De-escalation Immunotherapy mAintenance Duration Trial for Stage IV Lung Cancer Patients With Disease Control After Chemo-immunotherapy Induction

Inclusion Criteria:

1. Signed Written Informed Consent:

• Subjects must have signed and dated an IRB/IEC approved written informedconsent form in accordance with regulatory and institutional guidelines. Thismust be obtained before the performance of any protocol related procedures thatare not part of normal subject care.

• Subjects must be willing and able to comply with scheduled visits, treatmentschedule, and laboratory testing.

2. Patients with histologically confirmed metastatic NSCLC (Stage IV accordingly to 8thclassification TNM, UICC 2015). A cytologically-proven NSCLC is allowed if acytoblock has been prepared.

3. PD-L1 tumor content as assessed locally by the investigator center.

4. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

5. Weight loss< 10% within 3 months of study entry.

6. No prior systemic anticancer therapy (including EGFR or ALK inhibitors) given asprimary 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. The Investigator must confirm prior to enrolment that the patient has adequate tumortissue available. Tumor biopsy should be exploitable for molecular analysis. Ifarchival tissue is either insufficient or unavailable, the patient may still beeligible upon discussion with IFCT. Note: Tumor tissue collected after the patient was diagnosed with metastatic diseaseis preferred. Tumor tissue sample must not be from locations previously radiated. Tumor samplemust be 1 block or at least 7 unstained slides of analyzable tissue.

11. Adequate biological functions: Creatinine Clearance ≥ 45 mL/min (Cockcroft or MDRD or CKD-epi); neutrophils≥ 1500/mm3 ; platelets ≥100 000/mm3 ; Hemoglobin≥ 9g/dL ; AST and ALT< 3x ULN, totalbilirubin < 2xULN (patients with hepatic metastases or Gilbert's syndrome must haveAST and ALT ≤ 5 x ULN and a baseline total bilirubin ≤ 2xULN).

12. Women of childbearing potential (WOCBP) and sexually active should use anefficacious contraception method within the 28 days preceding the first dose andduring the 6 months following the last dose of treatment. Women must have a negativeserum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units ofHCG) prior to the start of study drug.

13. For Male subjects who are sexually active with WOCBP, an efficacious contraceptionmethod should be used during the treatment and during the 6 months following thelast dose.

14. Patient has national health insurance coverage.

Exclusion Criteria:

1. Small cell lung cancer or tumors with mixed histology including a SCLC component. Note : Sarcomatoid histology is allowed. Neuro-endocrine large cell lung cancer withmolecular features of small-cell lung cancer (i.e; Rb loss associated with TP53mutation) will not be eligible. Other neuro-endocrine large cell subtypes, i.e. withadenocarcinoma features (STK11 or K-Ras mutations) will be eligible. In case ofdoubt, please contact the sponsor.

2. Known EGFR activating tumor mutation (deletion LREA in exon 19, L858R ou L861Xmutations in exon 21, G719A/S mutation in exon 18, exon 20 insertion) or HER2 exon 20 insertion (either tissue or plasma cfDNA mutation).

3. Known ALK, ROS1, Ret, NTRK, NRG1 gene rearrangement as assessed byimmunohistochemistry, FISH or NGS (ADN or ARN) sequencing by local genetics and/orpathology laboratory.

4. Previous or active cancer within the previous 3 years (except for treated carcinomain situ of the cervix, or basal cell skin cancer treated or not). Patients with aprostate adenocarcinoma history within the previous 3 years could be included incase of localized prostate cancer, with good prognostic factors according to d'Amicoclassification (≤T2a, score de Gleason ≤ 6 and PSA ≤ 10 (ng/ml)) provided they weretreated in a curative way (surgery or radiotherapy, without any chemotherapy).

5. Superior vena cava syndrome persisting despite VCS stenting.

6. Radiotherapy needed at initiation of tumour treatment, except bone palliativeradiotherapy on a painful or compressive metastasis, respecting 1 week delay betweenthe end of radiotherapy and the beginning of treatment

7. Symptomatic untreated brain metastasis (without previous whole brain radiotherapy orstereotactic ablative brain radiotherapy or without surgical resection). At least 2weeks delay between the end of radiotherapy and the beginning of inductionimmunotherapy treatment should be respected. Asymptomatic brain metastasis, notneeding corticosteroids greater than 10 mg prednisone equivalent daily or mannitolinfusions, are allowed.

8. History of previous primary immunodeficiency, organ transplantation needing animmunosuppressive treatment, any immunosuppressive drug within 28 days beforerandomization date, or history of severe toxicity (grade 3/4) by immune mechanismlinked to another immunotherapy treatment.

9. Systemic treatment with corticosteroids with greater dose than 10 mg prednisoneequivalent daily, within 14 days before initiation of the immunotherapy induction.Inhaled, nasal or topic corticosteroids are allowed.

10. History of active autoimmune disease including but not limited to rheumatoidpolyarthritis, myasthenia, autoimmune hepatitis, systemic Lupus, Wegener'sgranulomatosis, vascular thrombosis associated with antiphospholipid syndrome,Sjogren's syndrome with interstitial pulmonary disease, recent Guillain-Barrésyndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Patients with type I diabetes, or hypothyroidism, or immune cutaneous disease (vitiligo, psoriasis, alopecia) or benign rheumatoid polyarthritis not needing anyimmunosuppressive systemic treatment, or benign sicca syndrome (Sjogren) withoutinterstitial pulmonary disease, or history of past Guillain-Barre syndrome, totallyreversible with no sequelae, no systemic immunosuppressive treatment during the last 20 years, are allowed to be included.

11. Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis,coeliac disease) or any serious chronic intestinal disease with uncontrolleddiarrhea.

12. Active uncontrolled infection including tuberculosis, known acute viral hepatitis Band C according to serological tests. Patients with serological sequelae of curedviral hepatitis are allowed to be included. Past primary pulmonary tuberculosis inyouth does not consist of a contra-indication. Past tuberculosis disease historydoes not consist of a contra-indication provided the patient was treated during atleast 6 months by anti-tuberculosis antibiotic treatment.

13. Known HIV infection

14. Living attenuated vaccine received within the 30 previous days

15. Previous treatment with anti-PD-1, anti-PD-L1, Anti-CTLA4 or any ICI antibody

16. Previous treatment with chemotherapy for lung cancer. However, if a patient has alung adenocarcinoma, previous cisplatin treatment for another cancer type withsquamous histology (Head and Neck, bladder) may be allowed provided the sponsoraccepts, and provided blood tests are normal (see above).

17. General serious condition such as congestive uncontrolled cardiac failure,uncontrolled cardiac arrythmia, uncontrolled ischemic cardiac disease (unstableangina or history of myocardial infarction within the previous 6 months), history orstroke within the 6 previous months. Patients with a significant cardiac history,even if controlled, should have a LVEF > 50%.

18. Pre-existing moderate or severe lung interstitial disease as assessed by thediagnosis CT-scan.

19. Inability to comply with study and/or follow-up procedures for family, social,geographic or psychological reasons.

20. Pregnant, lactating, or breastfeeding women.

21. Patients deprived of liberty by judicial or administrative decision

22. Patient who is subject to legal protection or who is unable to express his will