Maintenance Pembrolizumab at Usual or Low doSE in Non-squamous Lung Cancer: a Non-inferiority Study

Inclusion Criteria: A) To be checked before the induction phase (only for patient included before induction phase) : 1. Histologically or cytologically confirmed diagnosis of non-squamous non-small cell lung cancer (NSCLC). 2. Non-operable / non-irradiable stage III or stage IV. 3. Patient must be eligible to receive 3 or 4 cycles of induction treatment combination with pembrolizumab plus platinum (cisplatin or carboplatin) and pemetrexed. 4. In the presence of an EGFR mutation, an ALK or ROS1 rearrangement the patient must have received at least one specific targeted therapy line. 5. Age ≥ 18 years old. 6. Performance status 0 or 1. 7. Signed informed consent. 8. Patient affiliated to a social security system or beneficiary of the same. B) To be checked before the maintenance phase (for all patient) : 1. Histologically or cytologically confirmed diagnosis of non-squamous non-small cell lung cancer (NSCLC). 2. Non-operable / non-irradiable stage III or stage IV. 3. Received 3 or 4 cycles of induction treatment combination with pembrolizumab plus platinum (cisplatin or carboplatin) and pemetrexed. 4. Patient must be eligible to receive maintenance pembrolizumab with or without pemetrexed, last induction chemotherapy cycle within 42 days before randomization. 5. Stable disease, partial or complete response according to RECIST 1.1 criteria after induction chemotherapy and pembrolizumab. Targets lesions are not required before randomization. 6. In the presence of an EGFR mutation, an ALK or ROS1 rearrangement the patient must have received at least one specific targeted therapy line (not needed a second time if already checked before induction phase). 7. Patients with baseline brain metastases will be eligible in case of stability or no evidence of progression and if they remain clinically stable. 8. Age ≥ 18 years old. 9. Performance status 0 or 1. 10. Signed informed consent (only for patient included after induction phase). 11. Patient affiliated to a social security system or beneficiary of the same. 12. Creatinine clearance \> 30 ml/min by Cockcroft-Gault\* or MDRD in case that patient will start maintenance just with pembrolizumab but ≥ 45 ml/min if the patient will receive pemetrexed plus pembrolizumab. \*Cockcroft- Gault Formula: * Female CrCl = \[(140 - age in years) x weight in kg x 0.85\] / 72 x serum creatinine in mg/dL; * Male CrCl = \[(140 - age in years) x weight in kg x 1.00\] /72 x serum creatinine in mg/dL. 13. Neutrophils ≥ 1500/μL and platelets ≥ 100 000/μL. 14. Bilirubin ≤ 1.5 upper limit normal (ULN). 15. Transaminases, Alkaline phosphatase ≤ 2.5 x the ULN except in case of liver metastases (5 x ULN). 16. Patients might have received platinum-based chemotherapy as an adjuvant or neoadjuvant treatment, or with radiotherapy for a localized lung cancer, provided that the chemotherapy was ended more than 6 months before the first cycle of induction chemotherapy. 17. Patients might have received previous immune checkpoint inhibitors as an adjuvant or neoadjuvant treatment, or as a consolidation treatment after radiotherapy for a localized lung cancer, but the immune checkpoint inhibitors must be finished at least than 12 months before the first cycle of induction chemotherapy for advanced stage. 18. A woman is eligible for the study if she is no longer likely to procreate (physiologically unfit to carry out a pregnancy), which includes women who have had: a hysterectomy, an oophorectomy, a bilateral tubal ligation. Post-menopausal women: * Patients not using hormone replacement therapy should have had a complete cessation of menstruation for at least one year and be over 40 years of age, or, if in doubt, have an FSH (Follicle Stimulating Hormone) level \> 40 mIU/mL and an estradiol level \< 40 pg/mL (\< 150 pmol/L). * Patients using hormone replacement therapy must have had a complete cessation of menstruation for at least one year and be over 45 years of age or have evidence of menopause (FSH and estradiol levels) before starting hormone replacement therapy. 19. Women who are likely to procreate are eligible if they have a negative serum pregnancy test in the week before the first dose of treatment and preferably as close as possible to the first dose and if they agree to use an effective contraceptive method during the course of the study through 4 months after the last dose of study medication. Sexually active males patients must agree to use condom during the study and for at least 4 months after the last study treatment administration. Also, it is recommended their women of childbearing potential partner use a highly effective method of contraception. Exclusion Criteria: A) To be checked before the induction phase (only for patient included before induction phase) : 1. Mixed small-cell, squamous-cell carcinoma. 2. Mental or psychological illness that does not allow the patient to give informed consent. 3. Pregnant or breastfeeding women. 4. History of HIV or chronic hepatitis B or C. 5. Active or uncontrolled infection. 6. History of one or more of the following cardiovascular disorders in the previous 6 months: * Coronary artery bypass or peripheral arterial bypass, cardiac angioplasty or stent. * Myocardial infarction * Severe or unstable angina pectoris * Peripheral vascular disease, pulmonary embolism or untreated thromboembolic events, stroke or transient ischemic attack. Note: Patients with recent deep vein thrombosis (including pulmonary embolism) treated with anticoagulant for at least 4 weeks and clinically stable are eligible. * Congestive heart failure class III or IV as defined by the NYHA 7. Concomitant treatment with another experimental treatment or participation in another clinical trial. B) To be checked before the maintenance phase (for all patient) : 1. Presence of grade 3 or 4 toxicity related to pembrolizumab limiting maintenance treatment continuation. 2. Mixed small-cell, squamous-cell carcinoma. 3. Corticosteroids at a dose greater than 20 mg per day of prednisone or equivalent. 4. Patient unable to follow the therapeutic program. 5. Mental or psychological illness that does not allow the patient to give informed consent. 6. Pregnant or breastfeeding women. 7. Ongoing immunosuppressive systemic therapy (cyclophosphamide, aziatropin, methotrexate, thalidomide and anti-TNF). 8. Active autoimmune diseases. History of autoimmune diseases including myasthenia gravis, lupus erythematosus, rheumatoid arthritis, irritable bowel syndrome, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis or glomerulonephritis. Patients with a history of autoimmune hypothyroidism treated with a stable dose of hormone replacement therapy are eligible. Patients with diabetes treated with insulin are eligible. 9. History of idiopathic pulmonary fibrosis, organized pneumonia (i.e., obliterating bronchiolitis), drug-induced lung disease or active signs of pneumonia, pulmonary infiltration (regardless of cause) detected on the baseline chest CT-scan. 10. History of any other hematologic or primary solid tumor malignancy unless in remission for at least 2 years and without specific treatment (as example, not allowed hormonal therapy to replace for breast cancer or hormonal therapy substitution in prostate cancer). pT1-2 prostatic cancer Gleason score \< 6, superficial bladder cancer, non-melanoma skin cancer or carcinoma in situ of the cervix are allowed. 11. Presence of a condition or condition that makes patient participation in the study inappropriate, including serious unresolved or unstable toxicities from previous administration of another experimental treatment or any medical condition that could interfere with patient safety, obtaining consent or compliance with study procedures. 12. Administration of a live attenuated vaccine within the 4 weeks before day 1 of Cycle 1 or administration of a live attenuated vaccine planned for the duration of the study. The flu vaccine can be given during the flu season (approximately from October to May). Patients should not receive a live attenuated influenza vaccine during the 4 weeks preceding day 1 of Cycle 1 and should not receive this type of vaccine during the study. 13. History of HIV or chronic hepatitis B or C (not needed a second time if already checked before induction phase). 14. Active or uncontrolled infection. 15. History of one or more of the following cardiovascular disorders in the previous 6 months: * Coronary artery bypass or peripheral arterial bypass, cardiac angioplasty or stent. * Myocardial infarction * Severe or unstable angina pectoris * Peripheral vascular disease, pulmonary embolism or untreated thromboembolic events, stroke or transient ischemic attack. Note: Patients with recent deep vein thrombosis (including pulmonary embolism) treated with anticoagulant for at least 4 weeks and clinically stable are eligible. * Congestive heart failure class III or IV as defined by the NYHA 16. Concomitant treatment with another experimental treatment or participation in another clinical trial.