Patient can agree to participate in all or some parts of the translational study. Patient can refuse to participate in the tr anslational 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 i ncrease the pri ming and activation of T cell in the intent to increase the recognition of cancer cell by specific T cells (5, 72). The main objective s 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 TA A) Blood samples will be taken at baseline, then every 6 weeks until Cycle 7 (e.g. Day 1 of Cycle s 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 cycl e 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) OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 52 of 101 02 February 2022 o Tumor and tumor microenvironm ent (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 bi omarker 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 ev ent (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 Screenin g assessments Screening assessments and procedures must be completed within 35 days of randomization, in accordance wit h Table 1 and Table 2 : ➢ A complete medical history including oncology history (information on prior treatments and regimen) and concomita nt 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, abdome n 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 OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 53 of 101 02 February 2022 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. Clinic ally 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 n ecessary. A specific informed consent will be signed for this pre-screening . HLA -A genotype will be determined centrally by PCR in all patient s (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 posterior i. 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 . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 54 of 101 02 February 2022 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 select ed central lab oratory , should tumor tissue available. Samples will be FFPE b locks or slides . EGFR analysis EGFR testing will be performed in local laboratories with validated tests . If not available on sit e, 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 availabl e. 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 b one metastasis out of the area included by the basal CT scan, radiological test will be performed under discretion of the OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 55 of 101 02 February 2022 investigator . Then CT scan will be performed every 6 weeks after randomization with 1 week of allowance even it is between 2 study vis its. 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 tec hnic and CT should only be considered when there are contra -indications to MRI. Specific test s 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 MR I, 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 basel ine 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 t he 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 laborato ries 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 Immuno therapeutics 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 a fter 10 minutes resting in supine position. Oxygen saturation will be measured by pulse oximetry. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 56 of 101 02 February 2022 4.7.8 Physical examination A complete physical examination including an examination of major body systems, height (baseline visit only) and weight is perfor med 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 m eeting 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 d rug 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 adver se 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 d ay 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 OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 57 of 101 02 February 2022 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 saf ety 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 volunteer ed 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 investig ational 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 unde rgoing 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. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 58 of 101 02 February 2022 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 causalit y 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 b ut 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 docum ents 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 oc curred 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 investigat ional 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 examinat ion 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 stud y drug administration even though it may have been present prior to the start of the study. • Events considered by the investigator to be related to study -mandated procedures. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 59 of 101 02 February 2022 • 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 in vasive 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 v 5.0 (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 OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 60 of 101 02 February 2022 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 v 5.0 term is a Med DRA 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 instrument al 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; u rgent 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.