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 att aining 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 do cetaxel 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 w ith 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 dysgamm aglobulinemia; 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 he patitis 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 OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 11 of 101 02 February 2022 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 con traception 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 co ntraception will be based on the judgment of the principal investigator (See Appendix 4: Guidance on Contraception ) 18. Breastfeeding women 19. Women with a p ositive 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 p rogression 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 . OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 12 of 101 02 February 2022 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 compar ison of O S 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 QL Q 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 fr om 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 OSE2101 Protocol OSE2101C301 Confidential Version n° 6.0 Page 13 of 101 02 February 2022 endpoints laboratory abnormalities Translational study Patient can agree to participate in all or some parts of the translatio nal study . Patient can refuse to participate in the translational study without compromising his/her participation in the main study .