Multicenter, randomized (2:1), open-label phase 3 study in HLA-A2 positive patients with squamous and non-squamous metastatic NSCLC who progressed after ≥ 24 weeks of first line CT-ICI, including at least 12-weeks of anti-PD(L)1 monotherapy prior to randomization (i.e., with ICI secondary resistance).

Patients will be randomized into 2 arms (randomization 2:1): experimental Arm A with OSE2101 monotherapy or control Arm B SoC with docetaxel monotherapy.
Stratification factors will be:

• Histology (squamous versus non squamous)
• ECOG Performance Status (0 versus 1).

The exclusion of maintenance treatment with CT, other cytotoxic or antiangiogenics for 12 weeks before randomization may decrease the number of patients with non-squamous NSCLC. Thus, it is anticipated to recruit ≥ 35% up to 50% squamous NSCLC.

Primary objective:

• To confirm the superiority of OSE2101 versus docetaxel on Overall Survival (OS)

Secondary objectives:

• To confirm the clinical benefit of OSE2101 versus docetaxel including Patient Reported Outcomes (PROs)

Other objectives:

• To evaluate and confirm the better safety profile of OSE2101 versus docetaxel
• To evaluate other PROs of treatment tolerance and disease symptoms in each arm
• To evaluate efficacy based on tumour assessments using imaging (RECIST 1.1) in each arm
• To evaluate the overall improvement in health outcome combining key endpoints of efficacy, safety, and PROs
• To explore biomarkers that demonstrate the mechanism of action of OSE2101 and that could be predictive of clinical efficacy if data allow.

Patients will be included if they meet all the following inclusion criteria without non-inclusion criteria:
Inclusion criteria:

1. Male or female, aged ≥ 18 years
2. Patients expressing HLA-A2 phenotype in blood by pre-screening central laboratory
3. Patients with histologically or cytologically squamous or non-squamous documented NSCLC, metastatic stage at study entry, not eligible for definite surgery or radiation, without EGFR, ALK and ROS1 gene alterations eligible for targeted therapy; other sensitizing mutations known to be immunosensitive are eligible in case of lack of local access to targeted therapy (i.e.; KRAS G12C and BRAF mutations) after Sponsor’ agreement
4. Patients who progressed after ≥ 24 weeks of first-line CT-ICI, including ≥12 weeks of anti-PD(L)1 monotherapy prior to randomization (i.e.; ICI secondary resistance); a radiological tumor assessment by the Investigator at 24 weeks (± 2 weeks) after the start of ICI is needed to exclude PD; induction treatment with first-line CT-ICI should contain at least 2 cycles of platinum-based CT except if contraindication to platinum
5. Patients who permanently stopped ICI due to radiological PD (assessed by the Investigator) occurring after ≥ 24 weeks of ICI, including at least 12-weeks of anti-PD(L)1 monotherapy prior to randomization
6. Patients with ECOG performance status (PS) 0 or 1
7. Patients with measurable or non-measurable lesions per RECIST 1.1
8. Patients with adequate organ functions defined as:

• Albumin ≥ 3 g/dL
• AST and ALT up to 3.0 x ULN associated with Alkaline Phosphatase (ALKP) ≤ 2.5 x ULN, or ALPK ≥ 2.5 x ULN up to 5.0 x ULN associated with AST and ALT ≤ 1.5 x ULN
• Total serum bilirubin ≤ 1 x ULN; for patients with Gilbert’s syndrome, total bilirubin ≤ 3 ULN or direct bilirubin ≤ 1.5 ULN
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelets ≥ 100 x 109/L
• Haemoglobin ≥ 9 g/dL (in the absence of transfusion within 2 weeks before randomization)
• Creatinine clearance (CrCl) according to CKD-EPI (Chronic Kidney Disease – EPIdemiology) formula ≥ 30 ml/min/1.73m2

9. Patients without clinically significant ongoing toxicity from prior therapy (severity ≤ Grade 1; except alopecia)
10. If applicable, a wash out of at least 28 days or 5 half-lives (whichever is shorter) since the last anticancer treatment or investigational therapy; a wash out of at least 28 days after definitive radiation or prior major treatment-related surgery; wash out after palliative radiation of at least 2 weeks
11. Women of childbearing potential (WOCBP) participating in the study must agree to use highly effective methods of contraception (i.e., one that results in a less than 1% per year failure rate when used consistently and correctly) prior to study entry, during the study, and for 180 days after the last dose of study treatment. Highly effective methods of contraception are defined as one of the following methods: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner, sexual abstinence
12. Male patient with WOCBP partner must be willing to use male contraception (condoms) during the study, and for 90 days after the last dose of study treatment. WOCBP partners of male subjects participating in the study may use hormone-based contraceptives as one of the acceptable methods of contraception since they will not be receiving the study treatment (i.e.; oral hormonal contraception, cap, diaphragm, or sponge with spermicide)
13. WOCBP must have a negative blood pregnancy test within 7 days prior to first administration. Women who are postmenopausal for at least 1 year (defined as more than 12 months since last menses) or are surgically sterilised do not require this test
14. Patients having signed and dated informed consent (IC) prior to any trial-specific procedures
15. Patients must be affiliated to a social security system or an equivalent system (per local regulation).

Non-inclusion criteria:

1. 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 known hypersensitivity to the active substances or to any of the excipients of OSE2101 or docetaxel
3. Patients with PD during induction first-line CT-ICI (to exclude hyper progression and fast progression to CT-ICI) or with PD within 24 weeks of ICI; chemotherapy, other cytotoxic agent or antiangiogenics in combination with ICI within 12 weeks prior to randomization are not authorized; patients who stopped ICI due to toxicity or other reason than PD are not eligible
4. Patients with brain metastasis or previously treated brain metastasis, spinal cord compression, carcinomatous meningitis, or leptomeningeal disease
5. Patients with AST and/or ALT >1.5 × ULN concomitant with ALPK > 2.5 × ULN
6. Patients with active auto-immune disease and/or immune-related disease due to prior immunotherapy or other condition requiring systemic immunosuppressive treatments or chronic administration of corticosteroids > 10 mg daily prednisolone equivalent (except as replacement if adrenal insufficiency); short course of corticosteroids > 10 mg daily prednisolone equivalent is allowed if ≤ 10 days continuous duration (e.g. premedication to prevent contrast allergy, drug reaction…); topical, ocular, intra-articular, intranasal, and inhaled corticosteroids with minimal systemic absorption are allowed
7. Patients with interstitial lung disease or active non-infectious pneumonitis
8. Patients who have known hereditary, congenital or acquired immunodeficiencies; for human immunodeficiency virus (HIV) infection, patient may be eligible if CD4+ count ≥ 350 cells/μL, and no history of acquired immunodeficiency syndrome (AIDS) infections within 12 months prior to start of study treatment, and receiving an established antiretroviral therapy with NO known drug-drug interaction with docetaxel for at least 4 weeks prior to starting the study treatment, and have a viral load ≤ 400 copies/ μL (local laboratory)
9. Patients with an active infection requiring anti-infective therapy until all signs of infection have resolved before randomization
10. Patients with chronic Hepatitis B (HBV) infection who meet the criteria for antiviral therapy (according to local/international guidelines) and not treated prior to starting the study treatment; patients with an active Hepatitis C (HCV) with HCV viral load (by local laboratory) above the limit of quantification; patients who received a prior antiviral HCV treatment or no prior treatment but HCV natural resolution with HCV RNA not detectable are eligible
11. Patients with other active invasive cancer(s) within 3 years prior to randomization (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)
12. Patients with severe acute or chronic medical (i.e., severe liver impairment) or psychiatric conditions, or laboratory abnormalities that would expose to an excess risk associated with study participation or study drug administration in the opinion of the Investigator and/or the Sponsor
13. Patient participating in another clinical trial with an investigational medicinal product
14. Patient is the Principal Investigator or Investigator, research assistant, pharmacist, study coordinator, other staff directly involved in the conduct of the study.