This study must follow the IC H/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 proto col, 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). OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 39 of 101 02 February 2022 3.2 Ethics Committee/ Institutional Review Board The investigator will submit this protocol and any re lated 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 vo ted. 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 a ny 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 fr om 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 tran slations 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 sc ientific 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 a n 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 monito red in experienced oncology/pulmonology centers . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 40 of 101 02 February 2022 ➢ Randomization to Arm s 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 peri ods: 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 calcul ations . o Treatment: − For OSE2101 (Arm A): Day 1 each 21 -day cycle for 6 cycles , then every 8 weeks for the remain der 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, t reatment 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, invest igator 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 f ollow -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 ev ery 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 populatio n 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 recruitment hold. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 41 of 101 02 February 2022 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 pa tient 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 chemotherap y 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 tre ated (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 for bidden 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) OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 42 of 101 02 February 2022 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 UL N 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.