Overview

This is a multicentre, phase IIR, double non-comparative arm trial, with an initial safety run for the anti-LAG3 arm.

Approximately 40 sites will participate in the study and will enroll 126 patients with treatment-naive, unresectable malignant PM.

Treatment will be administered in 21-day cycles and will continue until disease progression, unacceptable toxicity, withdrawal of consent or for 2 years immunotherapy maximum.

Once the patient discontinues study treatment, the treatment period will end and the patient will enter the follow-up period. No cross-over is allowed between arms.

Eligibility

Inclusion Criteria: 1. Signed written Informed Consent. * Subjects must have signed and dated an 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. Histological diagnosis (no cytology allowed, thoracoscopy biopsy recommended). 3. Non resectable PM as evaluated by a specialist MTB comprising a specialized thoracic surgeon. 4. Measurable disease by CT with iodure injection according to RECIST 1.1 modified criteria for mesothelioma (pleural thickness perpendicular to the chest wall or mediastinum of 7 mm or more, on 2 positions, at 3 separate levels on transverse cuts of CT-scan, at least 1 cm apart, the sum of 6 measurements defining a pleural unidimensional measure), or according to RECIST1.1 criteria for mediastinal nodes or metastatic lesion. 5. ECOG PS 0 and 1. 6. Weight loss \<10% within 3 months of study entry. 7. Chemo-naive and immuno-naive. 8. Age ≥18 years, \<76 years. 9. Life expectancy \>3 months. 10. Available pathological samples (at least 10 slides from the thoracoscopy pleural biopsy sample). 11. Adequate biological functions: creatinine clearance ≥45 mL/min (Cockroft or MDRD or CKD-epi); neutrophils ≥1500/mm3; platelets ≥100 000/mm3; haemoglobin ≥9g/dL; AST and ALT \<3 x ULN, total bilirubin \<2 x ULN (patients with hepatic metastases or Gilbert's syndrome must have AST and ALT ≤5 x ULN and a baseline total bilirubin ≤2 x ULN). 12. WOCBP\* must have a negative serum (beta-hCG) at screening. \*WOCBP are defined as women who are fertile following menarche until becoming postmenopausal, unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the CTFG guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation. 13. Male study participants with WOCBP partners are required to use condoms during the study and until 6 months after the last dose of study treatment unless they are vasectomised or practice sexual abstinence. 14. Vasectomised partner or vasectomised study participant must have received medical assessment of the surgical success. NB: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and LAM are not acceptable methods of contraception. Female condom and male condom should not be used together. 15. WOCBP must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the entire trial and until 6 months after last treatment. 16. All men must agree not to donate sperm during the trial and for 6 months after receiving the last therapy dose. 17. As recommended in current French guidelines, a firm recommendation of radiation therapy for thoracocentesis tracts (3 x 7Gy) is made for patients with thoracocentesis or thoracoscopy within 2 months before accrual, with a firmly recommended interval between thoracoscopic procedure (removal of drains) and radiation of no more than 42 days. A 7-day interval between the end of radiotherapy and the initiation of treatment should be respected. Exclusion Criteria: 1. ECOG PS\>2. 2. Previous cancer treatment including chemotherapy or immunotherapy with anti-PD-1, anti-PD-L1, Anti-CTLA4 or any ICI antibody. 3. Pleural effusion as the only radiological abnormality without measurable pleural thickness or mediastinal node enlargement. 4. Peritoneal, pericardial or tunica vaginalis testis mesothelioma. 5. Previous diagnosis of adenocarcinoma from any anatomic site within the previous 5 years, with the exception of prostate adenocarcinoma history within the previous 5 years, in case of localized prostate cancer, with good prognostic factors according to d'Amico classification (\45%. 18. TnT or troponin I TnI \> 2x institutional ULN at baseline. Patients with TnT or TnI levels between \>1 to 2xULN are permitted if repeat levels within 24 hours are ≤ 1x ULN. If TnT or TnI levels are \>1 to 2xULN within 24 hours, the subject may undergo a cardiac evaluation and be considered for treatment by the investigator based on cardiological medical judgement in the patient's best interest. 19. Known hypersensitivity to the active substances or to any of the excipients. 20. Pre-existing moderate or severe lung interstitial disease as assessed by the diagnosis CT-scan and decrease of TLCO higher than 35% from theoretical normal values linked to such interstitial disease. 21. Inability to comply with study or follow-up procedures as estimated by the referent investigator. 22. Pregnant or breastfeeding women. 23. Women of childbearing potential (WOCBP)\* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include: 1. Stable use of combined (oestrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening; 2. Intrauterine device; intrauterine hormone-releasing system; 3. Bilateral tubal occlusion/ligation; 4. Vasectomized partner (provided that the male vasectomized partner is the sole sexual partner of the WOCBP study participant and that the vasectomized partner has obtained medical assessment of surgical success for the procedure); or 5. Sexual abstinence†. \*Pregnancy testing and contraception are required for WOCBP. †Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 24. For patients receiving cisplatin: patients with hearing problems; creatinine clearance \<60 ml/min; patients concomitantly receiving phenytoin with prophylactic aim.