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 r ecovered 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 hype rsensitivity 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 immun osuppressive medications OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 43 of 101 02 February 2022 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 becl omethasone 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, hypoga mmaglobulinemia 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 locali zed 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 investiga tor 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 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 serum pregnancy test at screening 4.3 Study Drugs 4.3.1 Description, packaging and labelling The i nvestigational 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 accord ance with GMP and local regulations . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 44 of 101 02 February 2022 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 material s to prepare the full treatment for one single administration. Control treatments ( i.e. docetaxel and pemetrexed) will be market -approved presentations . Supplier s may vary according to country/center. 4.3.2 Storage The i nvestigational 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 a dministration, 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 i n 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 . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 45 of 101 02 February 2022 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 inf requent 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 supe rvision. 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 B 12, 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. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 46 of 101 02 February 2022 Cross -over in Arm B is not permitted Patients in Arm B (docetaxel or pemetrexed) cannot receive OSE2101 at time of treatment interruption whic hever 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 sit e 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. Systemi c 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 lea st 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 dosi ng. 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 hematologica l toxicities. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 47 of 101 02 February 2022 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 firs t dose of pemetrexed and continuing daily until 3 weeks after the last dose of pemetrexed. Vitamin B 12, 1000 g, will be injected intramuscularly approximately 1 to 2 weeks before the first dose of pemetrexed and will be repeated approximately every 9 wee ks 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 d ose 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 elec tronic 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 p rogression. Subjects considered as having progressive disease should be considered for discontinu ing study t reatment, 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 wi th a global control of the disease with a clinical benefit for the patient and under discretion of the investigator, may warrant continu ing study treatment should be discussed with the sponsor . OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 48 of 101 02 February 2022 Authorized Concomitant palliative and supportive care for dise ase 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 w ithdrawn 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 w ill 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 stu dy, 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 contin ued 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 fo llow-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 accordanc e with local law. OSE2101 Protocol OSE2101C301 Confidential Version n°6.0 Page 49 of 101 02 February 2022 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 t o 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 medic al 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 inclu ded 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 porti on 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 Rando mization 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 approp riate 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.