobin ≥ 10 g/dL, total bilirubin ≤ 2 mg/dL, AST and ALT 2 ≤ 5 times the 
upper limit of normal, and serum creatinine ≤ 2 times the upper limit of normal. Patients with 
brain metastases were eligible if the disease was clinically stable for at least 2 months before 
study entry. 
A second group of patients who were HLA-A2 negative when screened for the study were 
identified to use as an observational comparator group. The patients were assessed for survival 
via access to the social security death index. 
 
Overall survival was estimated using the Kaplan-Meier method. Progression-free survival was to 
be determined from time of patient registration to date of progression, death or last assessment of 
tumor response.  
 
To measure CTL responses, 2*106 peripheral-blood mononuclear cells (PBMCs)/well (three to 
four wells per epitope) were stimulated in vitro with each peptide (10 µg/mL). Ten U/mL of rIL-
2 was added after 24 hours. After 10 days of culture, the in vitro–expanded PBMCs were tested 
for epitope-specific (T-specific immunotherapy epitope and wild-type epitope of an analog) CTL 
responses, measured by an 18-hour interferon gamma ELISPOT assay. 
Immune response relationship to survival was done by comparing the number of epitopes with 
measurable enzyme-linked immunosorbent spot assay (ELISPOT) responses in relation to 
survival using the log-rank statistic. 
 
Results:  
A total of 135 patients were enrolled; 64 patients were positive for HLA-A2 and 72 patients were 
HLA-A2 negative with the information provided only for survival. 
 
The 64 HLA-A2 positive patients were treated with one or more dose(s) of OSE2101 and 
represent the ITT population and the safety population.  Of these 64 treated patients, 31 (48%) 
completed the treatment phase and 11 (36%) subsequently completed the follow-up phase. 
 
The majority of the early withdrawals from the treatment phase (27%, 17/64 patients) as well as 
from the continuation and follow-up phases (19%, 12/64) were due to disease progression and/or 
decline in health status. Eight patients (13%) completed all phases of the study. Four patients 
(6%) withdrew from the study due to an AE.  
The characteristics of the 64 HLA-A2 positive patients were as follows: 
• Median age 64 (26-87) 
• Male 55%; Female 45% 
• Caucasian 83%, African American 9%, Asian 8% 
The majority of patients (43/64, 67%) had Stage IV NSCLC at inclusion. The median number of 
days since first diagnosis was 416 (range of 74 to 1921 days). 
Prior treatment lines for OSE2101 treated patients were: 
• one previous line in 31% of patients; 


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• two previous lines: 28%  
• 3 or more previous lines (up to 6 lines): 37.5% 
92% of the treated population had previously received a platinum-based chemotherapy and 34% 
a TKI (gefinitib or erlotinib). 
6 patients (9.4 %) had received previous radiotherapy for brain metastasis. 
18 patients were considered as progressive disease at entry, representing 28% of this treated 
OSE2101 population.  
The HLA-A2-negative non-treated population demographics were similar to the HLA-A2 
positive treated population: 72 patients: age 65 (33- 91); male 37 (51%), female 35 (49%); 
Caucasian 57 (79%). One out of the 72 patients was lost of follow-up. 
 
Overall survival 
Median survival for HLA-A2-positive treated patients was 17.3 months. In the HLA-A2-
negative non-treated group, the median survival was 12.0 months.  
One-year survival in OSE2101 treated patients was 60%, compared to 49% in the HLA-A2-
negative group (53). The two-year and three-year survival estimates for OSE2101 treated 
patients were 39% and 27%. 
 
Clinical evaluation on the 64 HLA-A2+ treated patients (ITT population) 
One patient had a complete response and one a partial response.  Stable disease of 3 months or 
greater was observed in 54 (86%) additional patients, translating into a clinical benefit in 89% of 
patients.  Seventeen (27%) patients continued treatment for one year and demonstrated no 
evidence of progressive disease. Fourteen (22%) patients completed two years of dosing and 
remained without evidence of progressive disease.   
Progression free survival was 285 days (median time to progression) 
 
Immune Response 
Immune response was assessed in 33 treated patients. 
 
All 9 epitopes were immunogenic in at least 1 patient. Five epitopes showed strong responses 
that cross-reacted with wild type (WT) peptide. In analyzing the strongest 5 epitopes, 91% of 
patients demonstrated CTL epitope response to at least one antigen. Eighty-five percent 
demonstrated responses to 2 or more, 64% to 3 or more, 39% to 4 or more, and 18% to 5 or 
more.  
 
Correlation with survival was demonstrated in patients generating immune response.  
Longer survival was correlated with a higher number of positive epitopes (response was assessed 
by ELISPOT for the 5 strongest, CEA24, CEA605, HER2.369, MAGE2.157 and MAGE3.112). 
The Log Rank test showed decreased survival among those with a low immune response level 
compared to those with a medium or high immune response level (p<0.001).  
• Low: 0-1-epitopes: 406 ± 58 days of survival (n=5; 95% CI for mean 292 -520)  
• Medium: 2 to 3-epitopes: 778 ± 72 days of survival (n=15; 95% CI for mean 637 -919)  
• High: 4 to 5-epitopes: 875 ± 67 days of survival (n=13; 95% CI for mean 743- 1007).  
 


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Interferon-γ producing helper T cells against PADRE were detected in 18 of 33 (55%) patients 
tested in a direct ELISA assay.  
The durability of the CTL induction was also demonstrated by responses to 4 of 5 epitopes in 3 
of 4 patients tested at 12 months.  
 
In conclusion, the OS difference observed is 17.3 months of median OS in the OSE2101 treated 
group versus 12 months in the observational HLA-A2 negative group.  The OS rate at one year 
was 59% in the treated HLA-A2 positive group versus 49% in the observational HLA-A2 
negative group. The HLA-A2 observational group represents a “worst case” control group given 
that the prognosis is superior to the treated HLA-A2 positive group.  The data collected from the 
observational group is adequate to allow a meaningful comparison of one-year OS to the 
OSE2101 treated group. The median survival achieved is important for the OSE2101 Phase II 
highly pretreated population (65.5% received more than 2 lines, 92% received previous 
platinum-based chemotherapy).  The median survival for the three registered treatments 
(docetaxel, pemetrexed and erlotinib) after first line therapy is approximately 8 months and the 
one-year survival rate is 33%. In the OSE2101 Phase II, longer survival was significantly 
correlated with a higher number of positive epitopes.  Furthermore, the long–term survival 
achieved at 4 years for the treated patients was complemented by a favorable safety profile. 
 
These OSE2101 clinical data support a recommendation that OSE2101 move forward to a Phase 
III trial in HLA-A2 positive patients with advanced NSCLC who have previously failed first or 
subsequent line of therapy. 
 
Additional information on OSE2101 is available in the investigator’s brochure.   
 
1.3 
Design considerations  
Target indication: 
Based on the Phase II OSE2101 results and ESMO and ASCO treatment guidelines (2, 3, 65, 
62), the targeted population in a Phase III trial should be patients with stage III unsuitable for 
radiotherapy or metastatic stage IV NSCLC in second- or third-line treatment. Since 2015, 
immunotherapies (PD-(L)1 ± CTL-A4 inhibitors) play an important role in the treatment of 
NSCLC with a meaningful improvement of long-term OS rate at 3 and 5 years of 25% in 
advanced disease. More recently in 2017, durvalumab as maintenance treatment for one year 
after radical treatment with concurrent chemo-radiotherapy in locally advanced unresectable 
NSCLC shown an improvement in median time to death or distant metastasis of 23.2 months in 
durvalumab arm vs. 14.6 months in placebo arm (1). This major improvement in therapy, albeit 
with limited response rate (10, 60) when used as monotherapy, led us to consider that, where 
available, checkpoint inhibition would be offered before moving to investigational therapy and 
thus that the Phase III target should include 2nd or 3rd line therapy in patients with no therapeutic 
alternative after failure of platinum and immune checkpoint inhibition. 
 
Therapy: 
Reference therapy should be available and approved alike in the US and Europe as the trial 
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Randomization: 
This Phase III study needs to be randomized but cannot be blinded as study treatment and 
reference therapies have different routes of administration, need concomitant therapy that would 
not be allowed for OSE2101 (steroids) and safety profile would easily help to recognize 
treatment allocated. Thus, the study will be open-labelled (not blind). 
The design of the study needs to consider prognostic factors in the randomization process. 
Although both patients with squamous and non-squamous NSCLC were included in the Phase II 
study for OSE2101, histology is a key prognostic factor as reference therapies do not have 
efficacy over the full range of NSCLC histologic subtypes. Pemetrexed for instance is not 
approved in squamous NSCLC, survival with docetaxel seems longer in non-squamous than in 
squamous cancer (10, 60) and some treatments (64) have positive results in non-squamous and 
negative in squamous. 
Best response to chemotherapy is documented as a prognostic factor (59) although patients will 
only be included in the trial once 1st line chemotherapy failed. 
Last, previous treatment with checkpoint inhibitors needs to be considered as 2nd or 3rd line 
therapy patients. They will be selected after failure of checkpoint-inhibitor regimens. Interaction 
between checkpoints inhibitors and T-specific immunotherapy with OSE2101 will have to be 
considered, supporting stratification as well on this criterion. 
 
Thus, randomization will be stratified by:  
• histology (squamous vs. non-squamous),  
• best response to first line treatment (objective response: complete or partial response, vs. no 
objective response: stabilization or progressive disease), and 
• before protocol v4.0 only: previous treatment with immune checkpoint inhibitors (yes vs. 
no). 
• from protocol v4.0: line rank of previous treatment with immune checkpoint inhibitor (first 
line vs. second line). 
 
Target endpoints: 
As recommended in current FDA and EMA (18, 21) guidelines the primary endpoint will be 
overall survival, secondary endpoint will be linked to assessment of tumor response with a 
cancer vaccine (adding post progression survival and time to ECOG deterioration as secondary 
endpoints) but a specific attention will also be paid to quality of life as patient reported outcome 
and 
analyzed 
per 
EORTC 
guidelines 
(https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf) and the FDA Guidance on 
June 
2021 
“Core 
Patient-Reported 
Outcomes 
in 
Cancer 
Clinical 
Trials” 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/core-patient-
reported-outcomes-cancer-clinical-trials). 
 
2 
STUDY OBJECTIVES 
Step 1 (Phase II): 2:1 randomized non-comparative one stage Fleming Phase II 
Primary objective 


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• To evaluate the overall survival (OS) rate at 12 months in HLA-A2 positive patients with 
advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint-inhibitor regimens 
Secondary objectives 
• To describe secondary measures of clinical efficacy including OS (median), disease control 
rate (DCR) at 6 and 12 months, Health-related Quality of life (QoL), progression free 
survival (PFS), objective response rate (ORR) and evaluate duration of response (DR) 
• To assess the safety and tolerability 
• To describe patient reported outcomes (PRO) disease/treatment-related symptoms of lung 
cancer 
 
Step 2 (conditional Phase III): 2:1 comparative randomized Phase III 
Primary objective 
• To demonstrate that OSE2101 is superior to control treatment with respect to OS in HLA-A2 
positive patients with advanced NSCLC as 2nd or 3rd line therapy after failure of checkpoint-
inhibitor regimens; primary population will be the Population of Interest (PoI) defined as 
patients with secondary resistance to ICI and ICI 2nd line; sensitivity analysis will be done in 
all patients  
Secondary objectives 
• To compare secondary measures of clinical efficacy including Post Progression Survival 
(PPS), Time to worsening ECOG PS deterioration, Health-related QoL, DCR at 6 and 12 
months, and PFS 
• To assess the safety and tolerability of OSE2101 compared to the control treatment 
Exploratory objectives 
• To compare other efficacy criteria (ORR, DR), other QoL criteria, time to next lung cancer 
therapy and COVID-19 impact in both treatment arms. 
 
3 
ETHICAL CONSIDERATIONS 
3.1 
Ethics and Good Clinical Practice 
The investigator must ensure that this study is conducted in full conformance with the principles 
of the “Declaration of Helsinki” and its amendments, and with the laws and regulations of the 
country in which the clinical research is conducted. This study must follow the ICH/GCP 
guidelines and applicable regulations and laws, including if applicable, the European Directive 
on Clinical Trials and the Code of Federal Regulations. The investigator agrees to the terms and 
conditions relating to this study as defined in the protocol, CRF and any other protocol-related 
documents.  
The investigator fully understands that any changes without previous agreement with the sponsor 
would constitute a violation of the protocol, including any ancillary studies or procedures 
performed on study subjects/patients (other than those procedures necessary for the wellbeing of 
the subjects/patients). 


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3.2 
Ethics Committee/ Institutional Review Board 
The investigator will submit this protocol and any related document provided to the subject (such 
as subject information used to obtain informed consent) to an EC/IRB. Approval from the EC/ 
IRB must be obtained before starting the study, and should be documented in a dated letter to the 
investigator, clearly identifying the trial, the documents reviewed and the date of approval.  
A list of members participating in the meeting must be provided, including the functions of these 
members. If study staff were present, it must be clear that none of these persons voted. 
Modifications made to the protocol after receipt of the EC/IRB approval must also be submitted 
as amendments by the investigator to the EC/IRB in accordance with local procedures and 
regulations (see section 7.1.1). 
 
3.3 
Informed consent and subject information 
It is the responsibility of the investigator to obtain signed informed consent from each of the 
subjects participating in this study before any study-mandated procedure, and after adequate 
explanation of the aims, methods, objectives and potential hazards of the study. The investigator 
must also explain to the subjects that they are completely free to refuse to enter the study or to 
withdraw from it at any time for any reason. Appropriate forms for documenting written 
informed consent will be provided to the site prior to the study. The Informed Consent Form and 
Subject Information Sheet will be provided in the local language with validated translations as 
appropriate. One signed informed consent form will be kept by the subject, and one will be filed 
by the investigator in the investigator’s file. 
 
3.4 
Governance of the study 
A Steering Committee has been appointed by OSE Immunotherapeutics; it is comprised of 
investigators (national coordinators). Representatives of OSE Immunotherapeutics will attend the 
Steering Committee meetings. The Steering Committee is responsible for scientific validity of 
the protocol and will assess the study quality and conduct on a regular basis.  
An Independent Data Monitoring Committee (IDMC) will review the safety and tolerability data 
and assess the risk/benefit ratio of the investigational drugs on a regular basis and give 
recommendations to the Steering Committee and the sponsor regarding continuation of the study. 
 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan   
➢ This is an open-label, multicenter, controlled, randomized, parallel group, 2-step design 
Phase II/III trial of OSE2101 (Arm A – experimental treatment) versus docetaxel or 
pemetrexed (Arm B – control treatments) as second or third line treatment in HLA-A2 
positive patients with advanced NSCLC.  
➢ Patients will be recruited and monitored in experienced oncology/pulmonology centers. 


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➢ Randomization to Arms A and B and will be stratified according to:  
o histology (squamous vs. non-squamous),  
o best response to first line treatment (objective response: complete or partial 
response, vs. no objective response: stabilization or progressive disease), and 
o and for new patients from version 4.0 of the protocol the 3rd stratification factor 
will be previous treatment with immune checkpoint inhibitors (used in 1st line vs. 
used in 2nd line). 
Treatment allocation will be made by IVRS/IWRS. 
➢ The total study duration for an individual subject will depend on the survival of the 
subject, including the following periods:  
o Pre-screening: HLA-A2 testing (using PCR methods) can be done at any time 
before inclusion (a specific consent form is available). 
o Screening: 1 to 35 days before treatment administration. 
o Randomization: treatment allocation and baseline for OS calculations. 
o Treatment:  
− For OSE2101 (Arm A): Day 1 each 21-day cycle for 6 cycles, then every 
8 weeks for the remainder of year one and, finally every 12 weeks beyond 
year one (see Figure 2: Schedule of OSE2101 administration) 
− For docetaxel or pemetrexed (Arm B): Day 1 each 21-day cycle (i.e. every 
3 weeks)  
− In both arms, treatment cycles will be repeated until unequivocal RECIST 
1.1-defined disease progression as determined by the investigator, 
unacceptable toxicity, or consent withdrawal. Should pseudo progression 
or delayed response to treatment suspected in arm A, investigator may 
continue treatment beyond the time of RECIST-defined progression, if the 
patient is perceived to be experiencing clinical benefit. 
o End of treatment: 4 weeks after the last treatment administration to obtain 
assessments from the 4 previous weeks. 
o Post-treatment follow-up: every 2 months after discontinuation of treatment for 
the post-treatment survival status. 
➢ The study key time points are the following: 
o Randomization: when screening is completed, baseline for OS calculation  
o Day 1 Cycle 1 for treatment administration (performed in a time to allow for 
premedication if needed) and baseline for schedule of on-treatment tumor 
assessments. 
o Tumor assessments every 6 (± 1) weeks 
o Survival assessments after treatment stop every 2 months. 
➢ Study duration 
The study design is built as a 2-step design. Analysis of the 1st step will decide whether 
the 2nd step is clinically relevant and analysis of the combined population included in 
Step 1 and 2 is planned when the target number of events is reached. However, the final 
analysis will exclude the 38 patients with previous ICI treatment randomized before the 
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4.2 
Study Population 
4.2.1 Subject population 
Patients will be enrolled into the clinical study after having been checked for their eligibility 
during the screening period.  
4.2.2 Inclusion criteria 
Protection of study subjects and compliance 
1. Signed and dated informed consent document indicating that the patient has been informed 
of all the pertinent aspects of the trial prior to enrollment 
2. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, 
and other study procedures 
Demography 
3. Female or male, 18 years of age or older 
Cancer Diagnosis and treatment  
4. Histologically or cytologically proven diagnosis of NSCLC that is locally advanced 
(stage III) unsuitable for radiotherapy or metastatic (stage IV) according to the 8th edition of 
tumor, node, metastasis (TNM) in Lung Cancer published by the International Union 
Against Cancer and the American Joint Committee on Cancer (11)  
5. Subjects with disease recurrence or progression after therapy with an immune checkpoint 
inhibitor and platinum-based chemotherapy: 
• either 1st line chemotherapy followed by 2nd line checkpoint inhibitor 
• or 1st line combination of checkpoint inhibitor and chemotherapy 
Patients with progression during or within 12 months after the end of ICI as sequential or 
concomitant platinum-based chemotherapy ± radiation for locally advanced disease (stage 
III) are eligible 
6. Subjects with measurable or non-measurable lesions 
7. Subjects must express HLA-A2 phenotype as assessed serologically 
8. Subjects must be considered suitable for chemotherapy with either single-agent pemetrexed 
or docetaxel 
9. Subjects with brain metastases are eligible if treated (whole brain radiotherapy, stereotaxic 
radiotherapy, surgery) at least 3 weeks prior to initiation of study treatment and have no 
symptoms related to brain metastases for at least 2 weeks before initiation of study 
treatment and are not taking any forbidden medications (see Section 4.3.5 of the protocol)  
10. Any prior chemotherapy, immunotherapy, hormonal therapy, radiation therapy or surgeries 
must have been completed at least 3 weeks prior to initiation of study treatment 
11. Any toxicity from prior therapy must have recovered to ≤ Grade 1 (except alopecia) 


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Clinical status 
12. ECOG performance status 0-1 
13. Adequate organ function as defined by all the following criteria:  
• Albuminemia > 25g/L 
• Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 1.5 x 
upper limit of normal (ULN) with alkaline phosphatase  2.5 x ULN, or AST and 
ALT  5 x ULN if liver function abnormalities are due to liver metastases 
• Total serum bilirubin  1.5 x ULN  
• Absolute neutrophil count (ANC)  1500/L  
• Platelets  100000/L 
• Hemoglobin  9.0 g/dL (in the absence of transfusion within 2 weeks from before 
randomization) 
• Creatinine clearance (based on modified Cockcroft-Gault formula) ≥ 45 ml/min. 
 
4.2.3 Exclusion criteria 
Cancer Diagnosis and treatment 
1. Small-cell lung cancer/mixed NSCLC with small cell component or other neuroendocrine 
lung cancers (typical and atypical carcinoids, large-cell neuroendocrine carcinomas) 
2. Patients with squamous cell carcinoma histology, and who had docetaxel as part of their 
prior chemotherapy will not be eligible for this trial 
3. Current or previous treatment with investigational therapy in another therapeutic clinical 
trial (interrupted less than 4 weeks before study treatment initiation) 
4. Patients whose tumor harbors EGFR gene mutation that sensitizes tumors to TKI (EGFR 
exon 18-21) or ALK rearrangement 
5. Ongoing immunotherapy (checkpoint inhibition, antigen immunotherapy that would be 
scheduled to continue concomitantly to the study) 
6. Spinal cord compression (unless treated with the patient attaining good pain control and 
stable or recovered neurologic function), carcinomatous meningitis, or leptomeningeal 
disease 
7. Patients with squamous cell histology or non-squamous cell histology previously treated by 
pemetrexed with a contraindication for docetaxel with grade ≥ 2 neuropathy or 
hypersensitivity reaction to medications formulated with polysorbate 80 (Tween 80) as they 
could be randomly assigned to Arm B 
Medical history and clinical status 
8. Patients with a condition requiring systemic treatment with either corticosteroids or other 
immunosuppressive medications 


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9. Treatment with corticosteroids in the last 3-week period before inclusion, except for topical, 
ocular, intra-articular, intranasal, and inhaled corticosteroids with minimal systemic 
absorption (e.g. with a dose ≤ 500 microgram beclomethasone equivalent for inhaled 
steroids), or steroid doses ≤ 10 mg daily prednisone equivalent which are permitted 
10. A recognized immunodeficiency disease including human immunodeficiency virus (HIV) 
infection 
and 
other 
cellular 
immunodeficiencies, 
hypogammaglobulinemia 
or 
dysgammaglobulinemia; 
subjects 
who 
have 
hereditary, 
congenital 
or 
acquired 
immunodeficiencies 
11. Patients with auto-immune disease, with the exception of type I diabetes or treated 
hypothyroidism 
12. Patients with interstitial lung disease 
13. Patients with active B or C hepatitis 
14. Other malignancy: patients will not be eligible if they have evidence of other active 
invasive cancer(s) (other than NSCLC) within 5 years prior to screening (except 
appropriately treated non-melanoma skin cancer or localized cervical cancer, or other local 
tumors considered cured (e.g. localized and presumed cured prostate cancer) 
15. Other severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities 
that would impart, in the judgment of the investigator and/or sponsor, excess risk associated 
with study participation or study drug administration, and which would, therefore, make the 
patient inappropriate for entry into this study 
16. Female patients must be surgically sterile or be postmenopausal, or must agree to use 
effective contraception during the period of the trial and for at least 90 days after 
completion of treatment (See Appendix 4: Guidance on Contraception) 
17. Male patients sexually active with a woman of childbearing potential must be surgically 
sterile or must agree to use effective contraception during the period of the trial and for at 
least 90 days after completion of treatment. The decision of effective contraception will be 
based on the judgment of the principal investigator (See Appendix 4: Guidance on 
Contraception) 
18. Breastfeeding women 
19. Women with a positive serum pregnancy test at screening 
 
4.3 
Study Drugs 
4.3.1 Description, packaging and labelling 
The investigational drug OSE2101 will be provided to the site in vials containing OSE2101 
1 mg/mL suspension for emulsion for subcutaneous (sc) injection. It is manufactured in 
accordance with Good Manufacturing Practice (GMP) as required by the current GCP. It is 
packaged and labelled in accordance with GMP and local regulations. 
 


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Two kits (one for OSE2101 and one for Montanide), corresponding to a single administration, 
will be provided to the sites. Each OSE2101 kit will contain 1 vial of OSE2101 and all ancillary 
materials to prepare the full treatment for one single administration.  
 
Control treatments (i.e. docetaxel and pemetrexed) will be market-approved presentations. 
Suppliers may vary according to country/center. 
 
4.3.2 Storage  
The investigational drug OSE2101 will be provided by the Sponsor as vials to be stored at 
-20°C/-4°F protected from light and the adjuvant Montanide ISA51TM will be provided as vials 
to be stored at 5°C/41°F.  
 
Control treatments must be stored at room temperature according to manufacturer’s 
recommendations. 
 
4.3.3 Study drug administration 
Study treatment administration in Arm A (OSE2101) 
Study treatment to be injected will be prepared (emulsification) by the pharmacist within one 
hour of administration, according to a specific study drugs preparation manual.  
Patients randomized to OSE2101 will receive 1 mL of OSE2101 administered subcutaneously on 
Day 1 every three weeks for six cycles, then every eight weeks for the remainder of year one 
and, finally every twelve weeks beyond year one until unequivocal RECIST 1.1-defined disease 
progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. 
Should pseudo progression or delayed response to treatment suspected in arm A, investigator 
may continue treatment beyond the time of RECIST-defined progression, if the patient is 
perceived to be experiencing clinical benefit. (Figure 2: Schedule of OSE2101 administration). 
 
It is intended that all OSE2101 injections be given at the same site (either the anterior thigh or 
deltoid region of the non-dominant arm).  
If pain or granuloma formation prevents using the same site, other areas may be used. If the 1-
mL injection cannot be given by a single injection, then it may be divided into two injections, 
preferably in the same lymph node drainage area. 
 
 
 
 
 
 
 
 
 
 


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Figure 2: Schedule of OSE2101 administration 
 
 
Patients are to be monitored for at least 4 hours after each injection, in order to detect any 
immediate allergic reaction or later symptoms related to possible cytokine release syndrome with 
appropriate equipment and treatment which may be needed for immediate intervention.  
 
Patients should be instructed to the risk of infrequent and delayed flu-like syndrome, malaise, 
fever, low blood pressure which would need to make contact with the investigator (refer to 
5.8 Management of adverse events, dosing adaptations and risk minimization strategy and the 
Investigator's Brochure). 
 
The investigator or his/her designee will administer the study drugs to the patients, exercising 
accepted medical practices. Under no circumstances will the investigator allow study drugs to be 
used otherwise than as directed by this clinical study protocol. All study drug administrations 
will be done under direct medical supervision.  
 
Study treatment administration in Arm B (control treatment) 
Patients randomized to docetaxel will receive standard approved NSCLC dose: 75 mg/m2 in 
1-hour infusion every 3 weeks. Docetaxel will be prepared as per the manufacturer’s 
recommendations. Patients will also be required to take dexamethasone, 8 mg orally, twice daily, 
the day before, the day of and the day after docetaxel dosing. Prophylactic G-CSF may be used 
to mitigate the risk of hematological toxicities at the discretion of the investigator. 
 
Patients randomized to pemetrexed will receive standard approved NSCLC dose: 500 mg/m2 in 
10-minute infusion every 3 weeks. Pemetrexed will be prepared as per the manufacturer’s 
recommendations.  Patients will also be required to take folic acid, 350-1000 g orally daily 
beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing daily 
until 3 weeks after the last dose of pemetrexed. Vitamin B12, 1000 g, will be injected 
intramuscularly approximately 1 to 2 weeks before the first dose of pemetrexed and will be 
repeated approximately every 9 weeks until discontinuation.  Patients will also be required to 
take dexamethasone, 4 mg orally, twice daily, the day before, the day of and the day after 
pemetrexed dosing. 


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Cross-over in Arm B is not permitted 
Patients in Arm B (docetaxel or pemetrexed) cannot receive OSE2101 at time of treatment 
interruption whichever the cause. 
 
4.3.4 Treatment Exposure and Compliance 
Records of study drug used, and dosages administered will be kept during the study. Study drug 
accountability will be performed on an ongoing basis by the study staff and checked by the 
monitor during site visits and at the completion of the study.  
 
4.3.5 Concomitant medications 
Patients in Arm A with OSE2101 
Authorized: 
Subjects can use topical, ocular, intra-articular, intranasal, and inhaled corticosteroids (with 
minimal systemic absorption) with a dose ≤ 500 microgram beclomethasone equivalent. Steroid 
doses ≤ 10 mg daily prednisone equivalent are permitted.   
 
Systemic steroids are only allowed for a brief (less than 1 week) course when prophylaxis (e.g., 
contrast dye allergy) or for acute treatment of non-autoimmune conditions (e.g., delayed-type 
hypersensitivity reaction caused by a contact allergen). 
 
Precautions: 
The potential for overlapping toxicities with radiotherapy and OSE2101 is not known currently: 
therefore, palliative radiotherapy is not recommended while receiving OSE2101. 
If palliative radiotherapy is required, then OSE2101 should be withheld for at least 3 days 
before, during, and 1 week after radiation. Subjects should be closely monitored for any potential 
toxicity during and after receiving radiotherapy, and AEs considered related to radiotherapy 
should resolve to Grade 1 prior to resuming OSE2101. 
 
Patients in Arm B 
Patients in Arm B will require premedication as per product information (refer to 3.3.3 study 
treatment administration in Arm B). Unless started earlier for other reasons, the premedication 
should start before day 1 of each cycle (i.e. day 1 of each cycle will be injection day for 
chemotherapy).  
➢ Patients in Arm B with docetaxel 
Mandatory/Authorized: 
Patients will be required to take dexamethasone, 8 mg orally, twice daily, the day before, the day 
of and the day after docetaxel dosing. Intramuscular or intraperitoneal administration of 
dexamethasone with the same total dose as oral dexamethasone, or equivalent corticosteroids, 
will be allowed per country regulations. Prophylactic G-CSF may be used to mitigate the risk of 
hematological toxicities. 
 


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Prohibited 
The following strong CYP3A4 inhibitors should be avoided for subjects receiving docetaxel 
during the study. This includes (but is not limited to): Ketoconazole, Itraconazole, 
Clarithromycin, 
Atazanvir, 
Indinavir, 
Nefazodone, 
Nelfinavir, 
Ritonavir, 
Saquinavir, 
Telithromycin, Voriconazole. 
 
➢ Patients in Arm B with Pemetrexed 
Mandatory/Authorized: 
Patients will be required to take folic acid, 350-1000 g orally daily beginning approximately 1 
to 2 weeks before the first dose of pemetrexed and continuing daily until 3 weeks after the last 
dose of pemetrexed.  
Vitamin B12, 1000 g, will be injected intramuscularly approximately 1 to 2 weeks before the 
first dose of pemetrexed and will be repeated approximately every 9 weeks until discontinuation. 
Patients will also be required to take dexamethasone, 4 mg orally, twice daily, the day before, the 
day of and the day after pemetrexed dosing. Intramuscular or intraperitoneal administration of 
dexamethasone with the same total dose as oral dexamethasone will be allowed per country 
regulations. 
 
Precautions: 
Refer to product labelling/SPC 
 
Patients in Arm A or Arm B 
Authorized palliative radiotherapy 
Only non-target bone lesions that do not include lung tissue in the planned radiation field or CNS 
lesions may receive palliative radiotherapy while on study treatment.  
Details of palliative radiotherapy should be documented in the source records and electronic case 
report form (eCRF). Details in the source records should include: dates of treatment, anatomical 
site, dose administered and fractionation schedule, and adverse events. Subjects requiring 
palliative radiotherapy should be assessed for disease progression. Subjects considered as having 
progressive disease should be considered for discontinuing study treatment, except if the patient 
is perceived to be experiencing clinical benefit.  
 
Prohibited for all patients 
The following are prohibited for all subjects during the study (unless utilized to treat a  
drug-related adverse event): 
➢ Immunosuppressive agents 
➢ Immunosuppressive doses of systemic corticosteroids (except as stated above in 
“allowed concomitant medication”) 
➢ Any concurrent antineoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, surgical resection of lesions, non-palliative radiation therapy, or 
standard or investigational agents for treatment of NSCLC). Unless a localised 
progression with a global control of the disease with a clinical benefit for the patient and 
under discretion of the investigator, may warrant continuing study treatment should be 
discussed with the sponsor. 


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Authorized 
Concomitant palliative and supportive care for disease related symptoms (including 
bisphosphonates and RANK-L inhibitors) is allowed if initiated prior to first dose of study 
treatment (prior radiotherapy must have been completed at least 3 weeks prior to initiation of 
study treatment). 
 
4.3.6 Study instructions, restrictions and exclusion period 
Subjects with active, known or suspected autoimmune disease cannot be enrolled. Subjects with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll. 
 
4.4 
Study premature discontinuation and withdrawal 
4.4.1  Premature discontinuation 
Subjects who will prematurely discontinue the study for example for an AE will undergo 
whenever possible the study assessments scheduled at the end of treatment visit.  
 
A subject will be considered as withdrawn from the study if, and only if, he/she has withdrawn 
his/her consent. The potential follow-up of subjects after their withdrawal of consent will depend 
upon local regulations or specific agreement with the subjects. However, subjects who withdraw 
their consent after first study drug administration will be advised to undergo the study 
assessments scheduled at the end of treatment visit. They will be advised that participation to the 
end of treatment visit is voluntary but is in their best interest.  
If a subject was withdrawn before completing the study, the reason for withdrawal must be 
entered on the appropriate case report form (eCRF) page. 
 
In this study, overall survival is a key endpoint of the study. Post treatment study follow-up is of 
critical importance and is essential to preserving subject safety and the integrity of the study. 
Subjects who discontinue study treatment must continue to be followed for collection of outcome 
and/or survival follow-up data as required until death or the conclusion of the study. Tumor 
assessments should be continued until documented RECIST 1.1 disease progression. Cancer 
treatment received after discontinuation of study treatment must be recorded as well. 
 
Subjects should notify the investigator of the decision to withdraw consent from future follow-up 
in writing, whenever possible. The withdrawal of consent should be explained in detail in the 
medical records by the investigator, as to whether the withdrawal is from further treatment with 
study drug only or also from study procedures and/or post treatment study follow-up, and entered 
on the appropriate CRF page.  
 
In the event that vital status (whether the subject is alive or dead) is being measured, publicly 
available information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
 


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4.4.2 Lost to Follow Up 
A subject will be considered as lost to follow-up only after having exhausted all means of 
contact; all reasonable efforts must be made to locate subjects to determine and report their 
ongoing vital status. 
Lost to follow-up is defined by the inability to reach the subject after a minimum of three 
documented phone calls, faxes or emails as well as lack of response by the subject to one 
registered mail/letter. All attempts should be documented in the subject’s medical records. If it is 
determined that the subject has died, the site will use permissible local methods to obtain the date 
and cause of death. 
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the subject’s informed consent, then the investigator may use a Sponsor 
retained third-party representative to assist site staff with obtaining subject’s contact information 
or other public vital status data necessary to complete the follow-up portion of the study. If after 
all attempts, the subject remains lost to follow-up, then the last known alive date as determined 
by the investigator should be reported and documented in the subject’s medical records. 
 
4.5 
Treatment Assignment 
4.5.1 Identification of subjects 
The identification of subjects in this study is based on the obligation for pseudonomysation.  
Eligible subjects will be assigned by the investigator a unique study number identifying the 
country, the site and the patient.  
4.5.2 Randomization 
Treatment assignment will be done through an IVRS/IWRS system. Phone number / Web 
address and information required for randomization (identification of the patient/center, criteria 
for inclusion, stratification and criteria for selection of appropriate Arm B treatment) will be 
specified in the study manual.  
Subjects will receive OSE2101 (Arm A) or docetaxel or pemetrexed (according to histology and 
previous treatment, refer to Figure 1) (Arm B).  
Before protocol 4.0, the randomization ratio was 1:1. From protocol 4.0, the randomization is 
2:1. 
Patients should be treated as soon as possible with the allocated treatment, and preferably within 
15 days after randomization. 
 
4.6 
Study Endpoints 
4.6.1 Efficacy endpoints 
Primary efficacy endpoint:  
• 
OS:  


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o In Step 1: OS rate at 12 months in experimental Arm A (OSE2101) in 84 
evaluable patients exposed to OSE2101 
o In Step 2: comparison of OS between experimental Arm A (OSE2101) and 
control Arm B (docetaxel or pemetrexed) when 278 events observed; due to early 
study discontinuation (219 patients included instead of 363 patients), statistical 
hypothesis was revised with a comparison between experimental Arm A and 
control Arm B in the PoI (refer statistical methodology section) 
 
Secondary efficacy endpoints (in Steps 1 & 2): 
• 
DCR at 6 and 12 months based on RECIST 1.1 
• 
QLQ-C30 (EORTC QLQ questionnaire): “Global health status/QoL” score based on 
questions 29 (How would you rate your overall health during the past week?) and 30 
(How would you rate your overall quality of life during the past week?) (in Step 1 only) 
• 
QLQ-LC13 (lung cancer module from EORTC QLQ questionnaire): time to 1st ≥ 10-
point deterioration in chest pain score (question 40), dyspnea score (question 33, 34, 35) 
or cough score (question 31) (in Step 1 only) 
• 
Post Progression Survival  
• 
Time to worsening of ECOG PS  
• 
QLQ-C30 Global health status score change from baseline (in Step 2 only) 
• 
QLQ-C30 Functional scores change from baseline (in Step 2 only) 
• 
QLQ-C30 Symptom scores change from baseline (in Step 2 only) 
• 
QLQ-LC13 Symptom scores change from baseline (in Step 2 only 
• 
PFS based on RECIST1.1 
• 
ORR (in Step 1 only) 
• 
DR (in Step 1 only) 
Exploratory efficacy endpoints: 
In Step 2 only: 
• 
ORR 
• 
DR 
• 
All the other scores of QoL 
• 
COVID-19 impact 
In Steps 1: 
• 
TTD in patient reported chest pain 
• 
TTD in patient reported dyspnea 
• 
TTD in patient reported cough 
In Steps 1 & 2: 
• 
Time to next lung cancer therapy 
 
4.6.2 Safety and tolerability endpoints 
• 
Incidence, severity, seriousness and relationship to study treatments of adverse events 
(AE) and immune-related adverse events (irAE) and any laboratory abnormalities. 
 


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4.6.3 Exploratory translational endpoints 
Patients who agreed to participate in this exploratory translational study, will have to sign a 
specific inform consent. Patient can agree to participate in all or some parts of the translational 
study. Patient can refuse to participate in the translational study without compromising his/her 
participation in the main study.  
The predicted mode of action of OSE2101 includes to increase the tumor associated antigen 
(TAA) presentation of the multiple neoepitope OSE2101 vaccine and to increase the priming and 
activation of T cell in the intent to increase the recognition of cancer cell by specific T cells (5, 
72). 
 
The main objectives of the translational research in the present study are to explore biomarkers 
and pharmacodynamic parameters before and after the start of study treatment (OSE2101 or 
chemotherapy) in a population of NSCLC patients who progressed after ICI treatment (41, 67, 
72). 
Therefore, the following exploratory translational studies will be done: 
 
In blood samples: 
• Pre-, on-treatment and after treatment collection of peripheric blood mononuclear cells 
(PBMCs) for: 
o Immunophenotyping  
o OSE2101 vaccine antigen-specific T-cell frequency  
• Pre-, on-treatment and after treatment collection of liquid biopsies (e.g. cell free DNA 
(cfDNA)): 
o Tumor Mutational Burden (TMB) and/or other mutation of interest (e.g. gene 
profiling of OSE2101 vaccine TAA) 
Blood samples will be taken at baseline, then every 6 weeks until Cycle 7 (e.g. Day 1 of Cycles 
3, 5 and 7), then every 12 weeks (e.g. at time of CT scan) until end of treatment and/or 
progression in all arms (see flow charts Table 1).  
In tumor tissue samples: 
• Specimens from archiving tumor biopsies (at first diagnosis and/or at any time before 
study entry) will be collected.  
• If possible, a new tumor biopsy will be collected within 35 days prior to the first study 
treatment administration (during the screening period). An archiving tumor biopsy 
collected before the screening period is acceptable, should the biopsy be collected after 
the end of ICI treatment. A second tumor biopsy (e.g. in the same tumor site) will be 
undertaken between cycle 3 and cycle 6 and/or at time of the disease progression; Of 
note, a blood sample will be collected for Whole-Exome sequencing (WES) for: 
o Determination of HLA class I expression in tumor (e.g. HLA-A2 and Beta-2 
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o Tumor and tumor microenvironment (TME) characterization by multiplex IHC 
and gene profiling (i.e. CD8-exhausted T cells, TIL infiltration…)  
 
Handling and shipping of blood and tumor samples for biomarkers analysis 
All blood and tumor samples will be stored in certified biobanks before being submitted to 
central laboratories for analysis. The procedure for collection, handling and shipping of the 
samples will be provided in a separate manual. 
Blood and tumor tissue banking for future biomarker analyses 
If the patient agrees, remaining specimens after analysis will be biobanked for future biomarker 
research and drug development projects, e.g. to identify patients that are more likely to benefit 
from a treatment or experience an adverse event (AE), or to gain a mechanistic or genetic 
understanding of drug effects and thereby. All sample will be stored at an external biobanking 
facility contracted by the Sponsor.  
 
Participation in biobanking is voluntary and not a prerequisite for participation in the trial or in 
the translational study. Biobanking will only occur after patient agreed for biobanking and 
having signed the specific informed consent in accordance with local ethical and regulatory 
requirements. Samples and/or data may be transferred to third parties and other countries as 
specified in the informed consent form (ICF). 
 
4.7 
Study Assessment Procedures 
The study assessments and their timing are depicted in Table 1 (Arm A) and Table 2 (Arm B). 
Informed consent must be obtained before any study related procedure. All assessments should 
be performed prior to dosing with study treatment unless otherwise indicated. All cycles are 21 
days in duration.  
4.7.1  Screening assessments  
Screening assessments and procedures must be completed within 35 days of randomization, in 
accordance with Table 1 and Table 2: 
➢ A complete medical history including oncology history (information on prior treatments 
and regimen) and concomitant medications  
➢ HLA-A2 testing (if there are local results with PCR methods, they can be used for 
inclusion, but a central determination is required posteriori. If PCR methods is not 
available on local sites, a central determination of HLA-A2 testing is mandatory) 
➢ EGFR & ALK determination, PD-L1 status: if there is not documented results in 
subject’s medical file, a central determination is recommended if tumor tissue is 
available (see section 4.7.3) 
➢ Tumor assessments: CT scan of thorax, abdomen and brain CT or brain MRI. CT scan of 
the pelvis will be performed only upon request according to clinical suspicion. In case of 
clinical suspicion of bone metastasis out of the area reported by CT scan, imaging test 
will be performed under discretion of the investigator. If imaging were realized as part as 


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routine practice before patient signed the ICF, these radiologic exams can be considered 
as baseline assessments if performed within 35 days of randomization 
➢ Assessment of pretreatment signs and symptoms from the screening visit (at least from 
14 days before randomization) 
➢ Vital signs  
➢ Physical examination  
➢ ECOG performance status  
➢ The safety laboratory (within 14 days prior to randomization):  
o Hematology: blood for complete blood count (CBC) with differential, including 
neutrophil and lymphocyte count  
o Biochemistry: serum for urea, creatinine, sodium, potassium, calcium, 
magnesium, phosphate, chloride, bicarbonate, glucose, LDH, bilirubin, ALT, 
AST, gamma GT, alkaline phosphatase, total proteins, albumin, TSH, free T3 and 
free T4  
o Coagulation: aPTT, PT/INR, fibrinogen  
o Virology: Hepatitis B (HBV HbsAg) and Hepatitis C (HCV RNA), HIV test 
➢ Female subjects with child-bearing potential are required to have a negative serum 
pregnancy test at screening. The test should be repeated whenever one menstrual cycle is 
missed during treatment or a potential pregnancy is otherwise suspected. 
Clinically relevant findings that exist prior to study treatment start must be recorded on the 
relevant Medical History CRF page. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified 
timeframe. 
 
4.7.2 HLA-A2 testing 
HLA-A2 testing can be done at any time before inclusion to screen potential patients. Remaining 
DNA will be stored until the end of the study for further HLA-A2 testing as necessary. A 
specific informed consent will be signed for this pre-screening.  
HLA-A genotype will be determined centrally by PCR in all patients (laboratory to be specified 
in laboratory manual). If there are local results with PCR methods, they can be used for 
inclusion, but a central determination will be done posteriori. If PCR methods is not available on 
local sites, a central determination of HLA-A2 testing is mandatory. HLA-A2 positive phenotype 
is mandatory for inclusion. 
  
This test is done on serum; one 4mL blood sample will be collected on an EDTA tube by 
venipuncture. Serum will be sent to central laboratory at ambient temperature. 
 


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All details on sample preparation and shipment will be described in the laboratory manual. 
 
For patients who agreed (optional): 
In order to be able to address future scientific questions, pre-screened patients will be asked to 
voluntarily donate remaining biospecimens for banking. If the patient agrees, banked samples 
may be used for future biomarker research and drug development projects (e.g. for future 
development a companion diagnostic). 
 
4.7.3 EGFR and ALK determination, PD-L1 expression at screening 
EGFR and ALK negative determination must be known before randomization. Patients must 
have their tumor screened for the absence of EGFR gene mutation that sensitizes tumors to TKI 
(EGFR exon 18-21) or ALK rearrangement. As per current recommendations EGFR and ALK 
determination need to be done only in patients with non-squamous cancer or never/light smokers 
(<15 pack*years) with squamous cancer.  
PD-L1 expression will be documented if local test has been done or, if remaining tumor tissue 
for central determination is possible.  
 
ALK analysis  
ALK testing will be performed in local laboratories with validated tests. If not available on site, a 
central determination will be performed by a selected central laboratory, should tumor tissue 
available. 
Samples will be FFPE blocks or slides. 
 
EGFR analysis  
EGFR testing will be performed in local laboratories with validated tests. If not available on site, 
a central determination will be performed by a selected central laboratory, should tumor tissue 
available. 
Biopsy samples will be FFPE blocks. 
 
PD-L1 expression 
PD-L1 testing will be performed in local laboratories with validated tests. If not available on site, 
a central determination will be performed by a selected central laboratory, should tumor tissue be 
available. 
 
Preparation and shipment details will be described in the laboratory manual. 
 
4.7.4 Tumor assessments 
CT scan of chest and abdomen and CT scan or MRI of the brain will be performed at screening. 
CT scan of the pelvis will be performed only upon request at screening according to clinical 
suspicion or during follow-up according to clinical suspicion or for monitoring purpose of 
identified target/non-target lesions. In case of clinical suspicion of bone metastasis out of the 
area included by the basal CT scan, radiological test will be performed under discretion of the 


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investigator. Then CT scan will be performed every 6 weeks after randomization with 1 week of 
allowance even it is between 2 study visits. Brain imaging must be included in subsequent tumor 
assessments if a patient has brain metastases, otherwise brain will only be evaluated when 
clinically indicated. For Germany, with respect to brain metastases, MRI should be the privileged 
imaging technic and CT should only be considered when there are contra-indications to MRI. 
Specific tests for bone metastasis are required every 12 weeks only if bone metastases are 
present at baseline or are diagnosed later, at investigator discretion. CT scan or MRI, where 
appropriate, should also be performed whenever disease progression is suspected (e.g. 
symptomatic deterioration). 
If imaging were realized as part as routine practice before patient signed the ICF, these 
radiologic exams can be considered as baseline assessments if performed within 35 days of 
randomization.   
 
4.7.5 Quality of life  
The questionnaires EORTC QLQ-C30, QLQ-LC13 (specific to lung cancer) will be used in this 
study (see Appendix 2). These questionnaires must be self-administered by the patient on his/her 
own. These questionnaires will be proposed in the local language to the patient at each study 
visit. A member of the onsite clinical study team can help the patient if he/she does not 
understand the question but must not suggest or impose any answer. 
 
The investigator will ensure that the questionnaires are complete and ask the patient to complete 
them should there be any missing answers. 
 
4.7.6 Safety laboratory assessments 
The safety parameters (Complete blood count with differential, Serum chemistry BUN or serum 
urea, creatinine, sodium, potassium, calcium, magnesium, phosphate, chloride, bicarbonate, 
glucose, LDH, total bilirubin, ALT, AST, gamma GT, alkaline phosphatase, total proteins, 
albumin, TSH, free T3 and free T4, aPTT, PT/INR, fibrinogen) will be measured by the local 
laboratories of investigational sites. All laboratories will provide OSE Immunotherapeutics or its 
designee with the name, professional degree and curriculum vitae of the laboratory director, the 
laboratory certification documents, validations methods, normal ranges, and all other appropriate 
documents. These laboratory references must be forwarded to OSE Immunotherapeutics or its 
designee before study start and updated whenever necessary.  
 
4.7.7 Vital signs 
It includes body temperature, blood pressure, heart rate, respiratory rate and oxygen saturation. 
Blood pressure (systolic and diastolic) will be recorded after 10 minutes resting in supine 
position. Oxygen saturation will be measured by pulse oximetry.  
 


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4.7.8 Physical examination 
A complete physical examination including an examination of major body systems, height 
(baseline visit only) and weight is performed during the study. 
 
4.7.9 ECG 
Standard digital 12-lead ECG (at least 3 complexes for each standard lead) will be recorded with 
the subject in the supine position for a 10-minute period. ECG will include date, time, subject's 
identification, and physician's signature, and will be kept as source document. 
 
4.7.10 Day 1 of study treatment cycle assessments 
These assessments must be done before study drug administration in accordance with Tables 
1&2. Clinically relevant findings meeting the definition of an AE must be recorded on an AE 
page of the CRF. 
 
4.7.11 End of treatment / withdrawal assessments 
These assessments must be obtained for the 4 previous weeks on study, meaning this visit is 
occurring 4 weeks after the last study drug administration. 
 
4.7.12 Post treatment follow-up assessments 
Monitoring of patients continues after the end of study treatment: 
• Tumor assessments should be continued until documented RECIST 1.1 disease 
progression (Arm A or B). 
• Survival status shall be recorded. Post study-treatment survival status will be collected 
every 2 months until death; telephone contact is acceptable. Date and reason of death will 
be recorded. 
• Assessment of adverse events and hospitalizations: Subjects must be followed for adverse 
events until 28 days after the last study treatment administration, or until all serious or 
study drug-related toxicities have resolved or are determined to be “chronic” or “stable”, 
whichever is later. Hospitalizations will be recorded until the last day of study drug 
administration. 
• Collection of subsequent anticancer therapies after study drug discontinuation. 
 
4.8 
Post-study access to study treatment 
At the conclusion of the study, subjects treated with OSE2101 who continue to have clinical 
benefit will be offered to continue treatment with OSE2101 at the request of the investigator and 
the patient either via an extension of the study, a rollover study requiring approval by responsible 
health authority and ethics committee, or through local procedures for compassionate use at the 


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discretion of the sponsor. The sponsor reserves the right to terminate access to study drug if any 
of the following occur:  
a) the marketing application is rejected by responsible Health Authority;  
b) the study is terminated due to safety concerns or development of the product is stopped or 
development strategy modified (e.g. other indication, population, and/or combination 
approach);  
c) the subject can obtain medication from a government sponsored or private health 
program; or  
d) therapeutic alternatives become available in the local market. 
 
5 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
5.1 
Reporting of adverse events 
All observed or volunteered AEs regardless of treatment group or suspected causal relationship 
to the investigational medicinal product(s) are to be reported by the investigator.  
For all AEs, the investigator must pursue and obtain information adequate to determine the 
outcome of the AE, assess whether it meets the criteria for classification as a SAE requiring 
immediate notification to OSE Immunotherapeutics or its designated representative, and 
determine the causality of the AE. For AEs with a causal relationship to the investigational 
medicinal product, follow-up by the investigator is required until the event or its sequelae resolve 
or stabilize at a level acceptable to the investigator, and OSE Immunotherapeutics concurs with 
that assessment. 
 
5.2 
Reporting period 
All SAEs require immediate notification to OSE Immunotherapeutics or its designated 
representative beginning from the time that the subject/patient provides informed consent, which 
is obtained prior to the subject’s participation in the clinical trial, i.e., prior to undergoing any 
trial-related procedure and/or receiving an investigational medicinal product, through the study 
treatment period until the last injection and including 28 calendar days after the final 
administration of the investigational medicinal product.   
Any SAE occurring any time after the end of treatment visit must be promptly reported if a 
causal relationship to investigational product is suspected. These SAEs will only be entered in 
the drug safety database, and hence will not affect study closure. 
All AEs (serious and non-serious) must be recorded on an AE specific CRF page from the time 
of consent through last subject visit. 
 


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5.3 
Assessment of causality  
The investigator’s assessment of causality (drug relationship) must be provided for all AEs 
(serious and non-serious). An investigator’s causality assessment is the determination of whether 
there exists a reasonable possibility that the investigational medicinal product caused or 
contributed to an AE.  If the investigator’s final determination of causality is unknown and the 
investigator does not know whether or not investigational product caused the event, then the 
event will be handled as “related to investigational product” for reporting purposes. If the 
investigator's causality assessment is "unknown but not related to investigational product", this 
should be clearly documented on trial records. 
In addition, if the investigator determines a SAE is associated with trial procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting requirements, 
if applicable. 
Guidelines to determine whether an event might be considered related include (but are not 
limited to) the following:  
• The event occurred in close temporal relationship to study drug administration. 
• The event abated (diminished) or disappeared when treatment with the study drug was 
down-titrated, interrupted, or discontinued.  
• The event re-occurred when treatment was re-introduced. 
• Environmental factors such as clinical state and other treatments could equally have 
caused the event. 
 
5.4 
Definitions of Adverse Events 
An AE is any untoward medical occurrence in a patient or healthy subject administered an 
investigational medicinal product and which does not necessarily have a causal relationship with 
this treatment. 
 
An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an investigational medicinal 
product, whether or not considered related to the investigational medicinal product. 
Examples of adverse events include but are not limited to:   
• Clinically significant symptoms and signs. 
• Clinically significant changes in physical examination findings. 
• Hypersensitivity. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical condition. 
• Lack of efficacy in the acute treatment of a life-threatening disease. 
• Disease or medical condition detected or diagnosed after study drug administration even 
though it may have been present prior to the start of the study. 
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• Clinically significant abnormal test findings. 
 
The criteria for determining whether an abnormal objective test finding (e.g., laboratory test, 
ECG) should be reported as an AE are as follows:  
 
Test result is associated with accompanying signs or symptoms; and/or requires additional 
diagnostic testing or medical/surgical intervention; and/or leads to a change in study drug trial 
dosing (outside of protocol-stipulated dose adjustments), dose reduction, interruption or 
permanent discontinuation; and/or significant additional concomitant drug treatment, or other 
therapy; and/or is considered to be an AE by the investigator or sponsor. 
 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE. 
 
Additionally, AEs may include the signs or symptoms resulting from: 
• Drug overdose. 
• Drug withdrawal. 
• Drug abuse. 
• Drug misuse. 
• Drug interactions. 
• Drug dependency. 
• Extravasation. 
 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, endoscopy, 
tooth extraction, transfusion should not be reported as AEs.  However, the medical condition for 
which the procedure was performed should be reported if it meets the definition of an AE.  
For example, an acute appendicitis should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE. 
 
5.5 
Severity of adverse events 
The NCI Common Terminology Criteria for Adverse Events will be used for assessing severity 
of adverse events reporting according to version CTCAE v5.0 (52). 
A grading (severity) scale is provided for each AE term. 
 
Components and Organization SOC 
System Organ Class, the highest level of the MedDRA hierarchy, is identified by anatomical or 
physiological system, etiology, or purpose (e.g., SOC Investigations for laboratory test results). 
CTCAE terms are grouped by MedDRA Primary SOCs. Within each SOC, AEs are listed and 
accompanied by descriptions of severity (Grade). 
CTCAE Terms 
An Adverse Event (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical 


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treatment or procedure that may or may not be considered related to the medical treatment or 
procedure. An AE is a term that is a unique representation of a specific event used for medical 
documentation and scientific analyses. 
Each CTCAE v5.0 term is a MedDRA LLT (Lowest Level Term). 
 
Definitions 
A brief definition is provided to clarify the meaning of each AE term. 
 
Grades 
Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique 
clinical descriptions of severity for each AE based on this general guideline: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental activities of daily living (ADL) *. 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL**. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE.  
A Semi-colon indicates ‘or’ within the description of the grade. A single dash (-) indicates a 
grade is not available. Not all Grades are appropriate for all AEs. Therefore, some AEs are listed 
with fewer than five options for Grade selection. 
 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. 
 
Activities of Daily Living (ADL) 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden. 
 
5.6 
Serious Adverse Events 
5.6.1 Definition 
A SAE or serious adverse drug reaction is any untoward medical occurrence at any dose that: 
• Results in death. 
• Is life-threatening; Life-threatening refers to an event in which the subject/patient was at 
immediate risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization; 
• Results in persistent or significant disability/incapacity; 
• Results in congenital anomaly/birth defect. 
• Important medical event. 


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Medical judgment should be exercised in determining whether an event is an important medical 
event to be reported as a SAE. An important medical event may not be immediately life-
threatening and/or result in death or hospitalization.  However, if it is determined that the event 
may jeopardize the subject and/or may require medical or surgical intervention to prevent one of 
the other outcomes listed in the definition above. 
 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
 
5.6.2 Hospitalization - Prolongation of existing hospitalization 
Hospitalization is defined as an overnight stay in a hospital unit and/or emergency room.  
An additional overnight stay defines a prolongation of existing hospitalization. 
All AEs associated with hospitalization or prolongation of hospitalization are considered serious. 
Admission also includes transfer within the hospital to an acute/intensive care unit (e.g., from a 
medical floor to a coronary care unit). 
Hospitalization does not include the following: 
• Rehabilitation facilities. 
• Hospice facilities. 
• Nursing homes. 
• Routine emergency room admissions. 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself a SAE.  Examples include:  
• Planned hospitalization for a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for chemotherapy for cancer, elective hip replacement for 
arthritis, coronary angiography for a patient with stable angina pectoris. 
• Admission for treatment of a preexisting condition not associated with the development 
of a new adverse event or with a worsening of the preexisting condition (e.g., for work-up 
of persistent pre-treatment lab abnormality); 
• Social admission (e.g., subject has no place to sleep). 
• Administrative admission (e.g., for yearly physical exam). 
• Optional admission not associated with a precipitating clinical adverse event (e.g., for 
elective cosmetic surgery); 
• Protocol-specified admission during a clinical trial (e.g., for a procedure required by the 
trial protocol).  
 
5.6.3 Serious Adverse Events related to study-mandated procedures  
They are defined as SAEs that appear to have a reasonable possibility of causal relationship (i.e., 
a relationship cannot be ruled out) to study-mandated procedures (excluding administration of 


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study drug) such as an event related to the discontinuation of subject's previous treatment during 
a washout period, or complication of a mandated invasive procedure (e.g., blood sampling), or 
car accident on the way to the hospital for a study visit. 
 
5.7 
Reporting of serious and non-serious adverse events  
5.7.1 Reporting requirements 
Each AE is to be assessed to determine if it meets the criteria for SAE.  If a SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate. 
All SAEs must be recorded on SAE forms, irrespective of the study drug received by the subject, 
whether or not this event is considered by the investigator to be related to study drug. These SAE 
forms must be faxed or scanned to the Clinical Research Organisation (CRO) in charge of 
pharmacovigilance for OSE Immunotherapeutics: 
STRAGEN SERVICES 
fax: +33 (0) 4 78 42 55 71 or email: OsePV@stragen.fr 
All AEs will be reported on the AE page(s) of the CRF. The SAE form and the AE CRF page 
must be completed in a consistent manner (e.g., same AE date, terms and drug relationship). 
 
5.7.2 Serious adverse event reporting requirements 
All SAEs must be reported by the investigator to Stragen Services in charge of 
pharmacovigilance within 24 hours of awareness of the event by the investigator. If the SAE is 
fatal or life-threatening, notification to Stragen Services must be made immediately, irrespective 
of the extent of available AE information.  This timeframe also applies to additional new 
information (follow-up) on previously forwarded SAE reports. Stragen Services acknowledges 
the receipt of the SAE information by email to the investigational site within one working day. In 
the absence of email acknowledging the receipt or in case of issue in sending the fax or email, 
the investigator shall contact Stragen Services by any means for ensuring the receipt of SAE 
information at the earliest opportunity. 
In the rare case that the investigator does not become aware of the occurrence of a SAE 
immediately (e.g., if an outpatient trial subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the AE. 
For all SAEs, the investigator is obligated to pursue and provide information to Stragen Services 
in accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Stragen Services to obtain specific additional follow-up information in an 
expedited fashion.  This information may be more detailed than that captured on the AE case 
report form. In general, this will include a description of the AE in sufficient detail to allow for a 


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complete medical assessment of the case and independent determination of possible causality.  
Information on other possible causes of the event, such as concomitant medications and illnesses 
must be provided.  In the case of a subject death, a summary of available autopsy findings must 
be submitted as soon as possible to Stragen Services.  
REFERENCE SAFETY INFORMATION 
The reference safety information (RSI) to guide for expedited reporting of Suspected Unexpected 
Serious Adverse Reaction is Investigator's Brochure for OSE2101 and the EU Summary of 
Product Characteristics for pemetrexed and docetaxel available at SUSAR processing date. 
 
5.8 
Management of adverse events, dosing adaptations and risk minimization strategy  
 
OSE2101 
Skin/injection site reactions 
• If grade 1 local toxicity [defined per NCI CTCAE v5.0 as tenderness ± associated 
symptoms (e.g. warmth, erythema, itching)] or grade 2 local toxicity [defined per NCI 
CTCAE v5.0 as pain, lipodystrophy, edema, phlebitis]:  
o apply a hot or cold compress to the injection site and consider giving an analgesic 
or antipruritic medication.  
o It is intended that all injections be given at the same site: either the anterior thigh 
or deltoid region of the non-dominant arm (see section 4.3.3). If pain or 
granuloma formation limit dosing in a patient despite measures such as pain 
medication or local hot or cold compresses, other areas may be used. If the 1-mL 
injection cannot be given by a single injection, then it may be divided into two 
injections, preferably in the same lymph node drainage area.  
• If grade 3 local toxicity [defined per NCI CTCAE v5.0 as ulceration or necrosis; severe 
tissue damage; operative intervention indicated] or grade 4 local toxicity (defined per 
NCI CTCAE v5.0 as life-threatening consequences; urgent intervention needed], local 
toxicity shall be considered dose limiting, and the patient will not to receive further 
injections. 
 
Cytokine release syndrome (CRS) 
CRS has been reported in the completed Phase I and Phase II studies. In 88 patients exposed to 
OSE2101 in these completed studies, 2 cases of CRS (1 grade 2, 1 grade 3) have been reported in 
2 patients (2.3%). Both adverse effects were resolutive.  
CRS caused by T cell-engaging therapies is related to elevation in effector cytokines, such as 
interferon gamma (Maude 2014, Lee 2014) and abnormal elevation in cytokines associated with 
macrophage activation and hemophagocytic syndrome, such as interleukin 6 and 10 (Lee 2014). 
CRS is a constellation of inflammatory symptoms resulting from cytokine elevations associated 
with T cell engagement and proliferation. In most patients, CRS symptoms are mild and flulike, 
with fevers and myalgias. However, some patients experience a severe inflammatory syndrome, 


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including vascular leak, hypotension, pulmonary edema, and coagulopathy, resulting in multi-
organ system failure. 
Serious adverse events that may be associated with CRS include pyrexia, headache, nausea, 
asthenia, hypotension, increased alanine aminotransferase, increased aspartate aminotransferase, 
and increased total bilirubin. These events may lead to treatment discontinuation. 
Disseminated intravascular coagulation, capillary leak syndrome, and hemophagocytic lympho-
histiocytosis/macrophage activation syndrome have been reported in the setting of CRS.  
Patients will be closely monitored for signs or symptoms of these events. Management of these 
events may require either temporary interruption or discontinuation of OSE2101, corticosteroids 
and other symptomatic treatments.  
 
The risk minimization strategy of CRS consists of: 
• As a first step, patients should be monitored at least 4h after injection and be informed of 
possible later symptoms like flu-like syndrome, malaise, fever, low blood pressure which 
would need to make contact with the investigator. 
• Should symptoms occur, CRS should be classified according to CTCAE 5.0 or other 
adapted classification (Lee 2014) in order to adapt treatment strategy (Lee 2014).  
Per NCI CTCAE v5.0 definition, CRS is a disorder characterized by fever, tachypnea, headache, 
tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. Also consider 
reporting other organ dysfunctions including neurological toxicities such as psychiatric disorders 
(e.g. hallucinations or confusion), nervous system disorders (e.g. seizure, dysphasia, tremor, or 
headache). 
Overall, in every grade of CRS, a vigilant supportive care including empiric treatment of 
concurrent bacterial infections and maintenance of adequate hydration and blood pressure. 
Immunosuppression should be used in all patients with grade 3 or 4 CRS and instituted earlier in 
patients with extensive comorbidities or older age (Lee 2014): 
• Grade 1 [defined per NCI CTCAE v5.0 as fever ± constitutional symptoms]: vigilant 
support care, assess for infection (e.g. treat fever and neutropenia if present, monitor fluid 
balance, antipyretics, analgesics as needed). 
• Grade 2 [defined per NCI CTCAE v5.0 as hypotension responds to fluid, hypoxia 
responding to <40% oxygen]: vigilant supportive care, monitor cardiac and other organ 
function closely, consider corticosteroids or other specific therapy according to 
comorbidities and expected benefit vs. cancer treatment needs. 
• Grade 3 [defined per NCI CTCAE v5.0 as hypotension managed with one pressor; 
hypoxia requiring ≥ 40% oxygen] and Grade 4 [defined per NCI CTCAE v5.0 as life-
threatening consequences, urgent intervention needed]: vigilant supportive care and 
intensive care monitoring for Grade 4 events, adapted vasopressor support and oxygen; 
specific treatment required : corticosteroids and/or tocilizumab (humanized monoclonal 
antibody against the interleukin-6 receptor (Actemra®) which has been FDA-approved 
for grade 3 or grade 4 CRS induced by CAR-T cell therapy, although off-label in Europe 
and off-label for other indications than CAR-T cell). 


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• Decision to continue subsequent injections of OSE2101 shall be taken considering 
condition of the patient, response to therapy with OSE2101 and alternate anticancer 
treatment options and the severity of CRS. 
o In grade 1 and 2 CRS, continuation of OSE2101 may be considered under strict 
surveillance if patient is having benefit of OSE2101 therapy; it has been reported 
that CRS did not systematically recur at subsequent injections in an instance 
where grade 2 CRS was reported with OSE2101 
o In grade 3 and 4 CRS, treatment with OSE2101 shall not be continued and 
alternate cancer therapy should be considered. Patient trial assessments shall 
continue as scheduled in the protocol. In case of reversible grade 3 CRS, if the 
investigator considers the patient to be experiencing clinical benefit with 
OSE2101, continuation of OSE2101 may be considered under strict surveillance 
after discussion and approval of the Sponsor. In case of grade 4 CRS, OSE2101 
will be permanently discontinued. 
 
Figure 3: Treatment algorithm for management of cytokine release syndrome (per Lee, 
2014) 
 
 
Anaphylactic and severe immunoallergic reactions 
Anaphylactic reaction should be treated with immediate adrenaline subcutaneous injection 
followed by intensive care management.  


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Immunoallergic reactions will require corticosteroids.  
In case of anaphylactic and severe (grade 3 and 4) immunoallergic reactions, OSE2101 will be 
permanently discontinued. 
 
OSE2101 dosing adaptation 
There will be no dose reduction of OSE2101. 
 
Treatment administration of OSE2101 may be delayed allowing enough time for recovery from 
toxicity. Toxicities must have improved to NCI CTCAE Grade ≤ 1 prior to re-treatment or NCI 
CTCAE as of baseline.  
A patient who has not received any study drug(s) for > 16 weeks since last OSE2101 
administration, should be permanently discontinued from study treatment. 
 
Pemetrexed 
Monitoring  
Complete blood cell counts, including platelet counts, should be performed on all patients 
receiving pemetrexed. Patients should be monitored for nadir and recovery, which were tested in 
the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin 
a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 
cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed 
to evaluate renal and hepatic function.  
 
Dose Reduction Recommendations  
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts 
or maximum non-hematologic toxicity from the preceding cycle of therapy. Treatment may be 
delayed allowing sufficient time for recovery. Upon recovery, patients should be retreated using 
the guidelines in Table 3, Table 4 and Table 5, which are suitable for using pemetrexed as a 
single-agent or in combination with cisplatin.  
 
Table 3: Dose Reduction for Pemetrexed – Hematologic Toxicities 
Nadir Absolute neutrophil count (ANC) <500/mm3 and 
nadir platelets ≥50,000/mm3 
75% of previous dose 
Nadir platelets <50,000/mm3 without bleeding regardless 
of nadir ANC 
75% of previous dose 
Nadir platelets <50,000/mm3 with bleeding, regardless of 
nadir ANC 
50% of previous dose 
If patients develop non-hematologic toxicities (excluding neurotoxicity) ≥ Grade 3, treatment 
should be withheld until resolution to less than or equal to the patient’s pre-therapy value. 
Treatment should be resumed according to guidelines in Table 4.  
Table 4: Dose Reduction for Pemetrexed – Non-hematologic Toxicities 


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Dose of pemetrexed 
(mg/m2) 
Any Grade 3 or 4 toxicities except mucositis  
75% of previous dose  
Any diarrhea requiring hospitalization (irrespective of Grade) or 
Grade 3 or 4 diarrhea  
75% of previous dose  
Grade 3 or 4 mucositis  
50% of previous dose  
In the event of neurotoxicity, the recommended dose adjustments for pemetrexed are described 
in Table 5. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. 
 
Table 5: Dose Reduction for Pemetrexed - Neurotoxicity CTC Grade 
 
Dose of pemetrexed (mg/m2)  
0-1  
100% of previous dose  
2  
100% of previous dose  
 
Discontinuation Recommendation  
Pemetrexed therapy should be discontinued if a patient experiences any hematologic or non-
hematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 
neurotoxicity is observed.  
 
Renal Impaired Patients  
In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments 
other than those recommended for all patients. Insufficient numbers of patients with creatinine 
clearance below 45 mL/min have been treated to make dosage recommendations for this group 
of patients. Therefore, pemetrexed should not be administered to patients whose creatinine 
clearance is <45 mL/min using the standard Cockcroft and Gault formula (below) or GFR 
measured by Tc99m-DTPA serum clearance method:  
 
[140 - Age in years] × Actual Body Weight (kg) = mL/min 
Males: 72 × Serum Creatinine (mg/dL)  
Females: Estimated creatinine clearance for males × 0.85  
Caution should be exercised when administering pemetrexed concurrently with NSAIDs to 
patients whose creatinine clearance is <80 mL/min. 
 
Docetaxel 
Patients who are dosed initially at 75 mg/m2 
and who experience either febrile neutropenia, 
neutrophils <500 cells/mm3 
for more than one week, severe or cumulative cutaneous reactions, or 
other grade 3/4 non-hematological toxicities during docetaxel treatment should have treatment 
withheld until resolution of the toxicity and then resumed at 55 mg/m2. Patients who develop 
≥grade 3 peripheral neuropathy should have Docetaxel Injection, USP treatment discontinued 
entirely. 
 


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Pemetrexed and docetaxel adaptation 
Dose reduction of pemetrexed and docetaxel will follow the guidance’s as their respective SCPs. 
Treatment administration may be delayed allowing sufficient time for recovery from toxicity. 
 
A patient who has not received any study drug(s) for > 6 weeks (e.g. equivalent to 2 cycles of 21 
days) since last study drug administration should be discontinued from study treatment. 
 
6 
STATISTICAL METHODOLOGY AND ANALYSES 
6.1 
Statistical Analysis Plan 
A statistical analysis plan (SAP) will be written and finalized before the database lock.  
The SAP will provide full details of analyses, data displays and algorithms to be used for data 
derivations.  
The SAP will include the definition of major and minor protocol deviations and the link of major 
protocol deviations to the analysis sets. Major and minor protocol deviations will be identified 
before the study closure.  
The final SAP v2.2 was finalized on 23-july-2021 before the database lock. This SAP also 
details the subgroup analyses and variables used to define subgroups, and precisely describes the 
hierarchical order to test secondary endpoints. 
6.2 
Analysis Sets 
Three different analysis sets are defined for the patients with previous treatment with ICI. 
The primary population will be a Population of Interest (PoI) identified during Step-1 analysis 
consisting of patients from the 2d line ICI stratification factor with secondary resistance to ICI 
(i.e. duration of ICI ≥ 12 weeks) having shown a benefit over SoC and being proposed as the 
main population for final analysis. Sensitivity analyses on primary endpoint (OS) will be done in 
all population (Kluger et al., 2020). 
Subjects not having a valid or substituted post-baseline value for a particular endpoint are 
excluded from the relevant analysis sets.  
➢ Safety set 
This analysis set includes all patients who were randomized and received at least one dose of 
study treatment. Patients will be analyzed in the group according to the treatment they actually 
received. All safety data analyses will be analyzed using the safety set. 
➢  Intent-to-Treat (ITT) set 
This analysis set includes all randomized patients. Patients will be analyzed in the group as 
randomized. All efficacy data analyses will be analyzed using the ITT set. 
➢ Modified Intent-to-Treat (mITT) set for testing the null hypothesis of the one 
stage Fleming Phase II design (at end of Step 1) 
For testing the null hypothesis of the one stage Fleming Phase II design at the end of Step 1 
(Phase II part), this analysis set includes all patients of the ITT set, enrolled up to the end of 
Step 1, who received at least one dose of OSE2101 and are evaluable at 12 months after 


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randomization, “evaluable” meaning either known alive for at least 12 months or having 
experienced death within 12 months. Patients will be analyzed in the group according to the 
treatment they actually received. 
➢ Per-protocol set  
This analysis set includes all patients of the ITT set who did not violate the protocol in a way that 
might affect the evaluation of the effect of the study drugs on the main endpoints,  
i.e., without major protocol deviations. Major protocol deviations will be defined in the SAP. 
Selected sensitivity efficacy data analyses will be performed using the per-protocol set.  
➢ Per protocol set for testing the null hypothesis of the one stage Fleming Phase II 
design (at end of Step 1) 
This analysis set includes all patients of the mITT set (for testing the null hypothesis of the one 
stage Fleming Phase II design) who have no major protocol deviations and comply with the 
revised inclusion criterion #5. Major protocol deviations will be defined in the SAP. Selected 
sensitivity efficacy data analyses will be performed using the per-protocol set. 
Nota bene: In addition, patients without previous treatment with ICI (included before 
recruitment hold) will be described separately. 
 
6.3 
Sample size  
Step 1 - Phase II 
The primary objective of Step 1 is to evaluate the overall survival rate after 12 months in 
OSE2101 arm. The following hypotheses are considered: 
- H0 (null): 25% of overall survival rate at 12 months (uninteresting to pursue any further 
investigation) 
- H1 (alternative): 40% of overall survival rate at 12 months (clinically relevant to discuss the 
interest of further investigation in a Phase III comparative trial). 
According to the previous hypotheses and a Fleming one step Phase II design with a 2.5% one-
sided type I error and a power of 80%, 84 evaluable patients have to be enrolled in the arm A. 
Fleming decision rules:  
Amongst the first 84 evaluable patients: 
To reject H0 we have to observe at least 30 (35.7%) patients alive at 12 months, then it will be 
interesting to run the next step of Phase III comparative trial.  
If less than 30 patients are alive at 12 months, H0 will not be rejected and it will be considered 
uninteresting to pursue any further investigation. 
The probability to conclude for inefficacy whereas the true rate is 40% is β=18.1%. 
The probability to conclude for efficacy whereas the true rate is 25% is α=1.9%. 
In order to limit the total number of patients needed in Step 1, a 2:1 randomization ratio to 
receive OSE2101 (Arm A) or pemetrexed or docetaxel (Arm B) will be used for new patients 
recruited when version 4.0 of the protocol comes into effect. A total of 38 patients with previous 
ICI treatment have been recruited before protocol version 4.0, from whom 18 patients 


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randomized in arm A (OSE2101), thus 84 - 18 = 66 new patients need to be recruited in arm A 
(OSE2101). Based on a 2:1 randomization ratio, 66/2 = 33 new patients need to be randomized 
in arm B, leading to a total of 99 new evaluable patients. With an expected 7% rate of patients 
not evaluable at 12 months or withdrawn, a total of 108 new patients will be randomized for 
Step 1. 
The analysis of the Phase II data will take place once 84 subjects of the OSE2101 arm are 
evaluable for survival at 12 months (meaning that death was observed within 12 months or that 
the patient has a follow-up time of 12 months or more). With this sample size, the lower limit of 
the exact binomial two-sided 95% confidence interval will be above 25% as soon as at least 30 
subjects will be alive at 12 months. In the situation where exactly 30 subjects out of 84 would be 
seen alive at 12 months, the observed survival rate at 12 months would be 35.7%, which seems 
reasonable in light of the 34.1% overall survival rate at 12 months published for 78 patients on 
durvalumab plus tremelimuab after failure to previous ICI (27). 
It may be noted that as soon as 55 deaths within 12 months are observed by the IDMC, there is 
no need to wait for 84 evaluable patients at 12 months since there is no possibility left to reach 
30 or more patients alive at 12 months among 84 patients evaluable at 12 months. Conversely as 
soon as 30 patients or more are observed alive at 12 months by the IDMC in patients evaluable at 
12 months, there is no need to wait for 84 patients evaluable at 12 months since the number of 
patients alive at 12 months cannot decrease with the additional observations (and since the lower 
limit of the 95% confidence interval is already above 25%). 
 
Step 2 - Phase III 
For Step 2, the same 2:1 randomization ratio will be continued. All the 38 patients randomized 
before the recruitment hold in the subgroup of patients with previous ICI treatment and all new 
patients included in Step 1 / Phase II will be followed during Step 2 /Phase III. However, the 
final analysis of Phase II/Phase III will exclude the 38 patients with previous ICI treatment 
randomized before protocol version 4.0. 
In order to reach a power of 80% for the two-sided log rank test at the 5% significance level 
when assuming a median OS of 7 months for the control and 10 months for the experimental 
arm, a total of 278 events is required. If the new patients (randomized since version 4.0 of the 
protocol came into effect) are uniformly included over an accrual period of 36 months followed 
by a follow-up of 6 months after the last inclusion, observing 278 events requires a total of 363 
new patients. The actual number of new patients may be reduced if the 278 events are observed 
earlier (this is an event-driven study). Both counts exclude the 38 patients enrolled before 
protocol 4.0. 
 
Step-1 analysis was reviewed by the independent data monitoring committee (IDMC) in March 
2020. Step-1 data showed that the predefined thresholds of 12 months-OS rate in OSE2101 arm 
was achieved. At this time, the IDMC was concerned about the impact of the COVID-19 
pandemic on the primary endpoint of the study (OS), on the risk on data integrity and 
recommended to stop accrual early. 


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The Sponsor decided to stop the accrual in April 2020. At that date, 219 patients have been 
enrolled instead of 363 patients and planned to be followed for survival up to mid-January 2021. 
From Step-1 analysis, a population of interest (PoI) consisting of patients from the 2d line ICI 
stratification factor with secondary resistance to ICI (duration of ICI ≥ 12 weeks) was identified 
as having a benefit over SoC and being proposed as the main population for final analysis 
(Kluger et al., 2020). 
Due to early study discontinuation due to COVID-19 (219 patients included instead of 363 
patients), the power decreased to 62% with the same hypotheses (HR=0.70). 
Considering Step 1 results in the PoI, the following hypotheses have been proposed for final 
analysis: 
Assuming a HR of 0.55 observed in PoI in Step-1 and a median OS of 7 months in SoC 
(unchanged as initially planned), a total of 90 events in the PoI will provide a power of 80% and 
a 2-sided logrank test at a 5% two-sided level, if the patients are included over an accrual period 
of 48 months followed by a follow-up of 6 months after the last inclusion. 
6.4 
Primary and secondary efficacy endpoints  
The primary endpoint is OS, defined as time from randomization to death, will be summarized 
on the ITT set using the Kaplan-Meier method and displayed graphically. The median event time 
for each treatment arm and the corresponding 2-sided 95% confidence interval (CI) will be 
provided.  A 2-sided log-rank test stratified for the same stratification factors as used for the 
randomization will be used to compare OS between the two treatment arms. The Cox regression 
model, stratified for the same stratification factors, will be fitted, and the estimated hazard ratio 
and 2-sided 95% CI will be provided. 
2-sided unstratified log-rank test and an unstratified Cox regression model will also be used as 
secondary analyses for OS. 
Subgroups analyses of OS will be performed to determine whether treatment effect is consistent 
among subgroups. The hazard ratios (obtained via a separate unstratified Cox model within each 
subgroup) and their 95% confidence intervals will be displayed as a forest-plot, the test of 
interaction between treatment and subgroup will be derived from an unstratified Cox model 
applied on the whole study population. The following variables will be used to define subgroups: 
• histology (squamous vs. non-squamous),  
• initial response to first line treatment (objective response, that is either complete or partial 
response, vs. no objective response, that is either stabilization or progressive disease)  
• line rank of ICI therapy (2nd line vs. 1st line). 
• best response to ICI (objective response, vs no objective response) 
• presence vs absence of brain metastases 
• tumor stage (III vs. IV) 
• previous number of systemic treatment lines (1 vs. 2 or more) 
• gender (male vs female) 
• age (< 75 vs. ≥ 75) 
• Smoking status: never, former or current smoker 
• baseline ECOG score (0 vs. 1) 


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• duration of PFS since previous treatment (shorter or longer than 6 months) 
Additionally, a Cox regression model, stratified for the same stratification factors as used for the 
randomization, will be used to explore the potential influences of the other factors (those 
defining subgroups in the text above) on the primary OS endpoint. The full list of subgroups of 
interest will finalized before database lock and detailed in the SAP. 
The 6-months survival probability will be estimated using the Kaplan-Meier method and a 2-
sided 95% CI for the log [-log(6-months survival probability)] will be calculated using a normal 
approximation and then back transformed to give a confidence interval for the 6-months survival 
probability itself.  The 1-year survival probability will be estimated similarly. 
Once the primary objective will be established (significant result on OS), each of the secondary 
efficacy endpoints will be tested at 5% significance level using a further hierarchical order (OS 
(PP), PPS, Time to worsening of ECOG PS, QLQ-C30 Global health status score change from 
baseline, QLQ-C30 Functional scores change from baseline, QLQ-C30 Symptom scores change 
from baseline, QLQ-LC13 Symptom scores change from baseline, DCR at 6 months, DCR at 12 
months, , followed by PFS) in order to control the overall type I error. If the primary objective is 
not established, these endpoints will still be analyzed but interpreted as exploratory endpoints, 
similarly if one secondary endpoint in the sequence is not significant, the lower rank secondary 
endpoint(s) will be considered exploratory. 
Based on the randomized patients with measurable lesions at baseline, the best response (CR, 
PR, SD or PD) will be determined by radiology review for each patient and will be summarized 
by treatment arm.  Assessment of response will be made using RECIST version 1.1 (Appendix 
1). Then DCR at 6 and 12 months will be calculated as the number of patients remaining within 
CR, PR or SD responses within the considered time period divided by the total number of 
randomized patients with measurable lesions at baseline in each treatment group. DCR will be 
analyzed as described for ORR. The corresponding exact 2-sided 95% confidence interval will 
be calculated. The Mantel Haenszel test will be used to compare DCR at 6 months between the 
treatment arms, using the randomization strata, the corresponding odds-ratio will be provided 
with its 95% confidence interval.  In addition, the difference in DCR at 6 months between the 
two treatments will be provided and its 95% confidence interval will be calculated based on the 
normal approximation. 
The secondary efficacy endpoints associated with HRQoL will be the change from baseline in 
the EORTC QLQ-C30 “Global health status/QoL” score (based on questions 29 and 30), for 
EORTC QLQ-C30 functional scores, and for EORTC QLQ-C30 and QLQ-C13 symptoms 
according to repeated measures mixed-effects modeling. 
The composite endpoint time to 1st ≥ 10-point deterioration in EORTC QLQ-LC13 “Chest pain 
symptom” score (based on question 40), “Dyspnea symptom” score (based on questions 33, 34, 
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be derived from the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires items according 
to the respective scoring manuals. 
PFS, defined as time from randomization to the first documented disease progression or death 
whichever occurs first, will be analyzed similarly as described for OS. A log-rank test, stratified 
by the same stratification factors as used for the randomization, will be used in analyzing PFS. 
 
PPS, defined as time from the first documented disease progression in patients having 
experienced a progression to death, will be analyzed similarly as described for OS. 
Time to worsening of ECOG PS, defined as the time from randomization to the earliest time 
when the ECOG becomes greater than 1 ignoring all assessments performed after the analysis 
cut-off date. Patients who die without having recorded an ECOG >1 will be assigned an ECOG = 
5 (Dead) at the time of death. Patients without worsening ECOG will be censored at the last time 
when an ECOG value was recorded. By protocol, ECOG is not collected anymore when a 
subject discontinues study treatment while the time between study treatment discontinuation and 
death can be quite long, an additional analysis without imputation for death will be performed. 
This analysis will exclude patients without any post-baseline ECOG assessment and censor 
patients without observed ECOG worsening at their last ECOG assessment. The endpoint will be 
analyzed as described for the PFS. 
 
6.5 
Exploratory efficacy endpoints 
ORR will be calculated as the number of patients with a best response of CR or PR divided by 
the total number of randomized patients with measurable lesions at baseline in each treatment 
group. ORR will be analyzed as described for DCR at 6 months. 
DR will be calculated for the subgroup of patients with objective disease response and 
summarized using the Kaplan-Meier method. 
The 3 endpoints TTD in patient reported pain (QLQ-LC13 “Chest pain symptom” score), TTD in 
patient reported dyspnea (QLQ-LC13 “Dyspnea symptom” score), and TTD to patient reported 
cough (QLQ-LC13 “Coughing symptom” score), will be defined as the time from randomization 
to the earliest time the patient’s score shows a 10-point or higher increase after baseline (7, 6). 
Patients will be censored at the last time when they completed an assessment for chest pain, 
dyspnea and cough if they have not deteriorated. A 10 point or higher change in the score is 
perceived by patients as clinically significant (58). TTD of each these 3 pre-specified symptoms 
(chest pain, dyspnea, and cough) scales will be summarized using Kaplan-Meier methods. The 
estimated Kaplan-Meier plots will be provided for each symptom and the unstratified log-rank 
test will be the primary method to compare the time to first deterioration between the two 
treatment groups. The median time and the corresponding 2-sided 95% CI also will be provided. 
The Hochberg procedure will be used to adjust for multiplicity of the three pre-specified 
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Patient reported HRQoL will also be assessed in a detailed manner in the SAP. Summary 
statistics (mean [and SE], median, range and 95% CI) will be reported by treatment arm and visit 
for the items and scales of the EORTC QLQ-C30 and QLQ-LC13 questionnaires. The mean 
change from baseline (and 95% CI) will also be reported.  Line charts depicting the means and 
mean changes of subscales over time will be provided for each treatment arm. The number and 
proportion of patients who improved, worsened, or remained stable for each of the symptom and 
functional domains, global QOL, and single items of the EORTC QLQ-C30 and QLQ-LC-13 
questionnaires will be summarized in a table and compared between the two treatment arms. 
Additional analyses may be performed such as repeated measures mixed-effects modeling. 
Time to next lung cancer therapy, defined as time from randomization to the first recording a 
lung cancer therapy, will be analyzed similarly as described for OS. A log-rank test, stratified by 
the same stratification factors as used for the randomization, will be used. 
COVID-19 Impact: it is proposed to test COVID-19 impact in the ITT population following 
FDA Guidance (Updated January 27, 2021 then August 2021 on “Conduct of Clinical Trials of 
Medical Products During COVID-19 Public Health Emergency: Guidance for Industry, 
Investigators, and Institutional Review Boards.” and “Statistical Considerations for Clinical 
Trials During the COVID-19 Public Health Emergency: Guidance for Industry” June 2020. The 
complete description of COVID-19 impact analyses is described in the SAP.  
 
6.6 
Safety and tolerability endpoints 
All AEs and SAEs will be coded using the MedDRA dictionary. All AEs will be tabulated by 
system organ class (SOC), preferred terms (PT) and low-level terms (LLT) within each SOC. 
The incidence of subjects who experienced AEs coded with the same preferred term will be 
tabulated (in descending order according to the incidence in the investigational study drug 
group). Adverse events will also be tabulated by severity and by relationship to study drug. 
Summary tables will be accompanied by individual subject listings.  
AEs corresponding to hypersensitivity reactions will be considered as adverse events of special 
interest and will be detailed in additional summary tables. 
SAEs occurring after study drug initiation will be listed and summarized similarly to AEs, while 
SAEs occurring before study drug initiation (only those related to study- mandated procedures) 
will be listed only. 
The same analyses will also be conducted on the irAEs. 
Vital signs (blood pressure and pulse rate) and ECG will be summarized by descriptive statistics 
by treatment group. Individual subject listings of vital signs and ECG data will be provided.  
Values for safety laboratory parameters will be summarized by descriptive statistics by treatment 
group. Individual subject listings will be provided.  
 
6.7 
Interim analysis  
No interim analysis of the primary endpoint will be performed. 
However, OS rate at 12 months will be analyzed on Arm A at end of Step 1 by the IDMC, before 
a decision to continue Step 2 can be made by the Steering Committee after recommendation by 


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the IDMC. The decision of moving forward in Step 2 (Phase III) will consider the expected 
benefit of OSE2101 as well the relevance of the specific design of the Phase III with regards to 
the state-of-the-art in the management of advanced NSCLC known at time of the analysis. 
6.8 
Exposure to study drugs 
Exposure 
to 
study 
drugs 
will 
be 
described 
in 
terms 
of 
administered 
doses.  
The exposure will be tabulated using the usual location and scale statistics.  
 
6.9 
Baseline Parameters and Concomitant Medications 
Continuous demographic variables (age, height, weight) will be summarized by descriptive 
statistics (mean, median, SD, minimum, maximum and number of available observations). 
Individual subject listings will be provided. 
Qualitative demographic characteristics (gender) will be summarized by counts and percentages. 
Other subject characteristics (medical history, physical examination findings, previous and 
concomitant medications) will only be listed. 
Previous and concomitant medications will be coded according to the WHO drug code and the 
ATC code. They will be summarized by type (i.e., previous and concomitant) by tabulating the 
number and percentages of subjects having received each medication. 
 
7 
PROCEDURES AND QUALITY ASSURANCE  
7.1 
Procedures 
7.1.1 Protocol amendments 
Any change to a protocol has to be considered as an amendment as soon as these documents 
have been submitted to Ethics Committee (ECs)/Institutional Review Board (IRB) and Health 
Authorities. Therefore, an amendment could occur before or after the approval of these 
documents by ECs/IRBs and Health Authorities. Potential amendments must be approved by the 
Sponsor after discussion within the Steering Committee, as appropriate. 
Changes in the core Subject Information sheet and Informed Consent form requested by 
ECs/IRBs are not considered as amendments, as long as they do not significantly affect the 
protocol. 
➢ Non-substantial amendment 
Administrative or logistical minor changes require a non-substantial amendment. Such changes 
include but are not limited to changes in study staff or contact details, change in laboratory 
normal ranges, or minor changes in the packaging of study drug, etc.  
The implementation of a non-substantial amendment could be done with or without (according to 
national regulations) notification to the appropriate ECs/IRBs and Health Authorities. It does not 
require their approval or to be signed by the investigators.  
➢ Substantial amendment 


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Significant changes require a substantial amendment. They include but are not limited to: new 
data affecting the safety of subjects/patients, change of the objectives/endpoints of the study, 
eligibility criteria, dose regimen, study assessments/procedures, treatment or study duration, with 
or without the need to modify the Subject Information and Informed Consent. 
Substantial amendments are to be approved by the appropriate ECs/IRBs and in some countries 
by the Health Authorities. The implementation of a substantial amendment can only occur after 
formal approval by the appropriate ECs/IRBs and/or Health Authorities and must be signed by 
the investigators. 
➢ Urgent amendment 
An urgent amendment might become necessary to preserve the safety of the subjects included in 
the study. The requirements for approval should in no way prevent any immediate action being 
taken by the Investigator or OSE Immunotherapeutics in the best interest of the subjects. 
Therefore, if deemed necessary, an investigator can implement an immediate change to the 
protocol for safety reasons. This means that, by exception, the implementation of urgent 
amendments will occur before submission to and approval by ECs/IRBs and Health Authorities.  
In such cases, the investigator must notify OSE Immunotherapeutics within 24 hours. A related 
substantial amendment will be written within 10 working days by OSE Immunotherapeutics and 
submitted to the appropriate ECs/IRBs and Health Authorities. 
7.1.2 Monitoring 
The OSE Immunotherapeutics monitor(s) or its designee will contact and visit the investigator 
regularly and will be allowed, on request, to have access to all source documents needed to 
verify the entries in the eCRF and other protocol- related documents; provided that subject 
confidentiality is maintained in agreement with local regulations. It will be the monitor's 
responsibility to inspect the eCRF at regular intervals throughout the study, to verify the 
adherence to the protocol and the completeness, consistency and accuracy of the data being 
entered in them. OSE Immunotherapeutics monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria, documentation of 
SAEs and the recording of the main safety and tolerability and efficacy endpoints.  
The investigator must ensure that subjects' anonymity will be maintained. On eCRFs or other 
documents submitted to OSE Immunotherapeutics, subjects should not be identified by their 
names, but by birth date (upon local regulation) and number. The investigator must keep a 
subject/patient log showing the subject’s number, name, date of birth and address or any other 
locally accepted identifiers. Documents identifying the subjects/patients (e.g., signed informed 
consent forms) must not be sent to OSE Immunotherapeutics and must be kept by the 
investigator in strict confidence. 
The investigator and co-investigators agree to cooperate with the monitor(s) to ensure that any 
issues detected in the course of monitoring visits are resolved. If the subject is hospitalized or 
dies in a hospital other than the study center, the investigator is in charge of contacting this 
hospital in order to document this SAE. 


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The investigator will supply OSE Immunotherapeutics or its designee on request with any 
required background data from the study documentation or clinic records. This is particularly 
important when errors in data transcription are suspected. In case of special problems and/or 
governmental queries, it is also necessary to have access to the complete study records, provided 
that patient confidentiality is protected. 
An initiation visit will be performed before the first subject is included. Monitoring visits and 
contacts will occur at regular intervals thereafter. A close-out visit will be performed after the 
database lock and resolution of all pending queries and follow-up of ongoing AEs/SAEs. 
 
7.1.3 Data management 
7.1.3.1 
Data collection 
An eCRF must be completed and signed by the principal investigator or co-investigator only 
when a patient has been randomized. This also applies to those subjects who prematurely 
discontinue the study. If a subject withdraws from the study, the reason must be noted on the 
eCRF. The eCRFs are to be completed on an ongoing basis.  
 
7.1.3.2 Database management and quality control 
All study data will be entered into the study database, according to validated procedures 
described in specific data management documents. Subsequently, the data will be systematically 
checked using specific quality control procedures. When the database will be declared complete, 
clean and accurate, it will be locked. Any changes to the database after that time can only be 
made by joint written agreement between the Clinical Research Physician and the Trial 
Statistician. 
 
7.1.4 Recording of data and retention of documents 
The investigator will maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents will be 
classified into two different categories: investigator's file, and subject clinical source documents. 
The investigator's file will contain the protocol/amendments, FDA form 1572 for studies 
conducted under an US IND, financial disclosure form, EC/IRBs and Health Authority approval 
with correspondence, informed consent forms, drug records, staff curriculum vitae and 
authorization 
forms, 
screening 
and 
enrollment 
logs, 
and 
other 
appropriate 
documents/correspondence as per ICH/GCP guidelines and local regulations. Electronic filing of 
eCRF must also occur. 
Subject clinical source documents include, but are not limited to subject hospital/clinic records, 
physician's and nurse's notes, appointment book, original laboratory reports, ECG, X-ray, 
pathology and special assessment reports, consultant letters, etc. 
These two categories of documents must be kept on file by the investigator for as long as needed 
to comply with national and international regulations (2 years after the last marketing 


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authorization in an ICH/GCP region or following local requirements is it is a longer period).  
No study document should be destroyed without prior written approval from OSE 
Immunotherapeutics or its designee. Should the investigator wish to assign the study records to 
another party, or move them to another location, OSE Immunotherapeutics or its designee must 
be notified in advance. 
When source documents are required for the continued care of the patient, appropriate copies 
should be made for storing outside of the site. 
 
7.1.5 Audit 
OSE Immunotherapeutics or its designee may conduct audits of clinical research activities in 
accordance with its internal Quality System to evaluate compliance with the protocol and the 
principles of ICH/GCP related guidelines. Health Authorities may also wish to conduct an 
inspection (during the study or after its completion). Should an inspection be requested by Health 
Authorities, the investigator must inform OSE Immunotherapeutics or its designee immediately 
that such request has been made. 
The investigator will permit such audits by OSE Immunotherapeutics (and its designee) or 
Health Authorities and facilitate them by providing access to the relevant source documents. 
7.1.6 Publication of study results 
The clinical study report will be signed by the chair of the Steering Committee. 
In accordance with standard editorial and ethical practice, results of OSE Immunotherapeutics 
sponsored studies will be published. 
Authors will be defined as meeting requirements of the International Committee of Medical 
Journal Editors. The list of authors will consider for ranking Committee members, investigators 
according to the number of inclusions, region representation. Other contributions may be 
acknowledged. 
The data collected during this study are confidential and proprietary to the sponsor. Any 
publications or abstracts arising from this study require approval by the sponsor prior to 
publication or presentation and must adhere to the sponsor’s publication requirements as set forth 
in the approved clinical trial agreement (CTA). All draft publications, including abstracts or 
detailed summaries of any proposed presentations, must be submitted to the sponsor at the 
earliest practicable time for review, but at any event not less than 30 days before submission or 
presentation unless otherwise set forth in the CTA. Sponsor shall have the right to delete any 
confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application. 
 
7.1.7 Disclosure and confidentiality 
By signing the protocol, the investigator agrees to keep all information provided by OSE 
Immunotherapeutics in strict confidence and to request similar confidentiality from his/her staff 
and the EC/IRB. Study documents provided by OSE Immunotherapeutics (Investigators' 


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Brochure, protocol, CRF and any other protocol-related documents) will be stored appropriately 
to ensure their confidentiality. The information provided by OSE Immunotherapeutics to the 
investigator may not be disclosed to others without direct written authorization from OSE 
Immunotherapeutics, except to the extent necessary to obtain informed consent from subjects 
who wish to participate in the trial. 
Furthermore, the investigator agrees that the sponsor is allowed to enter and utilize his/her 
professional contact details in an electronic database for internal purposes and for submission to 
worldwide Health Authorities. 
 
7.1.8 Premature termination or suspension of the study 
Both OSE Immunotherapeutics and the investigator reserve the right to terminate the study at 
any time.  
If a study is prematurely terminated or suspended, OSE Immunotherapeutics will promptly 
inform the investigator, the ECs/IRBs and Health Authorities, as appropriate, and provide the 
reason(s) for the termination or suspension. If the study is prematurely terminated or suspended 
for any reason, the investigator in agreement with OSE Immunotherapeutics should promptly 
inform the enrolled subjects and ensure their appropriate treatment and follow-up. 
In addition, if the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should promptly inform OSE Immunotherapeutics and the EC/IRB, and 
should provide the sponsor and the EC/IRB with a detailed written explanation of the termination 
or suspension. 
If the EC/IRB terminates or suspends its approval/favorable opinion of a study, the investigator 
should promptly notify OSE Immunotherapeutics and provide OSE Immunotherapeutics with a 
detailed written explanation of the termination or suspension. 
 
7.2 
Insurance and Compensation to subjects and investigators 
The sponsor is providing insurance in order to indemnify (legal and financial coverage) the 
investigator/center against claims arising from the study, except for claims that arise from 
malpractice and/or negligence. The compensation of the subject in the event of study-related 
injuries will comply with the applicable regulations. 


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9 
APPENDICES 
 
 
 


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APPENDIX 1: RECIST 1.1 CRITERIA 
 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, 
Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026. 
 
 
This Appendix has been excerpted from the full RECIST 1.1 criteria. For information pertaining 
to RECIST 1.1 criteria not contained in the study protocol or in this Appendix, please refer to the 
full publication (17). 
 
 
1 ASSESSMENT OF OVERALL TUMOR BURDEN AND MEASURABLE 
DISEASE 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Measurable 
disease is defined by the presence of at least one measurable lesion. 
 
1.1 Measurability of tumor 
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows. All baseline evaluations should be performed as close as possible to the treatment start 
and never more than 4 weeks before the beginning of the treatment. 
Measurable lesions must be accurately measured in at least one dimension (longest diameter 
inthe plane of the measurement to be recorded) with a minimum size of: 
➢ 10 mm by CT scan - (CT scan slice thickness no greater than 5 mm) 
➢ 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable) 
➢ 20 mm by chest x-ray 
➢ Malignant lymph nodes: To be considered pathologically enlarged and measurable, a 
lymphnode must be  15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only 
the short axiswill be measured and followed. 
All measurements should be recorded in metric notation, using calipers if clinically assessed. 
Special considerations regarding lesion measurability 
 
Bone lesions: 
➢ Bone scan, PET scan or plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
➢ Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross sectional imaging techniques such as CT or MRI can be 


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considered as measurable lesions if the soft tissue component meets the definition 
ofmeasurability described above. 
➢ Blastic bone lesions are non-measurable. 
 
 
Cystic lesions: 
➢ Lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, 
by definition, simple cysts. 
➢ Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. 
 
Non-measurable lesions are all other lesions, including small lesions (longest diameter 
< 10 mm or pathological lymph nodes with  10 to < 15 mm short axis), as well as non-
measurable lesions. Lesions considered non-measurable include: leptomeningeal disease, ascites, 
pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or 
lung, abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
1.2 Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be performed rather than clinical examination unless the lesion(s) being followed cannot 
be imaged but are assessable by clinical examination. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. Measurability of lesions on CT scan is based on the assumption that CT 
slice thickness is 5 mm or less. When CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. 
 
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than x-ray, particularly in identifying new lesions. 
However, lesions on chest x-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and  10 mm diameter as assessed using calipers. For the case of skin lesions, documentation by 
color photography including a ruler to estimate the size of the lesion is suggested. As noted 


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above, when lesions can be evaluated by both clinical exam and imaging, imaging evaluation 
should be undertaken since it is more objective and may be reviewed at the end of the study. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. 
 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. 
 
 
2 BASELINE DOCUMENTATION OF ‘TARGET’ AND ‘NON-TARGET’ 
LESIONS 
 
Target lesions: When more than one measurable lesion is present at baseline all lesions up to a 
maximum of five lesions total (and a maximum of two lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the longest 
diameter), be representative of all involved organs, and should lend themselves to reproducible 
repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
 15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum.  
 
All other pathological nodes (those with short axis  10 mm but < 15 mm) should be considered 
non-target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded or followed. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline sum 
diameters. The baseline sum diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions: All other lesions (or sites of disease) including pathological lymph nodes 
should be identified as non-target lesions and should also be recorded at baseline. Measurements 
are not required and these lesions should be followed as ‘present’, ‘absent’, or ‘unequivocal 
progression’. In addition, it is possible to record multiple non-target lesions involving the same 
organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ or 
‘multiple liver metastases’). 
 


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3 TUMOR RESPONSE EVALUATION AND RESPONSE CRITERIA 
3.1 Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm.  
Note: the appearance of one or more new lesions is also considered progression. 
 
Stable Disease (SD): Neither sufficient shrinkage from the baseline study to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Special notes on the assessment of target lesions 
➢ Lymph nodes: Lymph nodes identified as target lesions should always have the actual 
short axis measurement recorded and should be measured in the same anatomical plane 
as the baseline examination, even if the nodes regress to below 10 mm on study. This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not 
be zero even if complete response criteria are met, since a normal lymph node is defined 
as having a short axis of < 10 mm. 
➢ Target lesions that become ‘too small to measure’: All lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent 
evaluation, even when very small (e.g., 2 mm). If the radiologist is able to provide an 
actual measure, that should be recorded, even if it is below 5 mm. 
 
However, when such a lesion becomes difficult to assign an exact measure to then: 
(i) if it is the opinion of the radiologist that the lesion has likely disappeared, the measurement 
should be recorded as 0 mm. 
 
(ii) if the lesion is believed to be present and is faintly seen but too small to measure, a default 
value of 5 mm should be assigned (note: in case of a lymph node believed to be present and 
faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well). This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). 
 
Lesions that split or coalesce on treatment: When non-nodal lesions ‘fragment’, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in 
obtaining maximal diameter measurements of each individual lesion. If the lesions have 


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coalesced such that they are no longer separable, the vector of the longest diameter in this 
instance should be the maximal longest diameter for the ‘coalesced lesion’. 
3.2 Evaluation of non-target lesions 
While some non-target lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
(Note: the appearance of one or more new lesions is also considered progression). 
➢ The concept of progression of non-target disease requires additional explanation as 
follows: 
➢ When the patient also has measurable disease: To achieve ‘unequivocal progression’ on 
the basis of the non-target disease, there must be an overall level of substantial worsening 
in non-target disease such that, even in presence of SD or PR in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 
‘increase’ in the size of one or more non-target lesions is usually not sufficient to qualify 
for unequivocal progression status. 
➢ When the patient has only non-measurable disease: To achieve ‘unequivocal progression’ 
on the basis of the non-target disease, there must be an overall level of substantial 
worsening such that the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. Because 
worsening in non-target disease cannot be easily quantified (by definition: if all lesions 
are non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that 
would be required to declare PD for measurable disease: ie, an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% 
increase diameter in a measurable lesion). Examples include 
an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in lymphangitic 
disease from localized to widespread, or may be described in protocols as ‘sufficient to 
require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be 
considered to have had overall PD at that point. 
 
3.3 New lesions 
The appearance of new malignant lesions denotes disease progression. The finding of a new 
lesion should be unequivocal: ie, not attributable to differences in scanning technique, change in 
imaging modality or findings thought to represent something other than tumor (for example, 
some ‘new’ bone lesions may be simply healing or flare of pre-existing lesions). This is 
particularly important when the patient’s baseline lesions show partial or complete response. For 


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example, necrosis of a liver lesion may be reported on a CT scan report as a ‘new’ cystic 
lesion,which it is not. A lesion identified on a follow-up study in an anatomical location that was 
not scanned at baseline is considered a new lesion and will indicate disease progression. An 
example of this is the patient who has visceral disease at baseline and while on study has a CT or 
MRI brain ordered which reveals metastases. The patient’s brain metastases are considered to be 
constitute PD even if he/she did not have brain imaging at baseline.If a new lesion is equivocal, 
for example because of its small size, continued therapy and follow-up evaluation will clarify if 
it represents new disease. If repeat scans confirm that there is a new lesion, then progression 
should be declared using the date of the initial scan. 
 
3.4 Tumor markers 
Tumor markers alone cannot be used to assess objective tumor responses. If markers are 
initiallyabove the upper normal limit, however, they must normalize in order for a patient to be 
considered as having attained a complete response. 
 
 
4 EVALUATION OF BEST OVERALL RESPONSE 
4.1 Time point response 
A response assessment should occur at each time point specified in the protocol. 
For patients who have measurable disease at baseline Appendix Table 6 provides a summary of 
the overall response status calculation at each time point. 
 
Table 6: Summary of the Overall Response Status 
Calculation [Time point response - patients with target ± non-target disease] 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes  
PD 
 
4.2 Missing assessments and inevaluable designation 
When no imaging/measurement is done at all at a particular time point, the patient is not 
evaluable (NE) at that time point. If only a subset of lesion measurements are made at an 


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assessment, usually the case is also considered NE at that time point, unless a convincing 
argument can be made that the contribution of the individual missing lesion(s) would not change 
the assigned time point response. This would be most likely to happen in the case of PD. 
 
4.3 Best overall response: all timepoints 
Best response determination in trials where confirmation of complete or partial response IS 
required: Complete or partial responses may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol. In this circumstance, the best overall response 
can be interpreted as in Appendix Table 7. 
 
Table 7: Best overall response when confirmation of CR and PR required 
Overall Response 
First Timepoint 
Overall Response 
Subsequent Timepoint 
Best Overall response 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD 
duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD 
duration met, otherwise NE 
NE 
NE 
NE 
 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
inevaluable. 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR).  
Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be 
claimed when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR 
at the first time point. Under these circumstances, the original CR should be changed to PR and the best response is 
PR. 
 


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4.4 Special notes on response assessment 
When nodal disease is included in the sum of target lesions and the nodes decrease to 
‘normal’size (< 10 mm), they may still have a measurement reported on scans. This 
measurement should be recorded even though the nodes are normal in order not to overstate 
progression should it be based on increase in size of the nodes. As noted earlier, this means that 
patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as‘symptomatic 
deterioration’. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective 
response: it is a reason for stopping study therapy. The objective response status of such patients 
is to be determined by evaluation of target and non-target disease as shown in Appendix Table 6 
and Table 7. 
For equivocal findings of progression (eg, very small and uncertain new lesions; cystic changes 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
 
 
5 ADDITIONAL CONSIDERATIONS 
5.1 Duration of response 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are 
first met for CR until the first date that recurrent disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment (in 
randomized trials, from date of randomization) until the criteria for progression are met, taking 
as reference the smallest sum on study (if the baseline sum is the smallest, this is the 
reference for calculation of PD). 
 
5.2 Lesions that disappear and reappear 
If a lesion disappears and reappears at a subsequent time point it should continue to be measured. 
However, the patient’s response at the point in time when the lesion reappears will depend upon 
the status of his/her other lesions. For example, if the patient’s tumour had reached a CR status 
and the lesion reappeared, then the patient would be considered PD at the time of reappearance. 
In contrast, if the tumour status was a PR or SD and one lesion which had disappeared then 
reappears, its maximal diameter should be added to the sum of the remaining lesions for a 
calculated response: in other words, the reappearance of an apparently ‘disappeared’ single 
lesion amongst many which remain is not in itself enough to qualify for PD: that requires the 
sum of all lesions to meet the PD criteria. The rationale for such a categorization is based upon 


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the realization that most lesions do not actually ‘disappear’ but are not visualized because they 
are beyond the resolving power of the imaging modality employed. 
 
5.3 Use of FDG-PET 
While FDG-PET response assessments need additional study, it is sometimes reasonable to 
incorporate the use of FDG-PET scanning to complement CT scanning in assessment of 
progression (particularly possible ‘new’ disease). New lesions on the basis of FDG-PET imaging 
can be identified according to the following algorithm: 
 
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. Confirmatory CT is recommended. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: 
➢ If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD. 
➢ If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is progression occurring at 
that site (if so, the date of PD will be the date of the initial abnormal FDG-PET scan).  
➢ If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.  
 
 


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APPENDIX 2: EORTC QOL QUESTIONNAIRES 
 
As consulted on July 16th, 2015 at  
 
http://groups.eortc.be/qol/sites/default/files/img/specimen_lc13_english.pdf 
and 
http://groups.eortc.be/qol/sites/default/files/img/slider/specimen qlq-c30 english.pdf 
 
 
 
 
 
specimen_lc13_englis
h.pdf
specimen_qlq-c30_e
nglish.pdf


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APPENDIX 3: ECOG 
 
ECOG Performance Status 
 
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair 
(57) 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity 
and 
response 
criteria 
of 
the 
Eastern 
Cooperative 
Oncology 
Group. 
Am J Clin Oncol. 1982;5(6):649-55.  
 
GRADE 
ECOG PERFORMANCE STATUS 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; 
up and about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
 
 


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APPENDIX 4: GUIDANCE ON CONTRACEPTION  
 
ACCEPTABLE METHODS FOR PROTOCOLS WITH A TERATOGENIC DRUG OR 
WHEN THERE IS INSUFFICIENT INFORMATION TO DETERMINE 
TERATOGENICITY 
(CHOOSE ONE OF THE FOLLOWING 3 OPTIONS)a 
 
OPTION 1: Any TWO of the following methods 
➢ Hormonal methods of contraception b, c, d 
➢ IUD c, d, e 
➢ Vasectomy d, f 
➢ Tubal Ligationd 
➢ A Barrier method (Female or Male Condom with spermicide, Cervical Cap with 
spermicide,Diaphragm with spermicide) 
 
OPTION 2: Male condom (with spermicide) and diaphragmg 
 
OPTION 3: Male condom (with spermicide) and cervical capg 
 
a The theoretical failure rate for any of the options listed is considerably less than 1% per year 
b Excludes progestin-only pills 
d A highly effective method of birth control with a failure rate less than 1% per year 
e IUDS used should have a failure rate less than 1% (highly effective method), such as Mirena 
and ParaGard 
f Must be at least 90 days from date of surgery with a semen analysis documenting azoospermia 
g These 2 barrier methods together are acceptable for a teratogenic drug 
 
UNACCEPTABLE METHODS OF CONTRACEPTION 
Abstinence (including periodic abstinence) 
No method 
Withdrawal 
Rhythm 
Vaginal Sponge 
Any barrier method without spermicide 
Spermicide 
Progestin only pills 
Concomitant use of female and male condom 
In countries where spermicide is not available or its use is not considered compatible with male 
condoms, use of a male condom without spermicide in conjunction with a hormonal method, 
IUD, or tubal ligation will be acceptable to fulfill this recommendation. Any barrier method 
when used alone (without spermicide) or the concomitant use of a female and male condom, is 
not considered a sufficient method of contraception, as each carries a failure rate of > 1%. 
Women of childbearing potential (WOCBP) receiving OSE2101 will be instructed to adhere to 
contraception for a period of 90 days after the last dose of investigational product. Men receiving 


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OSE2101 and who are sexually active with WOCBP will be instructed to adhere to contraception 
for a period of 90 days after the last dose of investigational product.  
 
For women of childbearing potential (WOCBP) randomized to receive docetaxel, they will be 
instructed to adhere to contraception for a period of 33 days after the last dose of investigational 
product. 
Men randomized to receive docetaxel must follow instructions for birth control as per the SmPC 
(6 months after discontinuation of treatment), or package insert. 
 
Women of childbearing potential should be advised to use effective contraceptive measures to 
prevent pregnancy during the treatment with pemetrexed 

SAP_001.pdf: 
OSE Immunotherapeutics 
 
v2.2 
Study OSE2101C301 (ATALANTE 1) Statistical Analysis Plan 
 2021-07-23 
IND#: BB-IND 10802 
 
 
  
 
STATISTICAL ANALYSIS PLAN 
CONFIDENTIAL 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A randomized parallel group phase III trial of OSE2101 as 2nd or 
3rd line compared with standard treatment (docetaxel or 
pemetrexed) in HLA-A2 positive patients with advanced Non-
Small-Cell Lung Cancer with progressive disease after last 
treatment 
with 
immune 
checkpoint 
inhibitors 
(ICI) 
(OSE2101C301) 
 
Protocol Number: 
OSE2101C301 (ATALANTE 1) 
Phase: 
Phase III 
Sponsor: 
OSE Immunotherapeutics 
22 boulevard Benoni Goullin 
44200 Nantes 
France 
Author: 
Summit 
Analytical, 
LLC 
8354 
Northfield 
Blvd. 
Bldg. 
G 
Suite 
3700 
Denver, CO 80238 
SAP Date: 
2021-07-23 
Status: 
Draft v2.2_augmented after FDA Type C meeting (1st July 2021)  
 
SIGNATURES 


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The undersigned have approved this Statistical Analysis Plan for use in this study. 
 
 
 
 
 
 
Napoléon Oleka 
Lead Biostatistician 
Summit Analytical LLC 
 
Date 
 
 
 
 
Bérangère Vasseur, MD 
Chief Medical Officer Immuno-Oncology 
OSE Immunotherapeutics 
 
Date 
 
 
 
 
François Montestruc 
Statistician 
eXYSTAT 
 
Date 
 


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1. 
TABLE OF CONTENTS 
1. 
TABLE OF CONTENTS ............................................................................................................................... 3 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS................................................................... 6 
3. 
INTRODUCTION ......................................................................................................................................... 8 
3.1. 
Preface .............................................................................................................................................. 8 
3.2. 
Purpose of Analyses .......................................................................................................................... 8 
3.3. 
Summary of Statistical Analysis Changes to the Protocol ................................................................ 9 
4. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................................................... 12 
4.1. 
Study Objectives ............................................................................................................................. 12 
4.1.1. 
Primary Objective(s) ..................................................................................................... 12 
4.1.2. 
Secondary Objectives .................................................................................................... 12 
4.2. 
Efficacy Endpoints in step-2 ........................................................................................................... 12 
4.2.1. 
Primary Efficacy Endpoint ............................................................................................ 12 
4.2.2. 
Secondary Efficacy Endpoints ...................................................................................... 12 
4.2.3. 
Exploratory Efficacy Endpoints .................................................................................... 13 
4.2.4. 
Summary of the primary and secondary endpoints ....................................................... 13 
4.3. 
Safety and Tolerability Endpoints ................................................................................................... 14 
5. 
STUDY METHODS .................................................................................................................................... 14 
5.1. 
General Study Design and Plan....................................................................................................... 14 
5.2. 
Inclusion – Exclusion Criteria and General Study Population ........................................................ 19 
5.3. 
Randomization and Blinding........................................................................................................... 19 
5.4. 
Analysis Variables .......................................................................................................................... 19 
6. 
SAMPLE SIZE ............................................................................................................................................ 19 
7. 
GENERAL CONSIDERATIONS ............................................................................................................... 20 
7.1. 
Analysis Sets ................................................................................................................................... 20 
7.1.1. 
Safety Set PoI ................................................................................................................ 20 
7.1.2. 
Intent-to-Treat Set PoI (ITT_PoI) ................................................................................. 20 
7.1.3. 
Per-Protocol Set PoI (PP_PoI) ...................................................................................... 20 
7.1.4. 
Safety Set ...................................................................................................................... 20 
7.1.5. 
Intent-to-Treat Set (ITT) ............................................................................................... 20 
7.1.6. 
Per-Protocol Set (PP) .................................................................................................... 21 
7.2. 
Subgroups ....................................................................................................................................... 21 
7.3. 
Management of Analysis Data ........................................................................................................ 22 
7.3.1. 
Missing Data ................................................................................................................. 22 
7.3.1.1. 
Handling of Missing Date Values ............................................................ 22 
7.3.1.2. 
Imputation Methods ................................................................................. 23 
7.3.2. 
Coding Conventions for Events and Medications ......................................................... 23 
7.3.3. 
Analysis Software ......................................................................................................... 23 
7.3.4. 
Study Data ..................................................................................................................... 23 
7.4. 
Planned Study Analyses .................................................................................................................. 24 
7.4.1. 
Statistical Summaries: Descriptive and Inferential ....................................................... 24 
7.4.2. 
Interim Analyses and Data Monitoring ......................................................................... 25 
7.4.3. 
Final Analysis and Publication of Study Results .......................................................... 25 


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8. 
SUMMARY OF STUDY DATA ................................................................................................................ 26 
8.1. 
Subject Disposition ......................................................................................................................... 26 
8.2. 
Patients Randomized by Month ...................................................................................................... 26 
8.3. 
Protocol Deviations ......................................................................................................................... 26 
8.4. 
Demographics and Baseline Characteristics ................................................................................... 26 
8.5. 
Previous ICI Treatment ................................................................................................................... 29 
8.6. 
History of Immune-Related Adverse Events................................................................................... 30 
8.7. 
Randomization Stratification Factors .............................................................................................. 30 
8.8. 
Medical History .............................................................................................................................. 31 
8.9. 
Concomitant Medications ............................................................................................................... 32 
8.10. 
Treatment Compliance .................................................................................................................... 32 
8.11. 
Time Intervals ................................................................................................................................. 33 
8.11.1. 
Time Intervals between Cycles ..................................................................................... 33 
8.11.2. 
Survival Data Collected on the Censored Patients and Duration of 
Follow-up ...................................................................................................................... 33 
8.11.3. 
Time Intervals between RECIST Assessments ............................................................. 33 
8.11.4. 
Time Intervals between Quality of Life Assessments ................................................... 33 
9. 
EFFICACY ANALYSES ............................................................................................................................ 34 
9.1. 
Overall Survival (OS) ..................................................................................................................... 34 
9.2. 
Progression-free Survival (PFS) ..................................................................................................... 36 
9.3. 
Overall response Rate (ORR), Disease Control rate (DCR) and Duration of response 
(DR) ................................................................................................................................................ 37 
9.4. 
Time to next lung cancer therapy .................................................................................................... 38 
9.5. 
Post-progression Survival ............................................................................................................... 39 
9.6. 
Quality of life analyses ................................................................................................................... 40 
9.7. 
ECOG .............................................................................................................................................. 42 
10. SAFETY ANALYSES................................................................................................................................. 42 
10.1. 
Adverse Events ............................................................................................................................... 42 
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events ........................................ 44 
10.2.1. 
Deaths............................................................................................................................ 44 
10.2.2. 
Serious Adverse Events ................................................................................................. 45 
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug or 
Withdrawal from Study ................................................................................................. 45 
10.3. 
Clinical Laboratory Evaluations ..................................................................................................... 45 
10.4. 
Vital Signs ....................................................................................................................................... 45 
10.5. 
12-Lead ECG .................................................................................................................................. 46 
11. ADDITIONAL SAFETY ANALYSES ....................................................................................................... 46 
12. COVID-19 IMPACT ................................................................................................................................... 47 
12.1. 
Disposition ...................................................................................................................................... 50 
12.2. 
Sensitivity analysis on censor date .................................................................................................. 50 
12.3. 
Time-dependent covariate analyses ................................................................................................ 50 
 
 


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LIST OF TABLES 
 
Table 1 
Schedule of Time and Events for Arm A ...................................................................... 15 
Table 2 
Schedule of Time and Events for Arm B ...................................................................... 17 
 
 
LIST OF FIGURES 
 
Figure 1 
SDTM, ADaM, and TFL Development and Validation ................................................ 24 
 
 
 


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2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Only abbreviations and terms relevant to the SAP are repeated herein. The reader is referred 
to the protocol for the complete and comprehensive list of abbreviations and definitions of 
terms for the study. 
Abbreviation/Term 
Definition 
ADaM 
Analysis data Model 
AE 
Adverse Event 
ALK 
Anaplastic Lymphoma Kinase 
ATC 
Anatomic Therapeutic Chemical 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CR 
Complete Response 
CSR  
Clinical Study Report 
dNLR 
derived Neutrophils/(Leukocyte minus neutrophils Ratio) 
DCR 
Disease Control Rate 
DR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal Growth Factor 
HLA-A2 
Human Leukocyte Antigen - A2 
ICI 
Immune Checkpoint Inhibitor 
IDMC 
Independent Data Monitoring Committee 
irAE 
Immune-related Adverse Event 
ITT 
Intention to Treat 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention to Treat 
mPP 
Modified Per Protocol 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progressive Disease 
PD-L1 
Programmed Death-Ligand 1 


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Abbreviation/Term 
Definition 
PFS 
Progression Free Survival 
PoI 
Population Of Interest 
PP 
Per Protocol 
PR 
Partial Response 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SDTM 
Study Data Tabulation Model 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFL 
Tables, Figures, and Listings 
TTD 
Time to Deterioration 
ULN 
Upper Limit of Normal Range 
WHO-DD 
World Health Organization Drug Dictionary 


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3. 
INTRODUCTION 
3.1. 
Preface 
This document presents the final statistical analysis plan (SAP) for OSE Immunotherapeutics 
(A randomized parallel group Phase III trial of OSE2101 as 2nd or 3rd line compared with standard 
treatment (docetaxel or pemetrexed) in HLA-A2 positive patients with advanced Non-Small-Cell Lung 
Cancer with progressive disease after last treatment with immune checkpoint inhibitors (ICI 
[OSE2101C301 – ATALANTE 1]). The present SAP is intended to plan the analyses to be 
presented in the final CSR (update of the step 1 CSR). 
Reference materials for this statistical plan include the Protocol (Version 5.0 29MAR2019) 
and Annotated Case Report Form (Version 18.4 10DEC2019). 
The present SAP is an extension of the IDMC SAP (Planned step 1 analysis version 1.0 signed 
the 5 February 2021 – N=103 patients) and describes the SAP for the discontinued step-2 part 
of this Phase 3 trial.  
On March 25, 2020, the step-2 part was ongoing when the IDMC met to review the final Step-
1 results and concluded that the predefined thresholds of survival rate at 12 months in OSE2101 
arm was achieved (cut-off date of February 26, 2020 (n=103)). This analysis was blinded from 
the investigators and the Sponsor. At this time, the IDMC was concerned about the impact of 
the COVID-19 pandemic on the primary endpoint of the study (Overall Survival) and the risk 
on data integrity. Despite step-1 positive results, the IDMC and the Steering Committee (SC) 
recommended to halt patients screening and accrual and to continue the treatment of patients 
enrolled before April 2020.  
So, the trial was stopped in April 2020. At that date, 219 patients post ICI have been enrolled 
and followed for survival up to 15 January 2021 (cutoff date for final analysis).  
The present SAP is describing the final analysis on overall post ICI population (N=219 
patients). 
3.2. 
Purpose of Analyses 
The purposes of the planned analyses described in this SAP are to assess the safety and efficacy 
of OSE2101 in comparison with standard treatment (docetaxel or pemetrexed). Results from 
the analyses will be included in the final clinical study report for OSE2101C301, and may also 
be utilized for regulatory submissions, manuscripts, or other clinical development activities. 
The Step-1 results in 103 patients showed a 12-month OS rate of 46.0% [95%CI 33.4%, 
59.1%], and the step-1 objectives on 1-year OS rate (H0: OS rate at 12 months >25% and H1 
> 40%) were achieved. 


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An outstanding beneficial effect of OSE2101 in patients with secondary resistance to ICI given 
as last treatment was observed in step 1. It is proposed to confirm the efficacy and safety of 
OSE2101 in this population of interest (PoI) as primary analysis from the 219 randomized 
patients. Considering that the total number of randomized patients is 219 and that the initial 
hypotheses were 278 events (deaths) in 363 anticipated patients, statistical hypotheses were 
revised in this SAP for PoI. 
3.3. 
Summary of Statistical Analysis Changes to the Protocol 
The SAP update Version 2.0 reflects a major improvement to the SAP in clarity, detailedness, 
organization and coherence. The SAP update is completed after last patient last visit of this 
phase 3 trial was done on January 15th, 2021, and database cleaning up to June 2021. Database 
lock is anticipated in July 2021, after FDA’ meeting occurred July 1st, 2021.  
 
The aim of the update is to provide sufficient details to ensure accurate and correct execution 
of statistical programming of tables, figures, and listings in implementing this plan, improve 
clarity and coherence of the document to both internal and external stakeholders, as well as 
correcting some apparent errors and inconsistencies. Some new analyses were also added to 
ensure comprehensive and robust data analyses and interpretation. To this end, text was 
significantly added, revised, consolidated, or reorganized in appropriate sections. However, 
the specifics of study critical details such as those concerning definitions of primary endpoint,  
significance levels for testing OS are not changed. 
 
Notable changes are delineated below: 
- 
Primary analysis: The primary population of this analysis will be the PoI.  PoI is defined 
as patients with secondary resistance to ICI (ICI ≥ 2nd line administered for > 12 weeks). 
- 
Sensitivity analyses on primary endpoint (OS) (described in an ancillary SAP):  
o Additional subgroups (e.g., ICI as maintenance therapy in 1st line, OS with or 
without anti-cancer treatment after study treatment discontinuation, post-
progression survival with or without anti-cancer treatment, duration of stable 
disease, duration of OSE2101 treatment…) 
o OS according to Best Response to study treatment 
o OS for patients continuing study treatment beyond progression 
- 
Sequential analysis of secondary criteria: The secondary endpoints will focus on the 
clinical benefit provided by treatments: they will be Post progression Survival, Time to 
worsening of ECOG, QLQ-C30 Global health status score change from baseline, QLQ-
C30 Functional total scores change from baseline, QLQ-C30 total symptom scores 
change from baseline, QLQ-LC13 total score change from baseline, DCR at 6 and 12 
months, and Progression Free Survival.  
  


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Consequently, the order of secondary endpoints was updated (see 4.2.4). The 
hierarchical method in the ordering sequence of secondary endpoints to control the 
overall type I error remains unchanged. Once the primary objective is established, each 
of the secondary efficacy endpoints will be tested at 5% significance level using a 
further hierarchical order in the ordering sequence of the list described above to control 
the overall type I error. If the primary objective is not established, these endpoints will 
still be analyzed but interpreted as exploratory endpoints. Similarly if one secondary 
endpoint in the sequence is not significant, the lower rank secondary endpoint(s) will 
be considered exploratory. 
- 
Time to ECOG deterioration will be evaluated. It is an accepted endpoint for clinicians 
who use it to propose treatment strategy in clinical practice. It could be used later in 
development as a validated secondary endpoint. Complementary analyses will be 
described in the ancillary SAP. 
- 
Quality of Life analyses were updated and more detailed in this SAP. A complete 
analysis 
according 
to 
EORTC 
guidelines 
(https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf) and the FDA 
Guidance 
“Core 
Patient-Reported 
Outcomes 
in 
Cancer 
Clinical 
Trials” 
(https://www.fda.gov/regulatory-information/search-fda-guidance-documents/core-
patient-reported-outcomes-cancer-clinical-trials) is considered instead of the previous 
approach replacing the time to deterioration of the 3 selected symptoms. QLQ-C30 
Global health status/QoL score change from baseline, QLQ-C30 Functional scores 
change from baseline and QLQ-C30 Symptom scores change from baseline, and QLQ-
LC13 Symptom scores change from baseline were added in the analysis as secondary 
endpoints per EORTCguidance. As exploratory, quality of life items will be analyzed 
per FDA guidance to elaborate an instrument to measure the PRO (described in an 
ancillary SAP). As an example, summary score for the EORTC QLQ-C30 as described 
in the paper from Giesinger, Journal of Clinical Epidemiology 2015 “Replication and 
validation of higher order models demonstrated that a summary score for the EORTC 
QLQ-C30 is robust” will be explored. 
- 
Sensitivity analyses on PFS (described in an ancillary SAP) as described in FDA 
guidance 
(https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/clinical-trial-endpoints-approval-non-small-cell-lung-cancer-drugs-and-
biologics)  
- 
COVID-19 Impact: In the OSE2101C301 study, 110 patients out of the 219 (50.2%) 
were potentially impacted by the pandemic. Out of these 110 patients, 87 (79.1%) were 
included in France, Italy, Spain, or US. Following FDA Guidance on “Conduct of 
Clinical Trials of Medical Products During COVID-19 Public Health Emergency: 
Guidance for Industry, Investigators, and Institutional Review Boards.” and 
“Statistical Considerations for Clinical Trials During the COVID-19 Public Health 


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Emergency: Guidance for Industry”, it is proposed to test COVID-19 impact in the ITT 
population using:  
o Time-dependent OS survival analyses to test the heterogeneity of the periods of 
randomization with or without COVID-19. 
o OS analysis using different cut-off dates for censored data as previously 
proposed (www.ema.europa.eu/en/implications-coronavirus-disease-covid-19-
methodological-aspects-ongoing-clinical-trials; (Degtyarev et al., 2020; Meyer 
et al., 2020) 
- 
Baseline data of first line ICI population versus second line ICI and PoI population 
versus non-PoI population (described in an ancillary SAP). 
 


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4. 
STUDY OBJECTIVES AND ENDPOINTS 
Study objectives and endpoints defined in the protocol include safety and efficacy endpoints. 
Objectives and pre-specified endpoints are as follows.  
4.1. 
Study Objectives 
4.1.1. 
Primary Objective(s) 
The primary objective of the discontinued step-2 is to demonstrate that in the population of 
interest (patients with secondary resistance to ICI), OSE2101 is superior to control treatment 
with respect to OS in HLA-A2 positive patients with advanced NSCLC after failure to platin-
based chemotherapy and ICIs. 
4.1.2. 
Secondary Objectives 
The secondary objectives of the discontinued step-2 are as follows: 
• To compare secondary measures of clinical benefit including Post progression Survival, 
Time to worsening of ECOG, QLQ-C30 Global health status score change from baseline, 
QLQ-C30 Functional scores change from baseline, QLQ-C30 Symptom scores change 
from baseline, QLQ-LC13 Symptom scores change from baseline, DCR at 6 months, DCR 
at 12 months, and Progression-Free Survival (PFS) in the PoI 
• To assess the safety and tolerability of OSE2101 compared to the control treatment in PoI. 
 
Exploratory objectives are to compare other criteria: ORR, Duration of Response, and time to 
next lung cancer therapy in both treatment arms in PoI.  
Safety, tolerability, and efficacy including OS will also be done in ITT overall population as 
exploratory. 
4.2. 
Efficacy Endpoints in step-2  
4.2.1. 
Primary Efficacy Endpoint 
• Overall survival (OS) 
4.2.2. 
Secondary Efficacy Endpoints 
• Post Progression Survival 
• Time to worsening of ECOG  
• QLQ-C30 Global health status score change from baseline 
• QLQ-C30 Functional scores change from baseline 
• QLQ-C30 Symptom scores change from baseline 
• QLQ-LC13 Symptom scores change from baseline 


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• Disease Control Rate (DCR) at 6 months and 12 months 
• Progression-Free Survival (PFS) 
Once the primary objective will be established (null hypothesis rejected at 5% two-sided 
significance level), each of the secondary efficacy endpoints will be tested at 5% significance 
level using a further hierarchical order in the ordering sequence of the list described above to 
control the overall type I error. If the primary objective is not established, these endpoints will 
still be analyzed but interpreted as exploratory endpoints, similarly if one secondary endpoint 
in the sequence is not significant, the lower rank secondary endpoint(s) will be considered 
exploratory. 
4.2.3. 
Exploratory Efficacy Endpoints 
• Time to next lung cancer therapy 
• Objective Response Rate (ORR) 
• Duration of response (DR) 
• All the other scores of the quality of life questionnaires 
 
4.2.4. 
Summary of the primary and secondary endpoints 
The list of primary and secondary endpoints can be summarized as follows: 
 
Population 
Efficacy endpoint 
Status 
PoI-ITT 
OS 
P 
PoI-PP 
OS 
S01 
PoI-ITT 
Post progression Survival  
S02 
PoI-ITT 
Time to worsening of ECOG 
S03 
PoI-ITT 
QLQ-C30 Global health status change from 
baseline 
 
S04 
PoI-ITT 
QLQ-C30 Functional total scores change from 
baseline 
(Physical, 
Role, 
Emotional, 
Cognitive, and Social) 
 
S05 
PoI-ITT 
QLQ-C30 Symptom scores change from 
baseline (Fatigue, Nausea & Vomiting, Pain, 
Dyspnea, 
Insomnia, 
Appetite 
Loss, 
Constipation, 
Diarrhea, 
and 
Financial 
Difficulties) 
S06 
PoI-ITT 
QLQ-LC13 Symptom scores change from 
baseline change from baseline 
S07 
PoI-ITT 
DCR at 6 months 
S08 
PoI-ITT 
DCR at 12 months 
S09 
PoI-ITT 
Progression Free Survival  
S10 


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         P: primary, S: secondary, PoI: Population of Interest 
 
4.3. 
Safety and Tolerability Endpoints 
• The incidence, severity, seriousness, and relationship to study treatment of adverse events 
(AEs) and immune-related adverse events (irAEs) 
• The abnormalities in safety laboratory parameters 
• The abnormalities in vital signs 
• The abnormalities in 12-lead ECGs  
 
5. 
STUDY METHODS 
5.1. 
General Study Design and Plan 
As background for the statistical methods presented below, this section provides an overview 
of the study design and plan of study execution.  
This is an open-label, multicenter, controlled, randomized, parallel group, two-stage design 
phase II/III trial of OSE2101 (Arm A – experimental treatment) versus docetaxel or 
pemetrexed (Arm B – control treatments) as 2nd or 3rd line treatment in HLA-A2 positive 
patients with advanced NSCLC with progressive disease after last treatment with ICI. 
Randomization to Arms A and B was stratified according to histology (squamous vs. non-
squamous), initial response to first line treatment (objective response: complete or partial 
response, vs. no objective response: stabilization or progressive disease), and - from version 
4.1 of the protocol - previous treatment with immune checkpoint inhibitors (used in 1st line vs. 
used in 2nd line). Before this amendment, the 3rd randomization stratification factor was 
previous treatment with immune checkpoint inhibitor (yes vs. no). 
The schedule for assessments and timing of events is presented in Tables 1 and 2 (Arm A and 
Arm B respectively). 
 
 


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Table 1 
Schedule of Time and Events for Arm A 
 


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1 End of treatment: visit to obtain last assessments after the study drug stop from the 4 previous weeks.     
2 Post-treatment follow-up: data collection on survival status and any subsequent cancer therapy (if any) every 2 months after study drug discontinuation until death.  
3 HLA-A2 testing can be done at any time during patient management before inclusion. A pre-screening consent is available to test patients for instance during 1st or 2nd line 
therapy.   
4 EGFR/ALK alterations and PD-L1 expression on tumor tissue: if these results are not available, they have to be done in local or central laboratories during the screening 
period. EGFR/ALK alterations is mandatory before randomization in patients with non-squamous cancer or never/light smokers with squamous cancer. If PD-L1 expression is 
not documented and no tumor tissue available to perform the testing, then the PD-L1 status can be omitted.  
5 Hematology and biochemistry tests: to be done at Day 1 Cycle 1 only if screening assessment done more than 7 days before. Thereafter at Day 1 of each subsequent cycle, 
local laboratory tests will be done every 3 weeks (less than 72 hours (3 days) before study treatment administration) until Cycle 6, then every 8 weeks (less than 4 days before 
study administration) until Cycle 9, then every 12 weeks (less than 8 days before each subsequent administration.   
6 HIV test: to be done for all eligible patients with HIV status unknown.     
7 Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be done every 6 weeks (± 1-week allowance) after Day 1 Cycle 1, meaning it could be between 
2 treatment visits; CT scan of the pelvis will be performed only upon request according to clinical suspicion. In case of clinical suspicion of bone metastasis out of the area 
reported by CT scan, imaging test will be performed under discretion of the investigator and will be repeated every 12 weeks. For Germany, with respect to brain metastases, 
MRI should be the privileged imaging technic and CT should only be considered when there are contra-indications to MRI.  
8 Tumor assessments should be continued until documented RECIST 1.1 disease progression for patients who have not progressed during the treatment period.  
9 OSE2101 treatment will continue until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable toxicity, or consent withdrawal. 
Should pseudo progression or delayed response to treatment suspected in arm A, investigator may continue treatment beyond the time of RECIST-defined progression, if the 
patient is perceived to be experiencing clinical benefit.  
10 Separate informed consent (optional) will be obtained from the patient who agreed to participate in a translational study and authorizing the bio banking of the remaining 
samples to be used for future biomarker research and drug development projects. Patient can agree to participate in all and/or some parts of the translational study. Patient can 
refuse to participate in the translational study without compromising his/her participation in the main study.  
11 Blood samples for biomarkers will be taken at baseline (during the screening period), then every 6 (± 3) weeks until Cycle 7 (e.g., at D1 of Cycles 3, 5 and 7), then every 12 
(± 3) weeks (e.g., at time of imaging) until end of treatment and/or progression.  
12 Specimens from archiving tumor biopsies (at first diagnosis and/or at any time during previous treatment) will be collected. As possible, a new tumor biopsy will be collected 
within 35 days prior to the first study treatment administration (during the screening period). An archiving tumor biopsy collected before the screening period is acceptable, 
should the biopsy be collected after the end of ICI treatment. A second tumor biopsy (e.g., in the same tumor site) will be undertaken between Cycle 3 and Cycle 6 and/or at 
time of the disease progression. A blood sample will be collected for Whole-Exome sequencing (WES) at screening.   
 


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Table 2 
Schedule of Time and Events for Arm B 
 


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1 End of treatment: visit to obtain last assessments after the study drug stop from the 4 previous weeks.   
2 Post treatment follow-up: data collection on survival status and any subsequent cancer therapy (if any) every 2 months after study drug discontinuation until death.  
3 HLA-A2 testing can be done at any time during patient management before inclusion. A pre-screening consent is available to test patients for instance during 1st or 2nd line 
therapy.   
4 EGFR/ALK alterations and PD-L1 expression on tumor tissue: if these results are not available, they have to be done in local or central laboratories during the screening 
period. EGFR/ALK alterations is mandatory before randomization in patients with non-squamous cancer or never/light smokers with squamous cancer. If PD-L1 expression is 
not documented and no tumor tissue available to perform the testing, then the PD-L1 status can be omitted.  
5 Hematology and biochemistry tests: to be done at Day 1 Cycle 1 only if screening assessment done more than 7 days before. Thereafter at Day 1 of each subsequent cycle, 
local laboratory tests will be done every 3 weeks (less than 72 hours (3 days) before study treatment administration) until Cycle 6, then every 8 weeks (less than 4 days before 
study administration) until Cycle 9, then every 12 weeks (less than 8 days before each subsequent administration.   
6 HIV test: to be done for all eligible patients with HIV status unknown.   
7  Tumor assessments (CT scan of thorax, abdomen and brain CT or brain MRI) to be done every 6 weeks (± 1-week allowance) after Day 1 Cycle 1 meaning it could be between 
2 treatment visits; CT scan of the pelvis will be performed only upon request according to clinical suspicion. In case of clinical suspicion of bone metastasis out of the area 
reported by CT scan, imaging test will be performed under discretion of the investigator and will be repeated every 12 weeks. For Germany, with respect to brain metastases, 
MRI should be the privileged imaging technic and CT should only be considered when there are contra-indications to MRI.  
8 Tumor assessments should be continued until documented RECIST 1.1 disease progression for patients who have not progressed during the treatment period.  
9 Docetaxel and pemetrexed treatment will continue until unequivocal RECIST 1.1-defined disease progression as determined by the investigator, unacceptable toxicity, or 
consent withdrawal. Premedication is required with docetaxel and pemetrexed. Premedication will occur before Day 1 (i.e., Day 1 of each cycle will be injection day for 
chemotherapy).  
10 Separate informed consent (optional) will be obtained from the patient who agreed participating in a translational study and authorizing the bio banking of the remaining 
samples to be used for future biomarker research and drug development projects. Patient can agree to participate in all and/or some parts of the translational study. Patient can 
refuse to participate in the translational study without compromising his/her participation in the main study.  
11 Blood samples will be taken at baseline (during the screening period), then every 6 (± 3) weeks until Cycle 7 (i.e., at D1 of Cycles 3, 5 and 7), then every 12 (± 3) weeks (e.g., 
at time of CT imaging) until end of treatment and/or progression.   
12 Specimens from archiving tumor biopsies (at first diagnosis and/or at any time during previous treatment) will be collected. As possible, a new tumor biopsy will be collected 
within 35 days prior to the first study treatment administration (during the screening period). An archiving tumor biopsy collected before the screening period is acceptable, 
should the biopsy be collected after the end of ICI treatment. A second tumor biopsy (e.g., in the same tumor site) will be undertaken between Cycle 3 and Cycle 6 and/or at 
time of the disease progression. A blood sample will be collected for Whole-Exome sequencing (WES) at screening.


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5.2. 
Inclusion – Exclusion Criteria and General Study Population 
The inclusion and exclusion criteria defined in the protocol apply to all subjects and are not 
repeated herein the SAP.  
5.3. 
Randomization and Blinding 
All eligible and consented subjects will receive OSE2101 (Arm A) or docetaxel or pemetrexed 
(according to histology and previous treatment) (Arm B).  
The final analysis of step-2 will include a combination of patients recruited before amendment 
(ratio=1:1; 38 patients) and after amendment in 2017 (ratio=2:1, 181 patients). 
5.4. 
Analysis Variables 
Variables to be analyzed include demographics and baseline characteristics, safety variables 
(adverse events, concomitant medications, clinical laboratory investigations, vital signs, 
ECOG and ECG), efficacy variables (tumor assessments and survival status), and quality of 
life variables. 
6. 
SAMPLE SIZE 
Step 2 – Phase III sample size for all ICI population 
 
The initial hypotheses in the protocol version 4.0 were: “To reach a power of 80% for the two-
sided log rank test at the 5% significance level when assuming a median OS of 7 months for 
the control and 10 months for the experimental arm, a total of 278 events is required 
(HR=0.70). If the new patients are uniformly included over an accrual period of 36 months 
followed by a follow-up of 6 months after the last inclusion, observing 278 events would 
require a total of 363 new patients.” 
The Phase 3 sample size consists in 219 patients. With this final sample size of 219 patients, 
the power decrease to 62% with the same hypotheses (HR=0.70). 
Considering Step 1 results, statistical hypotheses have been revised to address the PoI as 
follow: 
Assuming a HR of 0.55 consistent with that observed in Step-1 (HR stratified =0.67, HR 
unstratified = 0.52) with a 7 months OS in the SoC group (unchanged as initially planned in 
the protocol), a total of 90 events in the PoI will provide a power of 80% and a 2-sided logrank 
test at a 5% two-sided level, if the patients are included over an accrual period of 48 months 
followed by a follow-up of 6 months after the last inclusion.  
 
 


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7. 
GENERAL CONSIDERATIONS 
7.1. 
Analysis Sets 
Six different analysis sets are defined in the post ICI population (N=219). The 3 analysis sets 
will be duplicated in the population of interest and in the overall post ICI population. 
For safety analyses, baseline is the first dose of study treatment and for « baseline 
characteristics » section, baseline is defined as last value before randomization. 
 
7.1.1. 
Safety Set PoI 
This analysis set includes all patients included in the PoI who were randomized and received 
at least one dose of randomized study treatment. Patients will be analyzed in the group 
according to the treatment they received. All safety data analyses will be analyzed using the 
safety set. 
7.1.2. 
Intent-to-Treat Set PoI (ITT_PoI) 
This analysis set includes all patients included in the PoI and randomized. Patients will be 
analyzed in the group as randomized. All efficacy data analyses will be analyzed using the 
ITT_PoI set. 
7.1.3. 
Per-Protocol Set PoI (PP_PoI) 
This analysis set includes all patients of the ITT_PoI set who did not violate the protocol in a 
way that might affect the evaluation of the effect of the study drugs on the overall survival. 
The patients to be excluded from the PP_PoI set will be identified before performing the 
analysis. Selected sensitivity efficacy data analyses will be performed using the PP_PoI set. 
7.1.4. 
Safety Set 
This analysis set includes all patients included who were randomized and received at least one 
dose of randomized study treatment. Patients will be analyzed in the group according to the 
treatment they received. All safety data analyses will be analyzed using the safety set. 
7.1.5. 
Intent-to-Treat Set (ITT) 
This analysis set includes all patients included and randomized. Patients will be analyzed in 
the group as randomized. All efficacy data analyses will be analyzed using the ITT set. 


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7.1.6. 
Per-Protocol Set (PP) 
This analysis set includes all patients of the ITT set who did not violate the protocol in a way 
that might affect the evaluation of the effect of the study drugs on the overall survival. The 
patients to be excluded from the PP set will be identified before performing the analysis. 
Selected sensitivity efficacy data analyses will be performed using the PP set. 
The exclusion of patients from the PP_PoI and PP sets was prepared using the minutes and the 
deviations report of the blind review meeting that was held on 08 April 2021. 
7.2. 
Subgroups 
The following variables will be used to define subgroups: 
 
Stratification criteria 
- 
Histology (squamous vs. non-squamous), 
- 
Best response to 1st line treatment (CR/PR vs. SD/PD) 
- 
Line rank of ICI therapy (2nd line vs. 1st line)* 
 
Other criteria 
- 
Gender (male vs. female) 
- 
Age (< 75 vs. ≥ 75) 
- 
Age (< 65 vs. ≥ 65) 
- 
Smoking status: never, former, or current smoker 
- 
Baseline ECOG score (0 vs. 1)  
- 
Best response to 1st line treatment (CR/PR/SD vs. PD) 
- 
Best response to 1st line treatment (CR/PR vs SD vs. PD) 
- 
Best response to ICI therapy (CR/PR vs. SD vs PD) 
- 
Best response to ICI therapy (CR/PR/SD vs. PD) 
- 
Duration of previous ICI therapy (weeks: 0-12, > 12-24, > 24 weeks)* 
- 
Duration of previous ICI therapy (weeks: 0-12, > 12 weeks)* 
- 
Time from end of ICI to study treatment initiation (weeks: 0-6, 6-12, > 12 weeks)  
- 
Time from end of chemotherapy to study treatment initiation (weeks: 0-24, 24-48, > 48 
weeks) 
- 
Duration of previous ICI therapy (>12 weeks) and Line rank of ICI therapy (2nd line)* 
- 
Duration of previous ICI therapy (>12 weeks) and Line rank of ICI therapy (1st line)* 
- 
Liver metastases at study entry (presence vs. absence) 
- 
Brain metastases at study entry (presence vs. absence) 
- 
Pleural metastases at study entry (presence vs. absence) 
- 
Number of different metastasis locations (0, 1, 2, ≥ 3) 
- 
Cancer staging at study entry (III vs. IV) 
- 
dNLR (derived Neutrophils/(Leukocyte minus neutrophils Ratio)) at baseline (< 3 vs ≥ 3) 
- 
LDH Classification at baseline (<= upper limit of normal range (ULN), > ULN) 
- 
PDL1 (Positive, Negative, Unknown) 


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- 
Albumin Classification at baseline (<35g/l, ≥35g/l) 
 
*: only in ITT or PP populations and not in ITT_PoI or PP_PoI 
 
'dNLR (derived Neutrophils/(Leukocyte minus neutrophils Ratio))' must be read as 'dNLR 
(derived Neutrophils/(Leukocyte minus Neutrophils) Ratio)' 
Additional subgroups will be explored in the ancillary SAP. 
7.3. 
Management of Analysis Data 
7.3.1. 
Missing Data 
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the electronic case report form (e-CRF) will be included in data listings that will 
accompany the clinical study report. 
7.3.1.1. 
Handling of Missing Date Values 
Partial or Missing Dates 
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications, if warranted.  Note that the imputed values outlined here may 
not always provide the most conservative date.  In those circumstances, the imputed value may 
be replaced by a date that will lead to a more conservative analysis. 
A. 
Start Dates 
1) 
If the year is unknown, then the date will not be imputed and will be 
assigned a missing value.  
2) 
If the month is unknown, then: 
i) If the year matches the first dose date year, then impute the 
month and day of the first dose date. 
ii) Otherwise, assign ‘January.‘  
3) 
 If the day is unknown, then: 
i) If the month and year match the first dose date month and year, 
then impute the day of the first dose date. 
ii) Otherwise, assign the first day of the month. 
B. 
Stop Dates 
1) 
If the year is unknown, then the date will not be imputed and will be 
assigned a missing value. 
2) 
If the month is unknown, then assign ‘December.’ 
3) 
If the day is unknown, then assign the last day of the month. 


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Unless having an end date before the first administration of the study drug, an adverse event 
with a completely missing start date will be interpreted as started between the first dose date 
included and 28 days after last administration of the study treatment (included) or the analysis 
cut-off date included, whichever comes first. 
No imputation should be used for the start date of immune-related adverse events recorded in 
medical history (MH2 VIEDOC dataset). 
A medication with a completely missing start date will be interpreted as started before the first 
dose date. 
A medication with a completely missing end date will be interpreted as ongoing at the time of 
data extraction (and therefore being not stopped before the first dose). 
 
7.3.1.2. 
Imputation Methods 
No safety or efficacy data will be imputed for this study. All data will be observed cases, 
without imputation, except specified otherwise (as for time to worsening of ECOG or quality 
of life sensitivity analyses as examples). 
7.3.2. 
Coding Conventions for Events and Medications 
All adverse events, and medical history will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA Version 20.1) system for reporting (preferred term and body 
system). 
Prior and Concomitant medications will be coded using WHO-DD (Drug Dictionary) (Version 
March 2018). 
7.3.3. 
Analysis Software 
Data manipulation, tabulation of descriptive statistics, calculation of inferential statistics, and 
graphical representations will be performed primarily using SAS (release 9.4 or higher) for 
Windows.  If the use of other software is warranted, the final clinical study report will detail 
what software was used and for what purposes. 
7.3.4. 
Study Data 
Study data identified in the schedule for time and events in the Protocol are collected, and 
source verified, on the electronic data capture tool: VIEDOC (PCG Solutions, Uppsala, 
Sweden).  
All study data will be formulated into regulatory compliant data sets to provide transparency, 
traceability, and integrity of trial analysis results from the collection source. Observed study 
data will be mapped to the CDISC Study Data Tabulation Model (SDTM) and serve as the 


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source data from the trial.  All study analyses will be completed using analysis data sets that 
are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) architecture.  
The methods for programming the CDISC SDTM and ADaM data sets are described in Figure 
1. 
Figure 1 
SDTM, ADaM, and TFL Development and Validation 
 
Where: 
1. Development, Validation, and Maintenance of SDTM Domains 
2. Development and Validation of Analysis Data Sets (ADaM), with input source the 
appropriate SDTM domains. 
3. Development and Validation of Tables, Figures, and Listings (TFL), with input data 
source the SDTM domains and analysis specific ADaM data sets. 
7.4. 
Planned Study Analyses 
7.4.1. 
Statistical Summaries: Descriptive and Inferential 
All statistical tests will be two-sided and a difference resulting in a p-value of less than or equal 
to 0.05 will be considered statistically significant (although possibly of exploratory nature).  
All p-values will be rounded to and displayed in four decimals.  If a p-value less than 0.0001 
occurs it will be shown in tables as <0.0001. 


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Descriptive summaries of variables will be provided where appropriate.  For continuous 
variables, the number of non-missing values (n), mean, standard deviation, median, minimum, 
and maximum will be tabulated by treatment.  For categorical variables, the counts and 
proportions of each value will be tabulated by treatment.  Expansion of descriptive table 
categories within each treatment may occur if such elaborations are thought to be useful. 
All study related data collected will be presented in listings.  Study related data not subject to 
analysis according to this plan will not appear in any tables or graphs but will be included in 
the data listings. 
7.4.2. 
Interim Analyses and Data Monitoring 
No interim analysis of the primary endpoint was planned. 
However, OS rate at 12 months was to be analyzed on Arm A at end of Step 1 before a decision 
to stop or continue enrollment in Step 2 could be made by the Steering Committee after 
recommendation by the IDMC. This analysis was considered as a futility analysis. 
Consequently, no adjustment for multiplicity (as combination test for example) was considered 
for the primary analysis of step 2. 
The enrolment stop because of the foreseen impact of the COVID-19 pandemic on the primary 
endpoint of the step 2 was not planned. 
7.4.3. 
Final Analysis and Publication of Study Results 
This analysis (cut-off date: 15 January 2021 - 219 post ICI patients) is considered as an update 
of the step 1 analysis. This CSR will be complemented by an addendum with this analysis.   


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8. 
SUMMARY OF STUDY DATA 
All the analyses described in this section will be duplicate in the population of interest and in 
the overall population. 
8.1. 
Subject Disposition 
A summary of the analysis sets considered in the CSR will include the number and percentage 
of subjects for the following categories: subjects randomized, subjects in the ITT sets, subjects 
not treated, subjects in the Safety sets, and subjects having permanently discontinued the study 
treatment, subjects in the PP sets. All percentages will be based on the number of subjects 
randomized.  
A table will present by treatment arm on the ITT sets the primary reason for not being treated 
and the primary reason for permanent treatment discontinuation (with sub-counts of patients 
having entered the follow-up and patients having not entered the follow-up). 
A table will present by treatment arm on the ITT sets the number and percentage of patients 
randomized by month. 
8.2. 
Patients Randomized by Month 
The number and percent of subjects randomized will be summarized by month by treatment 
arm for the ITT sets. 
8.3. 
Protocol Deviations 
Protocol deviations on inclusion/exclusion criteria will be summarized by treatment arm on 
the ITT sets. 
Major protocol deviations, as finalized during the blinded review of the data prior to database 
lock (organized by the Sponsor with the participation of two coordinating investigators and of 
one independent expert) may result in the removal of subjects from the PP sets. The Sponsor 
or designee will be responsible for producing the final major deviation file; this file will include 
a description of the protocol deviation leading to the exclusion from the PP sets. This file will 
be finalized prior to database lock, and all information will be included in the SDTM.DV 
domain (deviations domain). A summary table of the major protocol deviations will be 
generated on the ITT sets. 
8.4. 
Demographics and Baseline Characteristics 
Subject demographic data and baseline characteristics will be tabulated and summarized 
descriptively by treatment arm and overall.  The demographic data and baseline characteristics 


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will be summarized for the ITT sets. Individual subject demographics and baseline 
characteristics will be provided in listings. 
The demographics consist of age, gender, race, ethnicity, smoking status, BMI, BMI 
classification and country.  
The country will be derived from the 2 leading digits of the site as follows: 
Leading digits of 
site identification 
Country 
11 
Czech Republic 
12 
France 
13 
Germany 
14 
Hungary 
15 
Italy 
16 
Poland 
17 
Spain 
18 
United Kingdom 
19 
USA 
22 
Israel 
 
The baseline characteristics consist of: 
• Histology (Squamous/Non-Squamous) 
• Initial (i.e., best) response to 1st line treatment (CR/PR, SD/PD) 
• Previous treatment with ICI 
• Line rank of previous treatment with ICI 
• Previous Pemetrexed treatment 
• Line rank of study treatment 
• Previous radiotherapy combined with chemotherapy 
• Best response during 1st line therapy 
• Time from  end of previous line of therapy to study treatment initiation (weeks) 
• Best response during ICI therapy 
• Time from end of ICI to study treatment initiation (weeks) 
• Time from  end of chemotherapy to study treatment initiation (weeks) 
 
• Duration of ICI therapy (weeks: 0-12, >12-24, > 24) 
• Cancer staging at diagnosis (I/II, IIIA/IIIB/IIIC, IVA/IVB) 
• Cancer staging at study entry (III, IV) 
• T classification at diagnosis 


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• N classification at diagnosis 
• M classification at diagnosis 
• M classification at study entry 
• Location of metastases at diagnosis 
• Location of metastases at study entry 
• Number of different metastasis locations 
• ECOG score at baseline 
• HLA-A2 (negative, positive) as documented in NSCLC disease history 
• EGFR (negative, positive) as documented in NSCLC disease history 
• PD-L1 (negative, positive) as coded in the Data Management manually derived variable 
DIS_HIST.PDL1_POSNEG_D 
• Albumin Classification at baseline (< 35 g/L/>= 35 g/L) 
• LDH Classification at baseline (<= upper limit of normal range (ULN), > ULN) 
• dNLR at baseline (< 3 vs ≥ 3) 
• Antibiotic treatment within 30 days before randomization 
• Corticosteroid treatment within 30 days before randomization 
For the baseline characteristics, the baseline is defined as the last value available up to the date 
of randomization included. 
Previous medications for NSCLC were reviewed before database lock and identified as ICI, 
chemotherapy other than pemetrexed, pemetrexed, other. To get the drug name of the ICI 
treatment, a manually prepared Excel file (‘210415 Previous ICI description.xlsx') will also be 
used. This Excel file provides for each patient the name (variable ICI_DCI) and the class 
(variable Class) of the ICI treatment and a technical variable (ICI_DCI_link) allowing to match 
the other ICI information recorded in PRIOTHER. 
The line rank of ICI therapy was manually derived by Data Management after medical and 
clinical review of each patient prior medications. The category '3rd line therapy', recorded for 
one patient, will be displayed in the description of baseline characteristics but pooled with the 
category '2nd line therapy' in the overall survival subgroup analyses. 
To derive Best response during ICI therapy, Time since end of ICI therapy, Duration of ICI 
therapy, additional information about the ICI (best response, start date, end date) will be 
recovered by respectively retaining the best "best response" across records, the earliest start 
date across records, and the latest end date across records. 
An additional table will be provided presenting per arm and overall, the two variables Best 
response during ICI therapy crossed with duration of ICI therapy (weeks: 0-12, >12-24, > 24). 
The dataset DIS_HIST was collecting cancer stage according to TNM V7.0 until June 2017, 
i.e., during the first part of the study. The study restarted in June 2018. In the meantime, 
protocol 5.0 dated 15 March 2018 had introduced the use of TNM V8.0. Therefore, the dataset 
DIS_HIST collected cancer stage according to TNM V8.0 for all patients of the second part of 
the study. Therefore, cancer stage was reviewed and sometimes updated by clinical expert 


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before database lock. Reclassified cancer staging value will be analyzed, categorized as 
follows: 
• Cancer stage at diagnosis: (I/II) mapped to 'I/II', (IIIA, IIIB, IIIC) mapped to 'IIIA/IIIB/IIIC', 
(IV, IVA, IVB) mapped to 'IVA/IVB' 
• Cancer stage at study entry: (IIIB, IIIC) mapped to 'III', (IV, IVA, IVB) mapped to 'IV', (IIIA, 
Other) mapped to 'Other'. 
The category 'Other' will be displayed in the description of baseline characteristics but not 
retained in the overall survival subgroup analyses. 
Liver, Bone, and Brain will be counted as a metastasis location if the number of metastases 
reported is in (1, 2, 3, >3, NS). Other will be counted as a metastasis location if the number of 
metastases reported is in (1, 2, 3, >3, NS) for at least one of the 'Other' locations. Adrenal will 
be counted as a metastasis location if reported as ('Unilateral','Bilateral',NS). Pleura will be 
counted as a metastasis location if reported as 'Present'.  
'Number of different metastasis locations' must be understood as 'Number of different 
metastasis locations' at study entry'. This number is left missing if the M classification at study 
entry is missing. 
Protocol section 4.3.3 requires that patients of arm B take dexamethasone (a corticosteroid) 
twice daily before, the day of and the day after study drug (docetaxel or pemetrexed). 
Therefore, comparing the 2 treatment arms on presence/absence of corticosteroids on the day 
before randomization or on the day of randomization is biased. 'Corticosteroid treatment within 
30 days before randomization' is changed to 'Corticosteroid treatment within 2 to 30 days 
before randomization'. 
The Data Management manually derived variables WHODRUG.ANTIBIO_D and 
WHODRUG.CORTI_D identify systemic antibiotic treatments and corticosteroid treatments 
without selection on their administration dates. Start and end dates of these treatments will be 
checked versus the randomization date to identify antibiotic treatment within 30 days before 
randomization and corticosteroid treatment within 2 to 30 days before randomization. 
8.5. 
Previous ICI Treatment 
The number and percentages of patients by previous ICI treatment will be summarized on the 
ITT sets by treatment arm, Anatomical Therapeutic Chemical (ATC) level 4 (sorted according 
to the corresponding 5-digit ATC code), and PT. The previous ICI treatment information will 
be taken from information entered (not necessarily in a consistent way with the actual ICI line 
rank) for 1st line therapy, 2nd line therapy or 3rd line therapy in prior medications for NSCLC 
based on the Data Management manually derived variable PRIOTHER.LINE_ICI_D. 
A listing describing for the most used ICI treatments as nivolumab, pembrolizumab, 
atezolizumab, avelumab, durvalumab with a complete description will be provided (dose, 
treatment duration, response, …). 


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The description of the previous ICI treatment by class will be prepared from the Excel file 
('200720 Previous ICI description.xlsx') as described in section 8.4 under 'Addition or change 
after 04 June 2020'. 
8.6. 
History of Immune-Related Adverse Events 
The number and percent of subjects with a history of irAEs will be summarized by irAE 
category and preferred term by treatment arm for the ITT sets. The same presentation will be 
used to summarize the irAEs ongoing at screening. 
8.7. 
Randomization Stratification Factors 
Randomization stratification factors will be tabulated and summarized descriptively by 
treatment arm and overall, for the ITT sets.  
The following strata will be summarized: 
• Squamous/Non-squamous 
• Objective response/No objective response 
• First line therapy/Second line therapy. 
The values reported for the stratification factors will be those possibly corrected by the site 
after time of randomization and therefore may be different of the values used for the 
randomization. For analyses, corrected from eCRF (and not IWRS) values will be used. 
For the 38 ICI patients randomized before the amendment (i.e., at a time where the stratification 
factor First line therapy/Second line therapy was not yet applicable), the Data Management 
manually derived IC.RANDIMM2_1_D will be used in place of IC.RANDIMM2_1 (the data 
field IC.RANDIMM2_1was not existing in the database at the time the "Old" ICI were 
randomized). 
Randomization stratification factors as entered in the IVRS/IWRS at time of randomization 
will also be tabulated and summarized descriptively by treatment arm and overall, for the ITT 
set, separately for patients randomized before the amendment and patients after the 
amendment. Within each subset of patients (randomized before/after amendment), the 
randomization stratification factors as entered in the IVRS/IWRS for each randomized patient 
will be derived from the leading digit of the corresponding randomization number. 
For patients randomized before the amendment the correspondence is as follows: 


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Leading digit 
Histology 
Initial response to 1st 
line treatment 
Previous 
treatment 
with 
ICI 
1 
Squamous 
Objective response 
Previous ICI 
2 
Squamous 
Objective response 
No previous ICI 
3 
Squamous 
No objective response 
Previous ICI 
4 
Squamous 
No objective response 
No previous ICI 
5 
Non-Squamous Objective response 
Previous ICI 
6 
Non-Squamous Objective response 
No previous ICI 
7 
Non-Squamous No objective response 
Previous ICI 
8 
Non-Squamous No objective response 
No previous ICI 
 
For patients randomized before the amendment the correspondence is as follows: 
Leading digit 
randhist_1r 
randrsp_1r 
randimm2_1r 
1 
Squamous 
Objective response 
1st line ICI 
2 
Squamous 
Objective response 
2nd line ICI 
3 
Squamous 
No objective response 
1st line ICI 
4 
Squamous 
No objective response 
2nd line ICI 
5 
Non-Squamous Objective response 
1st line ICI 
6 
Non-Squamous Objective response 
2nd line ICI 
7 
Non-Squamous No objective response 
1st line ICI 
8 
Non-Squamous No objective response 
2nd line ICI 
 
A patient listing will display the patients with stratification factors discrepancies between the 
values entered in the IVRS/IWRS and values corrected by the site after time of randomization. 
The second table in this section applies to patients randomized after the amendment (not 
before). In this table ‘randhist_1r’, randrsp_1r, and randimm2_1r respectively correspond to 
Histology, Initial response to 1st line treatment, and line rank of ICI therapy. 
8.8. 
Medical History 
The number and percent of subjects with individual concurrent illness and medical histories 
will be summarized by treatment arm.  Individual subject listings will also be provided for 
concurrent illness and medical history. 


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Medical history will be coded using MedDRA Version 20.1. 
The number and percentage of subjects with any medical history will be summarized overall 
and for each system organ class (SOC) and preferred term (PT). Percentages will be calculated 
based on number of subjects in the ITT sets. 
Subject medical history data including specific details will be presented in a listing. 
8.9. 
Concomitant Medications 
A concomitant medication is defined as any medication taken on or after the day of first 
exposure to study drug up until 28 days after last dose of study drug. 
Prior medications are defined as any medication that is taken prior to the day of first exposure 
to any study drug. 
The number and percentages of all concomitant medications will be summarized on the ITT 
sets and by treatment arm, Anatomical Therapeutic Chemical (ATC) level 1 (sorted according 
to the corresponding first letter of the 5-digit ATC code), and Preferred Term.  The number 
and percentages of subjects with at least one concomitant medication will be summarized by 
treatment arm. 
Medications received for the disease after stopping study drug will summarized on the ITT sets 
by treatment arm using the same presentation. 
The total number of concomitant medications present at baseline (day of first exposure to 
study) and the corresponding number and percentages of subjects will also be summarized by 
treatment arm. 
Since treatment received for the disease after stopping drug is not limited to medications (it 
includes radiotherapy), the text ‘Medications received for the disease after stopping study drug 
will summarized on the ITT sets by treatment arm using the same presentation.’ should be 
changed to ‘Treatments received for the disease after stopping study drug will be summarized 
on the Safety set by treatment arm using the presentation (using ATC level 1 and PT for 
medications and SOC and PT for non-drug treatments)’. 
8.10. 
Treatment Compliance 
The number of days between first and last exposure to treatment up to the analysis cut-off date, 
the total administered dose up to the analysis cut-off date and the corresponding dose intensity 
– calculated as total administered dose as a proportion of total planned dose – will be 
summarized by treatment arm for the Safety sets. The total dose will be reported separately for 
each of the two treatments in arm B (docetaxel, pemetrexed). The descriptive statistics of the 
number of cycles where the study drug was administered received up to the analysis cut-off 
date will be summarized by treatment arm. 


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8.11. 
Time Intervals 
8.11.1. 
Time Intervals between Cycles 
Descriptive statistics by treatment arm of the number of weeks between Cycle 1 Day 1 and the 
randomization and then between each of the other Cycle Day 1 visits and the preceding Cycle 
Day 1 visit will be presented by treatment arm on the ITT sets. Cycles performed after the 
analysis cut-off date will be ignored. Patients with a cycle delayed more than 7 days after the 
theoretical date defined for the treatment arm will be listed. 
Cycles taken into account will be those with a study drug administration recorded. 
8.11.2. 
Survival Data Collected on the Censored Patients and Duration of Follow-
up 
Descriptive statistics by treatment arm of the weeks since randomization and days between last 
survival information and date of database extraction will be prepared on the censored patients 
(excluding withdrawals of consent) for the ITT sets. For patients with survival information 
collected after the analysis cut-off date witnessing that they were alive at the time of the cut-
off date, weeks since randomization are counted to the cut-off date and days between last 
survival information and date of database extraction is counted as 0 days. 
Duration of Follow-up will be presented using reverse Kaplan Meier methodology. This  
method  is  calculated  in  the  same  way  as  the  Kaplan-Meier estimate of the survival 
function, but with the meaning of the status indicator reversed so that our event of interest  
becomes the censor, and the censor becomes event. 
8.11.3. 
Time Intervals between RECIST Assessments 
Descriptive statistics by treatment arm of the number of weeks between the first post-baseline 
RECIST assessment and the randomization and then between each of the other post-baseline 
RECIST assessments and the preceding assessment will be presented on the ITT set. 
Assessments performed after the analysis cut-off date will be ignored. 
8.11.4. 
Time Intervals between Quality of Life Assessments 
Descriptive statistics by treatment arm of the number of weeks between the first post-baseline 
QOL questionnaire and the randomization and then between each of the other post-baseline 
QOL questionnaires and the preceding QOL questionnaire will be presented on the ITT set. 
Questionnaires completed after the analysis cut-off date will be ignored. 


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9. 
EFFICACY ANALYSES 
Unless otherwise noted, all efficacy analyses will be completed using the ITT sets and in PP 
sets only for primary endpoint analyses. All efficacy analyses will be completed using the 
treatment arms as assigned by the randomization. 
9.1. 
Overall Survival (OS)   
For the ITT sets, OS is defined as time from randomization to death, expressed in months, will 
be censored at the analysis cut-off date (15JAN2021). For instance, a patient with last news = 
alive after the cut-off date will be censored at the cut-off date, a patient with death after the 
cut-off date be counted as alive (but censored) at the cut-off date. [Note to programmers: the 
OS time and censoring flag derived without using the analysis cut-off date will also be derived 
and kept as supplementary records in the ADTTE ADaM dataset] 
OS will be summarized using the Kaplan-Meier method and displayed graphically. The median 
and Q1, Q3 event times for each treatment arm and the corresponding 2-sided 95% confidence 
interval will be provided. 
A 2-sided log-rank test stratified for the randomization stratification factors will be used to 
compare OS between the two treatment arms. The Cox regression model, stratified for the 
same stratification factors, will be fitted, and the estimated hazard ratio and 2-sided 95% 
confidence interval will be provided. The hazard ratio, as estimated in this Cox regression 
model, will be provided with its 2-sided 95% CI on the Kaplan-Meier plot. 
A two-sided unstratified log-rank test and an unstratified Cox regression model will also be 
used as additional secondary analyses for OS. 
The six-month survival rate will be estimated using the Kaplan-Meier method and a 2-sided 
95% confidence interval for the log [-log(6-months survival probability)] will be calculated 
using a normal approximation and then back transformed to give a confidence interval for the 
6-months survival rate itself. The 12-month survival rate will be estimated similarly. 
These analyses will be implemented by the following example SAS® code: 
Log-rank test stratified: 
 
proc lifetest; 
 strata factor1 factor2 factor3 / group= trt; 
 time time*cnsr(1); 
run; 
 
Log-rank test unstratified: 
 
proc lifetest; 


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 strata trt; 
 time time*cnsr(1); 
run; 
 
Cox model stratified: 
 
proc phreg; 
 class trt(ref="1");*1 = control group; 
 model time*cnsr(1) = trt / ties=exact rl; 
 strata factor1 factor2 factor3; 
run; 
 
Cox model unstratified: 
 
proc phreg; 
 class trt(ref="1");*1 = control group; 
 model time*cnsr(1) = trt / ties=exact rl; 
run; 
 
NB: ties=exact may be replaced by ties=efron in case of calculation issues. 
 
All survival analyses described above will be repeated on the PP set (OS). 
Subgroups analyses of OS will be performed on the ITT sets to determine whether treatment 
effect is consistent among subgroups. More specifically, results of the subgroup analyses will 
be displayed in a forest plot including: 
• For each subgroup level, the number of events, the sample size, the median survival time 
(months) and the estimate of the treatment effect (HR) with its 95% confidence interval as 
obtained for a separate unstratified and stratified Cox model within each subgroup level. 
• The logarithmic scale used to graphically represent the treatment effect estimates and their 
95% confidence interval will be restricted to 0.20 - 5.00 (a few confidence intervals may 
overflow these limits). 
• A p-value for the interaction test obtained from the unstratified Cox model including terms 
for “subgroup”, “treatment”, “treatment by subgroup” interaction. 
• A vertical reference line displayed at the level of the overall treatment effect. 
• The subgroup analysis will not be performed in subgroups with less than 10 patients (for 
variables with more than 2 levels, the level with the sample size below 10 may be collapsed 
with one of the adjacent levels, if appropriate). 
Additionally, multivariate Cox regression models, stratified for the same stratification factors 
as used for the randomization, will be used on the ITT sets to explore the potential joint 
influences of the other factors (those defining subgroups in the text above) on the primary OS 
endpoint. If deemed appropriate backward selection of variables will be used. 
The results of the subgroup analyses will be detailed in a summary table and summarized in a 
forest plot. The forest plot will present for each subgroup variable the p-value of the interaction 
test and for within each subgroup level the sample size by treatment arm, the median survival 


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time (months) by treatment arm with is 95% confidence interval, the HR with is 95% 
confidence interval. Same information will be provided in the Figures presenting the Kaplan-
Meier curves. 
9.2. 
Progression-free Survival (PFS)   
Progression-free survival (PFS) will be defined as time (in months) from randomization to the 
first documented disease progression (as defined using the RECIST 1.1 criteria and FDA 
Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and 
Biologics, Guidance for Industry, April 2015) or death whichever occurs first. 
The PFS derivation rule is as follows (ignoring information collected after the analysis cut-off 
date): 
• Check whether a candidate time point (for event or censoring) is more than 14 weeks (2 
times 6+1 weeks) after the last available tumor assessment before this time point;  apply 
Table C1 of FDA guidance: 
o No baseline tumor assessment: censored at randomization (0 days after randomization) 
o Progression documented in tumor assessment or in Survival Follow-up form or in End 
of Treatment form: 
▪ If previous tumor assessment without progression ≤ 14 weeks before: PD 
▪ If previous tumor assessment without progression > 14 weeks before: censored at 
previous tumor assessment without progression  
o Death without post-baseline tumor assessment   
▪ ≤ 14 weeks after randomization: event at date of death   
▪ > 14 weeks after randomization: censored at randomization 
o Death with at least 1 post-baseline tumor assessment   
▪ if previous tumor assessment without progression ≤ 14 weeks before: event at date of 
death   
▪ if previous tumor assessment without progression > 14 weeks before: censored at 
previous tumor assessment without progression ("more than one missed visit”) 
o new anticancer treatment started without documented progression recorded: 
censored at previous tumor assessment without progression 
o no documented progression, no death, no new anticancer treatment started: 
censored at previous tumor assessment without progression 
Since the protocol plans for a tumor assessment every 6 weeks (± 1 week) until documented 
RECIST 1.1 progression, the 14 weeks (98 days) mentioned above correspond to 'more than 
one missed visit' used in Table C1 in Appendix C of the FDA guidance 'FDA Clinical Trial 
Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics, Guidance 
for Industry, April 2015'. Other censoring strategies described in the guidance will be explored 
in the SAP appendix. 
As described in Appendix 3 of the FDA guidance 'Clinical Endpoints for the Approval of 
Cancer Drugs and Biologics, May 2007', clinical progression is not considered a progression 
endpoint. 


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In case of conflicting information between RECIST records indicating no progression of 
disease and EOT form or survival form reporting a 'documented clinical progression', the worst 
value (progression) will be retained in the PFS derivation. 
PFS will be summarized using the Kaplan-Meier method and displayed graphically. The 
median event time for each treatment arm and the corresponding 2-sided 95% confidence 
interval will be provided. 
A 2-sided log-rank test stratified for the randomization stratification factors will be used to 
compare PFS between the two treatment arms. The Cox regression model, stratified for the 
same stratification factors, will be fitted, and the estimated hazard ratio and 2-sided 95% 
confidence interval will be provided. The hazard ratio, as estimated in this Cox regression 
model, will be provided with its 2-sided 95% confidence interval on the Kaplan-Meier plot. 
The six-month PFS rate will be estimated using the Kaplan-Meier method and a 2-sided 95% 
confidence interval for the log [-log(6-months survival probability)] will be calculated using a 
normal approximation and then back transformed to give a confidence interval for the 6-
months PFS rate itself. The 12-month PFS rate will be estimated similarly. 
As sensitivity analysis, Clinical Progression-free survival (PFS) analysis will be performed 
with following definition of progression event: earliest date either of a RECIST tumor 
assessment with PD status (without consideration for the number of weeks since previous 
tumor assessment without progression) or of the mention of a documented progression in the 
Survival Follow-up form or in the End of Treatment form) or death whichever occurs first. 
 
9.3. 
Overall response Rate (ORR), Disease Control rate (DCR) and Duration 
of response (DR) 
Assessment of response will be made using RECIST version 1.1 (the protocol does not require 
confirmation at a subsequent time point for CR and PR) and ignoring assessments performed 
after the analysis cut-off date. 
Patients will be considered as without measurable lesions at baseline as soon as (at least) one 
post-baseline RECIST e-CRF form indicates 'No Target Lesions at Baseline'. The remaining 
patients will be considered as with measurable lesions at baseline. 
Based on the randomized patients, the last available response in patients still alive at the 
analysis cut-off date will be displayed in the summary of overall survival time (see DMC Table 
2.1.1). 
Based on the randomized patients with measurable lesions at baseline, the best response 
(complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), 
Not evaluable (NE) or no post-baseline assessment) and the ORR (counting as objective 
response the patients with CR and PR) will be determined for each patient and will be 
summarized by treatment arm (see DMC Table 2.2). The corresponding exact 2-sided 95% 
confidence interval of the ORR will be calculated for each treatment arm. The Mantel-
Haenszel test will be used to compare ORR between the treatment arms, using the 


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randomization strata. The corresponding odds-ratio will be provided with its 95% confidence 
interval. In addition, the difference in ORR between the two treatments will be provided and 
its 95% confidence interval will be calculated based on the normal approximation. 
DCR at 6 months will be calculated in each treatment arm as the number of patients remaining 
within CR, PR or SD responses within the considered time period divided by the total number 
of randomized patients with measurable lesions at baseline. For patients alive at 6 months the 
last RECIST assessment available up to 183 days (included) after randomization will be 
retained; a progression declared as 'documented progression' by the site will also be retained 
and counted as PD. Patients with death within 6 months from randomization will be counted 
as PD. Patients with consent withdrawal before 6 months from randomization will be excluded 
from this analysis. DCR will then be analyzed as described for ORR. DCR at 12 months will 
be calculated and analyzed as described for DCR at 6 months. 
Duration of DCR will be summarized for the subgroup of patients who have achieved CR, PR, 
or SD responses. The duration of DCR will be defined as the time (in months) from the date 
of the first initial occurrence of a CR or PR or SD to the PFS date (corresponding to a PFS 
event or to a censoring). Duration of DCR will be analyzed as described for the PFS. The rate 
à 6 months and 12 months will be also estimated as sensitivity analysis. 
DR will be summarized for the subgroup of patients who have achieved objective response. 
The DR will be defined as the time (in months) from the date of the first initial occurrence of 
a CR or PR to the PFS date (corresponding to a PFS event or to a censoring). DR will be 
analyzed as described for the PFS. 
Depending on the availability of the data waterfall plot (to described quantitative data on target 
lesion) or spider plots (to describe synthetically each patient) will be proposed. 
9.4. 
Time to next lung cancer therapy 
The date of initiation of a lung cancer therapy will be taken as the date of contact of the first 
survival follow-up form mentioning that the patient has received a treatment for the disease 
after stopping the study drug. This date will be censored at the analysis cut-off date for patients 
having received a lung cancer therapy. This date will be censored at the cut-off date or at the 
date of death, whichever comes first, for patients having not initiated a lung cancer therapy. 
The time (in months) from the randomization to this date will be analyzed as described for the 
PFS. As a sensitivity analysis, same analysis will be performed with the time (in months) from 
the earliest date either of a RECIST tumor assessment with PD status or of the mention of a 
documented progression in the Survival Follow-up form or in the End of Treatment form to 
this date. 
The text ‘This date will be censored at the cut-off date or at the date of death, whichever comes 
first, for patients having not initiated a lung cancer therapy.’ should be changed to ‘This date 
will be censored at the cut-off date or at the date of death (or at the date of last survival 
information for patients who did not experience death), whichever comes first, for patients 
having not initiated a lung cancer therapy’. 


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Sensitivity analysis using the date of progression (in months) to this date will be analyzed as 
described for the PFS. The date of progression will be defined as the earliest date either of a 
RECIST tumor assessment with PD status (without consideration for the number of weeks 
since previous tumor assessment without progression) or of the mention of a documented 
progression in the Survival Follow-up form or in the End of Treatment form. 
 
9.5. 
Post-progression Survival 
The date of progression will be defined as the earliest date either of a RECIST tumor 
assessment with PD status (without consideration for the number of weeks since previous 
tumor assessment without progression) or of the mention of a documented progression in the 
Survival Follow-up form or in the End of Treatment form. 
Post-progression survival of patients having experienced a progression will be summarized by 
treatment arm using the Kaplan-Meier method and displayed graphically. The median event 
time for each treatment arm and the corresponding 2-sided 95% confidence interval will be 
provided. 
An additional  analysis will be performed to explore impact on OS to continue study treatment 
beyond progression. The number of patients continuing study treatment 28 days or more after 
progression defined as the earliest date either of a RECIST tumor assessment with PD status 
or of the mention of a documented progression in the Survival Follow-up form or in the End 
of Treatment will be presented in each group. Post-progression survival of patients having 
continuing study treatment 28 days or more after progression versus patients not having 
continued study treatment 28 days or more after progression (other treatment after progression) 
will be summarized by treatment arm (4 curves) using the Kaplan-Meier method and displayed 
graphically. The median event time for each treatment arm and each subgroup and the 
corresponding 2-sided 95% confidence interval will be provided. Overall survival of patients 
having continued study treatment 28 days or more after progression versus patients not having 
continued study treatment 28 days or more after progression (other treatment after progression) 
will be summarized by treatment arm (4 curves) using the Kaplan-Meier method and displayed 
graphically. The median event time for each treatment arm and each subgroup and the 
corresponding 2-sided 95% confidence interval will be provided. 
A listing of patients continuing treatment after PFS will be provided with following 
information: date of RECIST progression and PFS in months, date of clinical progression, 
treatment start date, treatment end date, treatment duration, reason for treatment 
discontinuation, duration between date of RECIST progression and date of treatment 
discontinuation, date of death and OS in months. A summary table of number of patients 
continuing treatment after PFS in each arm (>=28 days) and overall will be provided. A table 
of study treatment exposure per cycle beyond 28 days post PFS will be provided in each arm 
and overall.  
. 


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9.6. 
Quality of life analyses  
The scores will be derived from the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires 
items according to the respective scoring manuals, ignoring assessments performed after the 
analysis cut-off date or after treatment discontinuation. 
A summary of each total score and sub-score for each dimension, for the EORTC QLQ-C30 
will be described by cycle and treatment arm.  
 
• Global health status / QoL 
• Functional scales 
o Physical functioning 
o Role functioning 
o Emotional functioning 
o Cognitive functioning 
o Social functioning 
• Symptom scales / items 
o Fatigue 
o Nausea and vomiting 
o Pain 
o Dyspnea 
o Insomnia 
o Appetite loss 
o Constipation 
o Diarrhea 
o Financial difficulties 
A summary of each total score and sub-score for each dimension, for the EORTC QLQ-LC13 
will be described by cycle and treatment arm.  
• Symptom scales / items 
o Dyspnea 
o Coughing 
o Hemoptysis 
o Sore mouth 
o Dysphagia 
o Peripheral neuropathy 
o Alopecia 
o Pain in chest 
o Pain in arm or shoulder 
o Pain in other parts 
 
After scoring process, domains score will be from 0 to 100. The higher the value, the higher 
the quality of life. After scoring process, symptoms score will be from 0 to 100. The lower the 
value, the poorest the quality of life. 


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Questionnaires collected as “end of treatment” visit will be mapped to next protocol visit if 
they are not duplicate compared to the last non-missing visit. 
Absolute changes from baseline will be summarized as well. Plots representing means and 
95%CI for raw data and absolute changes from baseline will be associated to graphically 
visualized this data. 
 
Missing data fractions for quality of life will be reported under different scenarios:  
- 
rate of patients completing baseline assessments and the assessments at designated time 
points over the total number of patients eligible and entered the trial. 
- 
rate of patients completing assessments at designated time points while on study  
treatment over the total number completing assessment at baseline.  
- 
rate of patients completing assessments at designated time points over the number of 
patients still on study, who were expected to complete questionnaires at each of those 
time points (excluding those who progressed or were dead at that time point). 
For each domain or symptom, mean changes within arms from baseline to the last cycle with 
more than 25% of the total number of included patients (Cycle 8) will be reported to provide a 
complete picture of QoL behavior. 
Changes in scores from baseline until treatment discontinuation will be assessed using mixed-
effects model for repeated measures (MMRM) analysis. Missing data are not imputed. The p 
value will be determined using MMRM analysis, with patient, treatment, visit, and treatment 
by visit interaction as explanatory variables and baseline score as covariate. Patient will be 
fitted as a random effect, and compound score covariance structure will be used for all models. 
The Least Squares Mean differences for each symptom will be reported and plotted with 
corresponding 95% CIs.  
Two sensitivity analyses for consistency with those from the main analysis will be conducted 
only on the quality of life secondary endpoints (QLQ-C30 Global health status, QLQ-C30  
Physical and Role functioning scores): 
- 
using only patients with complete data from cycle 1 to the median number of cycles 
- 
imputing the worst value to next protocol visit after the last non-missing visit of patients 
discontinued treatment for death 
Best QoL response from baseline will be derived for each domain or symptom as follows: a 
change score of at least 10 points from baseline will be defined as clinically relevant. Patients 
will be considered improved if they reported a score of 10 points or more better than baseline 
at any time and will be considered worsened if they reported a score 10 or more points worse 
than baseline (without improvement). Patients whose scores change less than 10 points from 
baseline will be considered stable. Only patients who had completed the baseline and at least 
one follow-up questionnaire will be included. An exact linear rank test will be used to test 
whether the two study arms had the same underlying multinomial distribution of the ordered 
QoL response 


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9.7. 
ECOG 
The time to worsening of ECOG will be defined as the time from randomization to the earliest 
time when the ECOG becomes greater than 1 ignoring all assessments performed after the 
analysis cut-off date. Patients who die without having recorded an ECOG >1 will be assigned 
an ECOG = 5 (Dead) at the time of death. Patients without worsening will be censored at the 
last time when an ECOG value was recorded. The endpoint will be analyzed as described for 
the PFS. 
By protocol, ECOG is not collected anymore when a subject discontinues study treatment 
while the time between study treatment discontinuation and death can be quite long. The 
analysis described above assigns an ECOG 5 at the time of death. This imputation may seem 
exaggerated as, for most of the imputed patients, a condition corresponding to a (unrecorded) 
Grade 2 or worse is likely to have occurred markedly earlier than the date of death imputed as 
Grade 5. In that situation the imputation artificially extends the TTD-free period. 
For this reason, an additional analysis without imputation for death will be performed. This 
analysis will exclude patients without any post-baseline ECOG assessment and censor patients 
without observed ECOG worsening at their last ECOG assessment. 
10. 
SAFETY ANALYSES 
All Safety analyses will be conducted using the Safety sets. An overall treatment summary will 
be included. All safety analyses will be completed using the actual treatment a subject received.  
For laboratory safety parameters, vital signs and ECGs, the baseline will be the last available 
value up to the date of first study drug administration included. 
10.1. 
Adverse Events 
All AEs and SAEs will be coded using the MedDRA dictionary for System Organ Class (SOC) 
and Preferred Term (PT), with the creation of an ad hoc SOC 'Injection site reactions' grouping 
all PTs with High Level Term 'Administration site reactions'. 
Level of intensity was graded according to the CTCAE v5.0 grading. 
Treatment-emergent adverse events (TEAEs) are defined as any adverse event or worsening 
of an existing condition after the date of the first administration of the study treatment 
(included) and up to 28 days after the date of the last administration of the study treatment 
(included) or up to the analysis cut-off date (whichever comes first).  
Immune-related TEAEs (irAEs) are defined as any TEAE that has been specifically flagged as 
immune-related on the e-CRF.  


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Serious adverse events were recorded from the date of informed consent, throughout the clinical 
trial, and for up to 28 days after the final administration of study drug.   
The number of emergent events and the number and percentage of subjects with TEAEs will 
be summarized by SOC and PT by treatment arm for different categories of TEAEs.  At each 
level of tabulation (e.g., at the PT level) patients will be counted only once if they had more 
than one such event reported during the AE collection period. 
The following summary tables will be presented for TEAE data:  
• Treatment-Emergent Adverse Events Overview 
• Treatment-Emergent Adverse Events, by Severity and Grade  
• Treatment-Emergent Adverse Events, by SOC and PT  
• Treatment-Emergent Severe Adverse Events, by SOC and PT  
• Treatment-Emergent Serious Adverse Events, by SOC and PT  
• Treatment-Emergent Adverse Events with Fatal Outcome, by SOC and PT  
• Treatment-Emergent Adverse Events leading to Withdrawal from the Study, by SOC and 
PT 
• Treatment-Emergent Drug Related Adverse Events, by SOC and PT  
• Treatment-Emergent Severe Drug Related Adverse Events, by SOC and PT  
• Treatment-Emergent Serious Drug Related Adverse Events, by SOC and PT  
• Treatment-Emergent Drug Related Adverse Events with Fatal Outcome, by SOC and PT  
• Treatment-Emergent Drug Related Adverse Events leading to Withdrawal from the Study, 
by SOC and PT 
The Treatment-Emergent Adverse Events Overview table will display by treatment arm the 
number of emergent events and the number and percentage of subjects with TEAEs for each 
of the following TEAE categories: 
• Treatment-Emergent Adverse Events 
• Treatment-Emergent Drug Related Adverse Events 
• Treatment-Emergent Severe Adverse Events 
• Treatment-Emergent Severe Drug Related Adverse Events 
• Treatment-Emergent Serious Adverse Events 
• Treatment-Emergent Serious Drug Related Adverse Events 
• Treatment-Emergent Adverse Events with Fatal Outcome 
• Treatment-Emergent Drug Related Adverse Events with Fatal Outcome 
• Treatment-Emergent Adverse Events leading to Withdrawal from the Study 
• Treatment-Emergent Drug Related Adverse Events leading to Withdrawal from the Study 
For each row of the overview table, the chi-square test comparing the two treatment arms on 
the proportion of patients with the considered TEAE category will be used as a flagging device. 
The same presentation will be repeated for the irAEs. 


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All the tables listed above will be repeated on the following subgroups: 
• Age (< 65 years vs. ≥ 65 years) 
• Sex (Male, Female 
• Age and sex (Male < 65 years, Male. ≥ 65 years, Female < 65 years, Female ≥ 65 years) 
• Region (US, non-US). 
Race is not retained for defining subgroups since the number of patients of non-white patients 
is very limited (1 Asian and 1 Black or African American within the treated patients). 
'Severe' will be defined as Grade 3 or above. A missing severity will be considered Grade 3. 
'Drug Related' will be defined as 'Definitely Related', 'Probably related' or 'Possibly Related', 
excluding 'Unlikely Related' and 'Not Related'. A missing relationship will be considered as 
'Definitely Related'. 
TEAEs 'leading to Withdrawal from the Study' are defined as TEAEs where the AE data 
'Withdrawn from Study?' is ticked Yes. 
The list of summary tables for TEAE data will include a table for 'Treatment-Emergent Drug 
Related Adverse Events by Severity and Grade'. 
The irAEs will be described by 2 tables: 'Treatment-Emergent Adverse Events Overview' and 
'Treatment-Emergent Adverse Events by SOC and PT'. No subgroup tables will be prepared 
for the irAEs. 
Since the number of patients in US is limited (7 within the treated ICI patients randomized 
before 26 February 2019, 16 within the ICI patients randomized and treated as of 26 February 
2020), the subgroup variable Region (US, non US) will not be retained for the CSR.  
The ad hoc SOC 'Administration site reactions' will be created by grouping all PTs with High 
Level Group 'Administration site reactions'. 
AEs not coded for patients 1514021 and 2202009  (respectively: 'Right arm inflammation' and 
'Increase of cholestasis' ) will be displayed in the summary tables by their reported term (in 
place of PT) within the ad hoc SOC 'Not coded'. 
10.2. 
Deaths, Serious Adverse Events and Other Significant Adverse Events 
10.2.1. 
Deaths 
All deaths occurring up to the analysis cut-off date, regardless of causality, will be summarized 
by cause of death. 


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10.2.2. 
Serious Adverse Events 
A listing of Serious Adverse Events (SAEs) occurring up to the analysis cut-off date will be 
provided.  
SAEs occurring before study drug initiation will be listed separately. 
10.2.3. 
Adverse Events Leading to Discontinuation of Study Drug or Withdrawal 
from Study 
A listing of all AEs occurring up to the analysis cut-off date and leading to discontinuation of 
study drug or withdrawal from study will be presented. 
10.3. 
Clinical Laboratory Evaluations 
Clinical laboratory values will be analyzed after conversion into standard international units. 
International units will be used in all listings and tables. 
The results will be graded according to the CTCAE v5.0, when applicable. The number and 
percentage of patients with laboratory abnormalities (all grades and by grade) using the worst 
grade between the date of the first administration of the study treatment (excluded) and up to 
28 days after the date of the last administration of the study treatment (included) or up to the 
analysis cut-off date (whichever comes first) will be displayed by treatment arm in a shift table 
stratifying the patients according to the grade observed at baseline. 
For safety laboratory parameters where the CTCAE v5.0 grading scale is not applicable, the 
number and percentage of patients with a value below the normal range and the number and 
percentage of patients with a value above the normal range will be displayed by treatment arm 
in a shift table stratifying the patients according to their situation at baseline (below the lower 
limit of normal range, within normal range, above the upper limit of normal range). A same 
patient may be present in both counts. 
For each parameter, and among each grade observed at baseline the percentages will be based 
on the number of subjects having at least one post-baseline value no later than the analysis cut-
off date. 
10.4. 
Vital Signs 
The number and percentage of patients with marked abnormalities between the date of the first 
administration of the study treatment (excluded) and up to 28 days after the date of the last 
administration of the study treatment (included) or up to the analysis cut-off date (whichever 
comes first) will be displayed for each type of abnormality by treatment arm in a shift table 
stratifying the patients according to their situation at baseline (with/without the considered 
marked abnormality at baseline). Marked abnormalities are classified as high or low based on 
values occurring above the higher limit or below the lower limit, respectively. It is possible 


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that, for a given parameter, the same subject is counted as a high marked abnormality for an 
observed value and as a low marked abnormality for a different observed value. 
 
Variable 
Abnormality 
Weight (kg) 
decrease from baseline > 10% 
increase from baseline > 10% 
Body temperature (°C) 
< 36 
> 39 
Systolic blood pressure (mm Hg) 
< 90 
> 140 
Diastolic blood pressure (mm Hg) 
< 60 
> 90 
Heart Rate (bpm) 
< 50 
> 100 
Respiratory rate (breaths/minute) 
< 10 
> 20 
Oxygen saturation (%) 
<95% 
 
For each parameter, the percentages will be based on the number of subjects having at least 
one post-baseline value no later than the analysis cut-off date. 
---- Addition or change after 04 June 2020 -------- 
For the weight, the percentages will be based on the number of subjects having a baseline value 
and at least one post-baseline value no later than the analysis cut-off date. 
 [Reference: e-mail of 18 August 2020]. 
10.5. 
12-Lead ECG 
The number and percentage of patients with clinically significant abnormal ECG between the 
date of the first administration of the study treatment (excluded) and up to 28 days after the 
date of the last administration of the study treatment (included) or up to the analysis cut-off 
date (whichever comes first) will be displayed by treatment arm in a shift table stratifying the 
patients according to their situation at baseline (with/without clinically significant abnormal 
ECG at baseline). The percentages will be based on the number of subjects having at least one 
post-baseline ECG no later than the analysis cut-off date.  
11. 
ADDITIONAL SAFETY ANALYSES 
The population of all ICI treated patients randomized until the analysis cut-off date will be 
described by treatment arm for the following items: 
• Demographics 
• Baseline characteristics 


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• Previous ICI treatment 
• History of immune-related AEs 
• Medical history 
• Concomitant medications 
• Medications received for the disease after stopping study drug 
All safety analyses described in the previous section will be repeated on this population. 
12. 
COVID-19 IMPACT 
According to the following guidance’s 
• 
European Medicines Agency (2020a), “Guidance on the Management of Clinical Trials 
During the COVID-19 (Coronavirus) Pandemic,” Version 3.  
• 
European Medicines Agency (2020b), “PoInts to Consider on Implications of Coronavirus 
disease (COVID-19) on Methodological Aspects of Ongoing Clinical Trials.” 
• 
“FDA Guidance on Conduct of Clinical Trials of Medical Products During COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards.”  
• 
Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency: Guidance for Industry 
and considering that 110 patients out of the 219 are potentially impacted by the pandemic on 
the 01JAN2020: 
• 60 patients untreated in follow-up for survival  
• 24 patients treated  
• 26 patients randomized between the 01JAN2020 and 30APR2020 
During the data review committee, protocol deviations related to COVID-19 (visits or 
infusions cancelled or delay, COVID-19 events, death related to COVID, follow-up visits 
delayed, …) will be reviewed. If some major deviations are decided related to COVID-19 
patients will be excluded from PP population. 
Number of deviations will be presented overall and per category of deviation (DVCAT in the 
ADDV database) and protocol deviation coded term (DV.DVDCOD) using 2 different periods 
of randomization with or without COVID-19 (Period without COVID-19: First inclusion to 
31DEC2019, then COVID-19 period: 01JAN2020 to last inclusion) using following table 


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Arm A (N=XX) 
Arm B (N=XX) 
Total (N=XX) 
 
Number 
of 
deviations 
Number 
of 
patients 
% 
Number 
of 
deviations 
Number 
of 
patients 
% 
Number 
of 
deviations 
Number 
of 
patients 
% 
 
 
 
 
 
 
 
 
 
 
At least one deviation 
DVCAT: EXCLUSION DVCAT:CRITERION 
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:NOT MET  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:INCLUSION DVCAT:CRITERION 
 NOT MET  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:NFORMED CONSENT  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:PROCEDURES/ TESTS  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:RANDOMIZATION  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:SERIOUS ADVERSE EVENTS  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:STUDY DRUG  
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
DVCAT:VISIT SCHEDULE 
    protocol deviation coded term1 
    protocol deviation coded term2 
    … 
 
 
 
 
 
 
 
 
 
 
Same table will be presented for patients excluded from PP. 
Analysis described in 8.11.1 Time Intervals between Cycles, 8.11.3 Time Intervals between 
RECIST Assessments, and 8.11.4Time Intervals between Quality of Life Assessments will be 


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repeated for the 2 different periods of randomization with or without COVID-19 (Period 
without COVID-19: First inclusion to 31DEC2019, then COVID-19 period: 01JAN2020 to 
last inclusion). This analysis will be performed at a patient level and at visit level and will be 
added in the ancillary SAP. 
Analysis described in 8.11.1 Time Intervals between Cycles, 8.11.3 Time Intervals between 
RECIST Assessments, and 8.11.4Time Intervals between Quality of Life Assessments will be 
repeated for the 2 different periods of randomization with or without COVID-19 (Period 
without COVID-19: First inclusion to 31DEC2019, then COVID-19 period: 01JAN2020 to 
last inclusion). This analysis will be performed at a patient level and at visit level and will be 
added in the ancillary SAP. 
The number of deaths any cause will be summarized by treatment arm for the 2 different 
periods of randomization with or without COVID-19 (Period without COVID-19: First 
inclusion to 31DEC2019, then COVID-19 period: 01JAN2020 to last inclusion). This analysis 
will be performed at a patient level and using the patient year unit during the 2 periods. 
These analyses will be added in the ancillary SAP. 
The number of emergent events and the number and percentage of subjects with TEAEs will 
be summarized by SOC and PT by treatment arm for different categories of TEAEs for the 2 
different periods of randomization with or without COVID-19 (Period without COVID-19: 
First inclusion to 31DEC2019, then COVID-19 period: 01JAN2020 to last inclusion). This 
analysis will be performed at event level and at patient level. This analysis will be repeated 
using the patient year unit during the 2 periods for the denominator. 
These analyses will be added in the ancillary SAP. 
• Death any cause 
• Treatment-Emergent Adverse Events Overview 
• Treatment-Emergent Adverse Events, by SOC and PT  
• Treatment-Emergent Drug Related Adverse Events, by SOC and PT  
• Treatment-Emergent Severe Drug Related Adverse Events, by SOC and PT  
 
Same analyses will be performed using the same 2 periods (without COVID-19, with COVID-
19) but considering start date of AE for the tables. In this analysis patients with AEs in the 2 
periods will be counted in the 2 periods. For patient without any AE during study, date of 
randomization will be considered for the denominator of the percentages.  
- Period1: AE which start between first inclusion and 31DEC2019 
- Period2: AE which start between 01JAN2020 and last inclusion 
 


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12.1. 
Disposition 
Status of the population before and after pandemic will be summarized using following table: 
N (%) 
Arm A (n=XX) 
Arm B (n=XX) 
Total (n=219) 
Randomized until 31DEC19 
Na 
Nb 
Na+Nb 
Alive on 01JAN20 or randomized 
after the 31DEC19 
 
 
 
    In Follow-up after the 01JAN20 
 
 
 
    Treated after the 01JAN20 
 
 
 
    Included after the 01JAN20 
 
 
 
12.2. 
 Sensitivity analysis on censor date 
Same analysis for OS as described in 9.1 will be repeated with a censor date at 3 following 
cut-offs: 31DEC2019, 31JAN2020 and 26FEB2020 (cut off for Step 1 analysis). 
12.3. 
Time-dependent covariate analyses 
Time-dependent covariates are those that may change in value over the course of observation. 
For a model with one time-invariant covariate and one time-dependent covariate, we have  
log h(t)=α(t)+β1X1 + β2X2(t) 
For example, if we want a model in which the hazard of OS depends on COVID-19 status, we 
could specify COVID as whether the person is currently COVID exposed in week t.  
Cox models taking into account COVID time dependent will be presented using  
- 3 different periods of randomization with or without COVID-19 (Period 1: Step1: First 
inclusion to 26FEB2019, then post step 1: 26FEB2019 to 31DEC2019, then COVID-19 period: 
01JAN2020 to last inclusion). 
- 2 different periods of randomization with or without COVID-19 (Step1: First inclusion to 
26FEB2019, then post step 1: 26FEB2019 to last inclusion). 
- 2 different periods of randomization with or without COVID-19 (Step1: First inclusion 
31DEC2019, then: 01JAN2020 to last inclusion). 
 
Using AIC criterion, the best model will be chosen. 


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• One simple model with overall population to test COVID impact 
proc phreg data = XX; 
class COVIDIMPACT /ref = last; 
model (before, after) * censored(1) = COVIDIMPACT /ties = EFRON 
rl;run; 
• One simple model for each treatment arm 
• One model with overall population to test COVID impact with treatment arm in the 
model with or without interaction 
proc phreg data = XX; 
class COVIDIMPACT ARMGR/ref = last; 
model (before, after) * censored(1) = COVIDIMPACT ARMGR /ties = 
EFRON rl;run;