Evaluating Ivonescimab as a Potential Treatment for Pleural Mesothelioma Patients Whose Cancer Has Returned After Previous Immunotherapy and Chemotherapy

Inclusion Criteria: 1. Signed 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. Histologically-proven Pleural Mesothelioma (no cytology allowed, biopsies by thoracoscopy recommended). Note: pathology certification by national expert network NETMESO/MESOPATH should be checked as already done in routine in France by NETMESO regional expert MTB for PM (or similar national certification if the patient had his/her PM diagnosis obtained outside France, e.g. Belgium). 3. Documented progression by CT with iodine injection according to modified RECIST 1.1 for mesothelioma (mRECIST 1.1; pleural thickness perpendicular to the chest wall or mediastinum of 7mm or more, on 2 positions, at 3 separate levels on transverse cuts of CT-scan, at least 1cm apart, the sum of 6 measurements defining a pleural unidimensional measure), or according to RECIST 1.1 for mediastinal nodes or metastatic lesion, after maximum 2 lines including immunotherapy by nivolumab ± ipilimumab, and standard P/P chemotherapy \[with (maximum 40% total of patients) or without bevacizumab\], sequentially (regardless of treatment order), or first-line combining standard chemotherapy + IO (pembrolizumab or other IO investigational drug but no anti-angiogenic drug). Note: treatment continued beyond disease progression because the patient derived clinical benefit, will not count as another line (limited to one oligoprogression with local ablative treatment ((stereotactic) radiotherapy / cryotherapy etc.). However, restarting a systemic therapy with an identical protocol after an interruption of \>3 months will be considered as a new line of treatment. 4. Measurable disease according to mRECIST 1.1. 5. ECOG PS 0 or 1. 6. Weight loss \<10% within 3 months of study entry. 7. Age ≥18 years. 8. Life expectancy \>3 months. 9. Available pathological samples (at least 10 slides from the thoracoscopy biopsies) for centralized PD-L1, MTAP, immunohistochemistry, and NGS / transcriptome analyses, all slides being centrally reviewed by the French panel MESOPATH for mesothelioma histological certification. If archival tissue is either insufficient or unavailable, the patient may still be eligible upon discussion with IFCT. 10. Adequate biological functions: Creatinine Clearance ≥45 mL/min (Cockroft or MDRD or CKD-epi); neutrophils ≥1500/mm3; platelets ≥100 000/mm3; haemoglobin ≥9 g/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), urine protein \<2+ or 24 hours urine protein quantification \<1.0 g, prothrombin time (PT) or international normalized ratio (INR) ≤1.5 x ULN, and partial prothrombin time (PTT) or activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless abnormalities are unrelated to coagulopathy or are secondary to prophylactic coagulation). 11. Women of childbearing potential and sexually active should use a highly effective 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. 12. For male subjects who are sexually active with women of childbearing potential, an efficacious contraception method should be used during the treatment and during the 6 months following the last dose. 13. Patient covered by a national health insurance. 14. Washout period: 21 days from last dose of treatment Exclusion Criteria: 1. ECOG PS\>1. 2. Previous treatment for PM by more than 2 lines of systemic treatment, or by bevacizumab (or another anti-angiogenic / anti-VEGF pathway drug) except if combined with P/P chemotherapy \[scheme validated by ASCO, NCCN, and ESMO guidelines\] in maximum 40% of the total of recruited patients (n=15). 3. Suspicion of hyperprogressive disease or rapid tumour progression when treated by previous IO (i.e. progressive disease within 9 weeks of treatment by previous nivolumab ± ipilimumab or alternative immunotherapy, starting from C1D1 or from randomization if previous experimental immunotherapy). 4. Pleural effusion as the only radiological abnormality without measurable pleural thickness or mediastinal node enlargement. 5. Peritoneal, pericardial or tunica vaginalis testis mesothelioma, without any pleural involvement at the time of diagnosis. 6. Previous diagnosis of adenocarcinoma from any anatomic site within the previous 3 years, with the exception of prostate adenocarcinoma history in case of localized prostate cancer with good prognostic factors according to d'Amico classification (\<T2a, Gleason score ≤6 and PSA ≤10 ng/ml), provided they were treated in a curative modality (surgery or radiotherapy, without any chemotherapy). 7. Previous or active cancer within the previous 3 years (except for already treated in situ carcinoma of the cervix, or basal cell skin cancer, treated or not). 8. Uncontrolled pleural effusion despite previous (talc or other) pleurodesis, requiring thoracocentesis (by pleural aspiration) more often than every 21 days. However, patients with efficient indwelling pleural catheter (IPC) are eligible. 9. Symptomatic untreated brain metastasis (without previous whole brain radiotherapy or stereotactic ablative brain radiotherapy or without surgical resection). At least 2 weeks delay between the end of radiotherapy and the beginning of the treatment should be respected. Asymptomatic brain metastasis, not needing corticosteroids (\>10 mg prednisone equivalent daily) or mannitol