Double Immune Checkpoint Inhibitors in PD-L1-positive Stage IV Non-small Lung CancEr

Inclusion Criteria:

1. Signed Written Informed Consent:

   Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.

   Subjects must be willing and able to comply with scheduled visits, treatment schedule, and laboratory testing.
2. Histologically-proven NSCLC (squamous or non-squamous)
3. Stage IV (M1, including M1a pleural involvement) disease (8th classification TNM, UICC 2015)
4. ECOG PS \< 1
5. Weight loss\< 10% in previous 3 months
6. No prior systemic anticancer therapy (including EGFR or ALK inhibitors) given as primary therapy for advanced or metastatic disease.
7. Age≥ 18 years, \<75 years
8. Life expectancy \> 3 months
9. Measurable tumor disease by CT or MRI per RECIST 1.1 criteria
10. Available tumor samples for centralized PD-L1 immunohistochemistry analysis
11. PD-L1 tumor content ≥ 1% and \< 50% tumor cells as assessed locally by the investigator center
12. Adequate biological functions:

    Creatinine Clearance ≥ 50 mL/min (Cockcroft or MDRD or CKD-epi); neutrophiles ≥ 1500/mm3 ; platelets ≥100 000/mm3 ; Hemoglobin ≥ 9g/dL ; hepatic enzymes \< 3x ULN, total bilirubin ≤ 1,5 x ULN except for patients with proved, Gilbert syndrome (≤ 5 x ULN) or patients with hepatic metastases (≤ 3,0 mg/dL)
13. Women of childbearing potential (WOCBP) and sexually active should use an efficacious contraception method within the 28 days preceding the first dose and during the 6 months following the last dose of treatment. Women must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.

    For Male subjects who are sexually active with WOCBP, an efficacious contraception method should be used during the treatment and during the 7 months following the last dose.

    Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of \< 1% when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective.
14. Patient inclusion validated by a multidisciplinary meeting.

Exclusion Criteria:

1. Small cell lung cancer or tumors with mixt histology including a SCLC component
2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861X mutations in exon 21, G719A/S mutation in exon 18) or HER exon 20 insertion (either tissue or plasma cfDNA mutation).
3. Known ALK or ROS1 gene rearrangement as assessed by immunohistochemistry, FISH or NGS sequencing
4. Previous or active cancer within the previous 5 years (except for treated carcinoma in situ of the cervix or basal cell skin cancer). Patients with a prostate adenocarcinoma history within the previous 5 years could be included in case of localized prostate cancer, with good prognostic factors according to d'Amico classification (≤ T2a and Score de Gleason ≤ 6 and PSA (ng/ml) ≤ 10), provided they were treated in a curative way (surgery or radiotherapy, without any chemotherapy)
5. Superior vena cava (SVC) syndrome persisting after SVC stenting
6. Thoracic radiotherapy needed at initiation of tumor treatment, except bone palliative radiotherapy on a painful or compressive metastasis, respecting 4 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment
7. Symptomatic untreated brain metastasis (without previous whole brain radiotherapy or stereotactic ablative brain radiotherapy or without surgical resection). At least 4 weeks delay between the end of radiotherapy and the beginning of induction immunotherapy treatment should be respected. Asymptomatic brain metastasis, not needing corticosteroids greater than 10 mg prednisone equivalent daily or mannitol infusions, with no evolution on brain MRI or CT-scan within the previous month are allowed.
8. History of previous primary immunodeficiency, organ transplantation needing an immunosuppressive treatment, any immunosuppressive drug within 28 days before randomization date, or history of severe toxicity (grade 3/4) by immune mechanism linked to another immunotherapy treatment.
9. Systemic treatment with corticosteroids with greater dose than 10 mg prednisone equivalent daily, within 14 days before initiation of the immunotherapy induction. Inhaled, nasal or topic corticosteroids are allowed.
10. History of active autoimmune disease including rheumatoid polyarthritis, Lupus, Wegener disease. Patients with type I diabetes, or hypothyroidism, or immune cutaneous disease (vitiligo, psoriasis, alopecia) not needing any immunosuppressive systemic treatment, are allowed to be included.
11. Active inflammatory intestinal disease (diverticulosis, Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea
12. Active uncontrolled infection including tuberculosis, known acute viral hepatitis B and C according to serological tests. Patients with serological sequelae of cured viral hepatitis are allowed to be included.
13. HIV known infection
14. Living attenuated vaccine received within the 30 previous days
15. Previous treatment with anti-PD-1, anti-PD-L1 or Anti-CTLA4 antibody
16. Previous treatment with chemotherapy
17. General serious condition such as congestive uncontrolled cardiac failure, uncontrolled cardiac arrythmia, uncontrolled ischemic cardiac disease (unstable angina or history of myocardial infarction in the previous 6 months), history or stroke within the 6 previous months
18. Pre-existing lung interstitial disease as assessed by the diagnosis CT-scan.