• Pathologically confirmed diagnosis of malignant pleural mesothelioma

• Unresectable per thoracic surgeon assessment

• At least one prior line of systemic therapy. Note: Patients who were on prior immunotherapy are eligible.

• ECOG 0-1

• PFTs: DLCO \>40% predicted, FEV1 \>50% predicted

• Male/female participants who are at least 18 years of age on the day of signing informed consent

• Disease outside the ipsilateral thorax allowed as long as it has either been treated definitively and been stable for 6 months

∙ Male participants:

• A male participant must agree to use a contraception as detailed in Appendix 1 of this protocol during the treatment period and for at least 30 days, corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and or any active comparator/combination) plus an additional 120 days (a spermatogenesis cycle) for study treatments with evidence of genotoxicity at any dose after the last dose of study treatment and refrain from donating sperm during this period.

∙ Female participants:

• A female participant is eligible to participate if she is not pregnant (see Appendix 1), not breastfeeding, and at least one of the following conditions applies:

‣ Not a woman of childbearing potential (WOCBP) as defined in Appendix 1 OR

⁃ A WOCBP who agrees to follow the contraceptive guidance in Appendix 1 during the treatment period and for at least 120 days (corresponding to time needed to eliminate any study treatment(s) (pembrolizumab and or any active comparator/combination) plus 30 days (a menstruation cycle) for study treatments with risk of genotoxicity after the last dose of study treatment.

• The participant (or legally authorized representative if applicable) provides written informed consent for the trial.

• Have a ECOG performance status of 0 to 1. Evaluation of ECOG is to be performed within 30 days prior to the date of allocation.

• Have adequate organ function as defined in the following table (Table 1). Specimens must be collected within 45 days prior to the start of study treatment.

∙ Table 1: Adequate Organ Function Laboratory Values

∙ System: Hematological Absolute neutrophil count (ANC) ≥ 1.5 K/mcL Platelets ≥ 100 K/mcL Hemoglobin ≥ 9.0 g/dL

∙ System: Renal Creatinine OR Measured or calculated\^b creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤ 1.5 x ULN OR ≥ 30 mL/min for participant with creatinine levels \>1.5 x institutional ULN

∙ System: Hepatic Total bilirubin: ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels \>1.5 x ULN AST (SGOT) and ALT (SGPT): ≤ 2.5 x ULN (≤ 5 x ULN for participants with liver metastases)

∙ ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal. Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.

∙ \^b: Creatinine clearance (CrCl) should be calculated per institutional standard.

∙ Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.