• Male or female, aged ≥ 18 years

• Signed and dated informed consent form (ICF) prior to any trialspecific procedures.

• ECOG performance status 0-1

• Patients must be affiliated to a social security system or an equivalent system, if applicable as per local regulations.

• Patients expressing HLA-A2 phenotype on blood sample performed by an experienced laboratory using a validated test (PCR or NGS). Additional patients HLA-A2 negative will be included in PART C.

• Tumor type: a) Histologically or cytologically documented Stage IV squamous or non-squamous NSCLC not eligible for definite surgery or radiation, without EGFR sensitizing mutation or ALK and ROS1 gene alterations eligible for targeted therapy or other mutations for which an approved therapy exists in 1st line metastatic (see protocol); b) PD-L1 expression by TPS ≥ 50% (local)

• Patients with NO prior systemic therapy including immunotherapy in the first-line metastatic setting. In case of neoadjuvant/adjuvant therapy, therapy was completed at least 6 months prior to the diagnosis of metastatic disease.

• Patients with at least one measurable lesion according to RECIST v1.1.

• Adequate organ function:

∙ Bone marrow: neutrophils ≥ 1.5 x 109/L, hemoglobin ≥ 90 g/L, platelets ≥ 100 x 109/L

‣ Renal function: serum creatinine ≤ 1.5 ULN or CKDEPI creatinine clearance ≥ 30 mL/min

‣ Liver function: AST and ALT ≤ 3 ULN, bilirubin ≤ 1.5 ULN. In case of liver metastasis: AST and ALT ≤ 5 ULN. For patients with Gilbert's syndrome total bilirubin ≤ 3 ULN or direct bilirubin ≤ 1.5 ULN.

• Patient eligible to surgical resection or another approved therapeutic regimen known to provide clinical benefit; Known hypersensitivity to the active substances or to any of the excipients of OSE2101 or docetaxel.

• Patient previously treated with approved/investigational anti-PD-1/PD-L1

• Patient with active autoimmune disease or a documented history of autoimmune disease requiring systemic treatment (i.e., corticosteroids or immunosuppressive drugs); see exceptions in protocol

• Patient participating in another clinical trial with a medicinal product

• Patients who have not recovered from AEs (i.e. \> G1 according to CTCAE v5.0) due to prior treatment with anti-cancer agents with exception of G2 neuropathy or any Grade alopecia. (see protocol)

• Patients with known additional malignancy progressing or requiring active treatment. Basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer are not non-inclusion criteria

• Patients with known active central nervous system metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least 4 weeks prior to C1D1 and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids (at doses \> 10 mg/day methylprednisolone or equivalent) for 4 weeks prior C1D1

• Patients with active or history of non-infectious pneumonitis requiring steroids, or interstitial lung disease

• Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the duration of the study

⁃ Patients with a history of uncontrolled or symptomatic, clinically significant cardiovascular disease: stroke, myocardial infarction, angina pectoris, arrhythmias, congestive heart failure (NYHA Class \>2), or myocarditis within 6 months prior to first study drug administration