PEmbRolizumab verSus chEmotherapy and pEmbrolizumab in Non-small-cell Lung Cancers (NSCLC) With PDL1 ≥ 50 % (PERSEE)

Inclusion Criteria:

1. Age 18 years or older at diagnosis.
2. Histologically or cytologically confirmed NSCLC.
3. Stage IV NSCLC. Unresectable and non-eligible to radiotherapy stage III NSCLC are permitted.
4. For non-squamous NSCLCs and non-smoking squamous NSCLCs, no known activating mutations of EGFR and no ALK or ROS-1 rearrangements.
5. PD-L1 expression on ≥ 50 % of tumor cells, which will be determined locally.
6. No prior systemic treatment for lung cancer. Patients who received adjuvant therapy are eligible if the adjuvant therapy was completed at least 12 months prior to the development of metastatic disease.
7. Palliative radiotherapy completed within one day before randomization (stereotaxic or not) is authorized.
8. At least 1 target lesion in a non-irradiated area, measurable according to RECIST v1.1.
9. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
10. Life expectancy >12 weeks.
11. Patients with brain metastases at inclusion are accepted, provided that these metastases are asymptomatic, or symptomatic but treated (surgery or radiotherapy without or with corticosteroids ≤10 mg/day), and that they are stable on the day of inclusion.
12. No history of other malignant tumor during the previous 5 years, except for adequately treated carcinomas (in situ cervical carcinoma, basal cell carcinoma, squamous cell skin carcinoma) and low grade localized prostate cancer (Gleason <6).

13. Adequate organ function, as demonstrated by laboratory results within 7 days prior to the first administration of study treatment:

    1. Normal hepatic function: bilirubin ≤1.5 x upper limit of normal (ULN), alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) ≤2.5 x ULN or ≤5 x ULN in case of liver metastases
    2. Normal renal function: calculated creatinine clearance (CrCl, using local formula) of at least 60 mL/min for cisplatin or 45 ml/mn for carboplatin
    3. Normal hematological function: absolute neutrophil count ≥1.5 giga/L and/or platelets ≥100 giga/L, hemoglobin ≥8 g/dL
    4. Normal coagulation function: International Normalized Ratio (INR) or prothrombin time ≤1.5 x ULN and activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless the patient is receiving anticoagulant therapy.

14. For patients of childbearing potential: use of an adequate method of contraception during the course of the study through 180 days after the last dose of study treatment (women of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to the first administration of study treatment).

    Note: Abstinence is acceptable if this is the usual lifestyle and the patient's preferred contraception. For male subjects, male condom or abstinence are acceptable.

15. Signed informed consent to participate in the study
16. Affiliation with or benefit from French social security.

Exclusion criteria :

1. NSCLC with expression of PD-L1 <50%.
2. NSCLC with known activating mutation of EGFR or ALK or ROS-1 translocation.
3. Neuroendocrine tumor. In cases of mixed tumors, if small cell elements are present, the patient is ineligible.
4. Any previous treatment with immunotherapy regardless of the line of treatment.

5. Before the first dose of study treatment:

   1. Has received prior systemic treatment for metastatic disease (chemotherapy or targeted therapy).
   2. Had major surgery <3 weeks prior to first dose.
   3. Received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study treatment.
6. Uncontrolled and untreated superior cava syndrome.
7. Untreated and unstable symptomatic brain metastases.
8. Leptomeningeal disease.
9. Serious concurrent conditions during the previous 6 months (severe or unstable angina pectoris, coronary or peripheral artery bypass graft of <6 months, class 3 or 4 congestive heart failure, ischemic stroke, grade ≥2 peripheral neuropathy, psychiatric or neurological disorders that may interfere with the patient's understanding of the study or with his/her informed consent.
10. Severe or non controlled systemic diseases deemed incompatible with the protocol.
11. Severe infections within 4 weeks prior to inclusion, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
12. Other previous or concomitant cancers, with the exception of basal cell carcinoma, squamous cell skin carcinoma, in situ cervical carcinoma treated, and low grade localized prostate cancer (Gleason score <6) if appropriately treated, unless the initial tumor has been diagnosed and definitively treated >5 years prior to the study, with no signs of relapse.
13. Psychological, family, social, or geographical factors that may interfere with the monitoring of the patient as defined by the protocol.
14. Any protected person (legal person protected by legal protection [guardianship, tutorship], person deprived of liberty, pregnant woman, breastfeeding woman, and minor).
15. Patients who participated in other concomitant studies unless observational and received study therapy or used an investigational device within 4 weeks prior to start of study treatment.
16. Known or suspected active autoimmune disease requiring an immunosuppressive therapy during the previous 6 months (corticosteroids or other immunosuppressive treatment). Any hormone replacement therapy (i.e. thyroxine [T4], insulin, or replacement systemic corticosteroids for adrenal or pituitary insufficiency, etc.) is not considered an immunosuppressive treatment and is authorized. Patients with hyperthyroidism or hypothyroidism who are stable under hormone replacement therapy may also be included.

17. Chronic use of immunosuppressive drugs and/or corticosteroids (>10 mg of prednisone daily). However, during the 14 days prior to randomization the use of the following is authorized:

    1. Corticosteroids as pre treatment for the administration of chemotherapy and/or for allergies or type IV hypersensitivity responses
    2. Daily prednisone (≤10 mg) as replacement therapy
    3. Inhaled or topical steroids.
18. Live-virus vaccination within 30 days of planned start of study treatment (seasonal flu vaccines that do not contain live virus are permitted).
19. Previous allogenic tissue or organ transplant.
20. History of human immunodeficiency virus (HIV) infection (positive HIV1/2 antibody test results).
21. Active hepatitis B or C.
22. Previous history of interstitial lung disease (ILD) or non infectious pneumonia (other than chronic obstructive pulmonary disease [COPD]), requiring oral or systemic steroids, current pneumonia, or anticipated ILD.
23. Known allergies or adverse reactions to the study drugs or hypersensitivity reaction to treatment with another monoclonal antibody (mAb).