Inclusion Criteria:  Male or female subjects aged ≥ 18 years and capable of giving signed informed consent or requirement per local legislation. ECOG performance status of 0-2. Histologically confirmed malignant pleural mesothelioma (all histological subtypes are eligible), unresectable advanced or metastatic. Patients that progressed or be intolerant to ≤ 2 regimens of chemotherapy, including platinum-based chemotherapy with pemetrexed. Prior bevacizumab treatment given during chemotherapy are allowed. Evaluable disease or measurable disease as assessed according to the modified RECIST v1.1 criteria. Availability of tumor tissue for translational research (at least 10 slides); Archival tumor tissue at diagnosis can be sent if it was obtained less than 18 months ago. Life expectancy of at least 3 months. Adequate hematologic and organ function defined by the following laboratory results obtained within 14 days prior to enrollment:  Hematologic: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100 × 109/L, and hemoglobin ≥ 9 g/dL Hepatic: Total bilirubin level ≤ the upper limit of normal (UNL) range, AST and ALT levels ≤ 1.5 x ULN and ALP ≤ 2.5 x ULN. For participants with liver involvement in their tumor, AST ≤5 x ULN, ALT ≤ 5 x ULN, and bilirubin ≤ 3.0 x ULN.  Renal: Creatinine level ≤1.5 x ULN or estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method) For participants with Creatinine > 1.5 x ULN, glomerular filtration rate (GFR) can also be used.  Coagulation: normal international normalized ratio (INR), PT ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN.  Stable HIV infection on ART for at least 4 weeks, no documented evidence of multi-drug resistance, viral load of < 400 copies/ml and CD4+ T-cells ≥ 350 cells/μL. Controlled HBV/HCV infection on a stable dose of antiviral therapy, HBV viral load below the limit of quantification. HCV viral load below the limit of quantification. All patients are notified of the investigational nature of this study and signed a written informed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention. For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly throughout the study and for at least 2 months after last bintrafusp alfa treatment administration . For male patients with female partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate [< 1% per year] when used consistently and correctly. Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 8 days prior to initiation of study drug.  Exclusion Criteria:  Prior immune checkpoint therapy with an anti-PD-1, anti-PD-L1, anti-CD137, or anti-CTLA-4 antibody. Known severe hypersensitivity [Grade ≥ 3 NCI CTCAE 5.0]) to investigational product or any component in its formulations, any history of anaphylaxis, or recent, within 5 months, history of uncontrollable asthma. Previous malignant disease (other than the target malignancy to be investigated in this study) within the last 3 years. Participants with a history of cervical carcinoma in situ, superficial or noninvasive bladder cancer, localized prostate cancer or basal cell or squamous cell carcinoma in situ previously treated with curative intent and endoscopically resected GI cancers limited to the mucosal layer without recurrence in > 1 year are NOT excluded. Active central nervous system (CNS) metastases and/or carcinomatous meningitis that require therapeutic intervention or are causing clinical symptoms. Patients with previously treated brain metastases may participate provided the participants are stable and are not using steroids for at least 7 days prior to randomization. Prior major surgery within 4 weeks prior to the first dose of study intervention. Unstable or unresolved surgical or chemotherapy-related toxicity that would compromise the patient's capacity to participate in the trial. Persisting Grade > 1 NCI CTCAE 5.0 toxicity (except alopecia and vitiligo) related to prior therapy; however, sensory neuropathy Grade ≤ 2 is acceptable. Prior organ transplantation including allogenic stem-cell transplantation, except transplants that do not require immunosuppression. Live vaccines given 30 days prior to first dose of protocol treatment (M7824). Seasonal flu vaccines that do not contain a live virus are permitted. Also, COVID-19 vaccines approved by the authorities that do not contain live virus are permitted. Drug-induced interstitial lung disease (ILD) or participant has had a history of drug-induced pneumonitis that has required oral or IV steroids, and/or other diseases, which in the opinion of the Investigator might impair the participant's tolerance for the study or ability to consistently participate in study procedures. Active and serious autoimmune disease that might deteriorate upon treatment with immunotherapy. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) or topical therapy (e.g., steroids) for psoriasis or eczema is not considered a form of systemic treatment. Ongoing clinically serious infections requiring systemic antibiotic or antiviral, antimicrobial, or antifungal therapy. Known history of active tuberculosis or any active infection requiring systemic therapy. Patients with diagnosed immunodeficiency or receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to randomization. Clinically significant cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication. History of bleeding diathesis or recent major bleeding events (i.e. Grade ≥ 2 bleeding events in the month prior treatment) Patients with any serious underlying medical condition that might impair patient's capacity to participate in the trial. Substance or alcohol abuse, medical, psychological or social conditions that may interfere with the patient's participation in the trial or evaluation of the trial results. Women who are pregnant or in the period of lactation.