• This is a randomized (1:1), open-label, Phase III trial in participants with untreated unresectable PM evaluating volrustomig (MEDI5752) in combination with carboplatin and pemetrexed compared to investigator’s choice of nivolumab and ipilimumab or platinum plus pemetrexed chemotherapy for participants with epithelioid histology, and nivolumab plus ipilimumab for participants with non-epithelioid histology.

• The trial hypothesis is that combining PDx and CTLA-4 inhibition with chemotherapy in both histologies has the potential to provide greater efficacy over currently available SoC regimens of nivolumab plus ipilimumab or pemetrexed plus cisplatin or carboplatin.

• To demonstrate the superiority of volrustomig in combination with carboplatin plus pemetrexed relative to investigators choice of nivolumab in combination with ipilimumab or platinum plus pemetrexed by assessment of OS in PM participants with epithelioid histology

• Advanced unresectable disease that cannot be treated with surgery with curative intent (with or without chemotherapy)
• WHO/ECOG performance status of ) or 1 with no deterioration over the previous 2 weeks prior to day of first dosing
• Provision of existing (leftover) tumor sample obtained within 6 months prior to screening is required, if available.
• Prior palliative radiotherapy is permitted, but at least 14 days must elapse prior to first dose and all signs of toxicity must be resolved.

Medical conditions

• As judged by the investigator, any condition that would interfere with evaluation of the investigational product or interpretation of participant safety or study results.
• History of another primary malignancy except for:
  • Malignancy treated with curative intent and adequate follow-up with no known active disease or have not required active treatment within the past 2 years before the first dose of study intervention and of low potential risk for recurrence.
  • Adequately treated nonmelanoma skin cancer or lentigo maligna without evidence of disease.
  • Adequately treated carcinoma in situ, including Ta bladder tumors, without evidence of disease. Cancer participants with incidental histologic findings of prostate cancer that, in the opinion of the investigator, is not deemed to require active therapy (eg, incidental prostate cancer identified following cystoprostatectomy that is tumor/node/metastasis stage ≤ pT2N0) may be enrolled, pending discussion and approval by the investigator.
• Active or prior documented autoimmune or inflammatory disorders including inflammatory bowel disease (eg, colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), celiac disease, systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, pneumonitis (past medical history of ILD, drug-induced ILD, or radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD), etc. The following are exceptions to this criterion:
  • Participants with vitiligo or alopecia.
  • Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
  • Any chronic skin condition that does not require systemic therapy.
  • Participants without active disease in the last 5 years prior to enrolment may be included.
  • Participants with celiac disease controlled by diet alone.
• History of active primary immunodeficiency.
• Untreated or progressive CNS metastatic disease, any leptomeningeal disease, or cord compression. Participants with suspected brain metastases at screening should have a CT/MRI of the brain prior to study entry. The following participants can be included:
  • Participants previously treated with radiation or surgical resection within 3 month prior to first dose of investigational products for CNS metastases who are asymptomatic, and clinically stable who do not require corticosteroids for at least 14 days prior to the first dose of investigational product.
• As judged by the investigator, any evidence of diseases and/or history of organ transplant or allogeneic stem cell transplant, which, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
• Evidence of the following infections:
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination, and radiographic findings and tuberculosis testing in line with local practice),
  • HIV infection that is not well controlled.
  • Active or uncontrolled hepatitis B (HBV) or hepatitis C (HCV)
• Participant meets one or more of the following:
  • Resting corrected QT interval >480 ms, obtained from electrocardiograms (ECGs) performed at screening.
  • History of QT prolongation associated with other medications that required discontinuation of that medication.
  • Congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives.
  • History of arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia. Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the investigator judgment with cardiologist consultation recommended.

Prior/Concomitant Therapy

• Prior therapy for PM, including chemotherapy (adjuvant, neoadjuvant), radical pleuropneumonectomy with or without intensity modulated radiotherapy (excluding debulking surgery), and non-palliative radiation therapy, intraoperative or intracavitary chemotherapy for PM.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of investigational product; the following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (eg, intraarticular injection).
  • Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) or a single dose for palliative purpose (eg, pain control).
• Prior exposure to immune-mediated therapy including, but not limited to, other anti- CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
• Radiotherapy treatment with a wide field of radiation or to more than 30% of the bone marrow within 4 weeks, prior to the first dose of study intervention.
• Major surgery within 4 weeks prior to the first dose of study intervention or still recovering from prior surgery.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of investigational product.
• Any concurrent chemotherapy, radiotherapy, investigational, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (eg, insulin for diabetes and HRT) is acceptable.
• Any concomitant medication known to be associated with Torsades de pointes.
• History of anaphylaxis to any biologic therapy or vaccine.

Prior/Concurrent Clinical Study Experience

• Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study.
• Participants with a known allergy or hypersensitivity to investigational product(s), or any excipients of the investigational product(s).
• Medical contraindication to platinum pemetrexed (carboplatin or cisplatin)-based chemotherapy.
• Previous enrolment or randomization in the present study.

Diagnostic Assessments

• Primitive peritoneal, pericardial, testis or tunica vaginalis mesothelioma.
• Undetermined histology of epithelioid vs. non-epithelioid mesothelioma.

Other Exclusions

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
• Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
• Participants must refrain from breastfeeding and must not donate, or retrieve for their own use, ova from enrolment throughout the study and until 90 days after last dose of volrustomig, and 180 days or per local prescribing information after the last dose of all other study treatments.
• Participants must refrain from fathering a child or donating sperm from enrolment, throughout the study and until 90 days after the last dose of volrustomig, and 180 days or per local prescribing information after the last dose of all other study treatments.