eVOLVE-Meso Trial

eVOLVE-Meso Trial
Phase 3 Volrustomig (PD-1/CTLA-4 Bispecific) in Pleural Mesothelioma
Registry ID	NCT06097728
Trial Type	Phase 3, randomized, open-label, multicenter, global
Sponsor	AstraZeneca
Investigational Drug	Volrustomig (MEDI5752), PD-1/CTLA-4 bispecific antibody
Population	Untreated, unresectable pleural mesothelioma; all histologies
Planned Enrollment	~825 participants (1:1 randomization)
Primary Endpoint	Overall survival (OS)
Status (2026)	Recruiting; started November 2023
Primary Completion	Estimated November 2027

Executive Summary

The eVOLVE-Meso Trial (NCT06097728) is a Phase 3, randomized, open-label, global study evaluating volrustomig (MEDI5752) — a first-in-class bispecific antibody that targets the immune checkpoints PD-1 and CTLA-4 on a single molecule — in combination with chemotherapy as first-line treatment for unresectable pleural mesothelioma. Sponsored by AstraZeneca, the trial plans to randomize approximately 825 participants across all histologic subtypes 1:1 to volrustomig plus carboplatin and pemetrexed or to the investigator's choice of standard-of-care therapy.

What distinguishes eVOLVE-Meso from earlier mesothelioma immunotherapy trials is its active comparator. Rather than testing the experimental regimen against placebo or chemotherapy alone, the control arm is the investigator's choice of the current standard of care: nivolumab plus ipilimumab — the dual-immunotherapy regimen approved on the basis of the CheckMate 743 trial — or platinum-plus-pemetrexed chemotherapy. eVOLVE-Meso therefore measures volrustomig plus chemotherapy head-to-head against the established immunotherapy standard, not against an inactive control.

The scientific premise is that a single, engineered bispecific antibody can deliver dual PD-1 and CTLA-4 checkpoint blockade more precisely than two separate antibodies. Volrustomig is designed to concentrate CTLA-4 blockade on PD-1-positive, tumor-reactive T cells while sparing the peripheral T cells that drive much of the autoimmune toxicity seen with conventional ipilimumab — a strategy intended to decouple anti-tumor efficacy from immune-related side effects.

As of 2026, eVOLVE-Meso is recruiting, having opened in November 2023, with estimated primary completion in November 2027. No efficacy results are available; the trial's overall-survival readout is years away. Volrustomig is investigational and has not been approved by the U.S. Food and Drug Administration (FDA) for mesothelioma or any other indication.

At a Glance

eVOLVE-Meso at a glance:

• eVOLVE-Meso (NCT06097728) is a Phase 3, randomized, open-label, multicenter global trial sponsored by AstraZeneca in untreated, unresectable pleural mesothelioma
• It plans to enroll approximately 825 participants across all histologic subtypes, randomized 1:1
• The experimental arm is volrustomig plus carboplatin and pemetrexed; the comparator is the investigator's choice of nivolumab plus ipilimumab or platinum plus pemetrexed
• Volrustomig (MEDI5752) is an IgG1 monovalent bispecific antibody targeting PD-1 and CTLA-4 on a single molecule
• The molecule is engineered to preferentially block CTLA-4 on PD-1-positive T cells, aiming to separate efficacy from the autoimmune toxicity of conventional dual checkpoint blockade
• The primary endpoint is overall survival (OS)
• The trial compares the experimental regimen against the current standard of care — including the CheckMate 743 regimen of nivolumab plus ipilimumab
• The trial is recruiting as of 2026, opened November 2023, with estimated primary completion in November 2027
• Volrustomig is investigational and not FDA-approved for any indication

Key Facts

Fact	Source
eVOLVE-Meso (NCT06097728) is a Phase 3, randomized, open-label, multicenter, global study of volrustomig plus carboplatin and pemetrexed versus the investigator's choice of standard of care, sponsored by AstraZeneca, in untreated unresectable pleural mesothelioma.	ClinicalTrials.gov NCT06097728
Planned enrollment is approximately 825 participants across all histologic subtypes, randomized in a 1:1 ratio. The primary endpoint is overall survival (OS).	ClinicalTrials.gov NCT06097728
Volrustomig (MEDI5752) is an immunoglobulin G1 (IgG1) monovalent bispecific antibody engineered to target programmed death-1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) on a single molecule, preferentially blocking CTLA-4 on PD-1-positive T cells.	Dovedi et al., Cancer Discovery 2021
In the first-in-human Phase 1 study (NCT03530397), 86 patients with advanced solid tumors received volrustomig across dose-exploration and immunotherapy-naïve expansion cohorts; the most common treatment-related adverse events were pruritus (30.2%), hypothyroidism (26.7%), and hyperthyroidism (24.4%).	Tran et al., Clin Cancer Res 2026
The comparator arm includes nivolumab plus ipilimumab, the dual-immunotherapy regimen that became first-line standard of care for unresectable pleural mesothelioma after the CheckMate 743 trial (FDA approval October 2020).	Baas et al., Lancet 2021 (CheckMate 743)
Bispecific antibodies that engage two immune checkpoints represent a growing drug class in solid-tumor oncology, with volrustomig among the agents advancing into Phase 3 development.	ElBeblawy et al., Cancer Medicine 2025

Why Was eVOLVE-Meso Designed?

First-line treatment of unresectable pleural mesothelioma changed in 2020, when the CheckMate 743 trial established that dual immunotherapy with nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) extended overall survival compared with platinum-plus-pemetrexed chemotherapy. That regimen received FDA approval in October 2020 and became a standard of care, particularly valuable for the nonepithelioid subtypes that respond poorly to chemotherapy.

Dual checkpoint blockade, however, carries a cost. Combining a full-dose anti-CTLA-4 antibody with an anti-PD-1 antibody produces high rates of immune-related adverse events — colitis, hepatitis, endocrinopathies, and skin toxicity — because CTLA-4 blockade acts broadly across the T-cell compartment, including peripheral T cells that are not directed at the tumor. A meaningful fraction of patients discontinue treatment for toxicity rather than disease progression.

eVOLVE-Meso tests a different way to deliver the same two-checkpoint concept. Instead of two separate antibodies given at full systemic dose, it uses a single engineered molecule, volrustomig, built to focus CTLA-4 blockade where it matters — on the PD-1-positive T cells already engaged against the tumor — while limiting the systemic CTLA-4 exposure that drives autoimmune toxicity. The trial also adds platinum-pemetrexed chemotherapy to the immunotherapy backbone, drawing on the rationale, established in non-small-cell lung cancer, that chemotherapy and checkpoint inhibition can act synergistically through immunogenic tumor-cell death.

The Biology: Volrustomig and Dual Checkpoint Blockade

How Volrustomig (MEDI5752) Works

Volrustomig (development name MEDI5752) is an IgG1 monovalent bispecific antibody. A bispecific antibody is a single engineered protein that binds two different targets at once; "monovalent" here means the molecule presents a single binding site for each of its two targets. Volrustomig binds:

1. PD-1 (programmed death-1) — the checkpoint targeted by nivolumab and pembrolizumab. Blocking PD-1 prevents tumors from switching off T cells through the PD-L1 ligand.
2. CTLA-4 (cytotoxic T-lymphocyte antigen 4) — the checkpoint targeted by ipilimumab. Blocking CTLA-4 enhances the priming and activation of T cells.

The engineering goal is selectivity. Because the molecule binds PD-1 with high affinity, it concentrates on PD-1-positive T cells — the activated, frequently tumor-reactive population — and there delivers CTLA-4 blockade. Peripheral T cells that express CTLA-4 but little PD-1 receive comparatively less blockade. In preclinical models this design enhanced CTLA-4 blockade on PD-1-positive activated T cells while maintaining durable PD-1 inhibition, the mechanistic basis for the hypothesis that volrustomig can decouple anti-tumor efficacy from immune-related toxicity.

This places volrustomig within a broader and rapidly expanding class of dual-checkpoint bispecific antibodies being developed across solid-tumor oncology, several of which target the PD-1 and CTLA-4 axes simultaneously.

First-in-Human Phase 1 Background

Volrustomig entered clinical testing in a first-in-human Phase 1 study (NCT03530397), reported in Clinical Cancer Research in 2026. The study evaluated safety, tolerability, pharmacokinetics, immunogenicity, pharmacodynamics, and preliminary antitumor activity in patients with advanced solid tumors. Across the dose-exploration and immunotherapy-naïve expansion cohorts, 86 patients received volrustomig intravenously every three weeks, the large majority of whom were immunotherapy-naïve.

The most common treatment-related adverse events were pruritus (30.2%), hypothyroidism (26.7%), and hyperthyroidism (24.4%) — a profile consistent with immune checkpoint inhibition, weighted toward skin and thyroid effects. These early-phase safety and pharmacology data, together with preliminary signals of antitumor activity, supported the selection of a dose and schedule for the Phase 3 program, of which eVOLVE-Meso is the mesothelioma component.

Trial Design

eVOLVE-Meso (NCT06097728) is a Phase 3, randomized, open-label, multicenter, global study. Enrollment opened on November 9, 2023, with estimated primary completion in November 2027. Because the trial is open-label, treating clinicians know each participant's assignment; to protect the integrity of the survival analysis, outcome assessment is masked and AstraZeneca personnel involved in trial conduct do not access efficacy data by arm before the primary readout.

Eligibility

• Adults aged 18 years or older
• Histologically confirmed, unresectable pleural mesothelioma (all histologic subtypes — epithelioid and nonepithelioid)
• No prior systemic therapy for mesothelioma (first-line setting)
• Adequate performance status and organ function for combination immunotherapy and chemotherapy

Randomization and Arms

Approximately 825 participants are randomized 1:1. Assignment within the comparator arm depends on histology, reflecting standard-of-care practice.

Arm	Regimen
Experimental	Volrustomig (MEDI5752) in combination with carboplatin plus pemetrexed (Pem+Carbo) intravenously (IV).
Comparator (investigator's choice of standard of care)	For epithelioid histology: nivolumab plus ipilimumab (Nivo+Ipi) or platinum plus pemetrexed (Plat+Pem) chemotherapy. For nonepithelioid histology: nivolumab plus ipilimumab.

Endpoints

• Primary endpoint: Overall survival (OS) in the experimental arm relative to the comparator arm
• Secondary endpoints (typical for this design): progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety

What eVOLVE-Meso Is Measuring (Status: Recruiting)

As of 2026, eVOLVE-Meso is actively recruiting and no efficacy results have been reported. The central question the trial is built to answer is whether volrustomig plus chemotherapy improves overall survival compared with today's standard of care in first-line, unresectable pleural mesothelioma.

Because the comparator includes nivolumab plus ipilimumab, a positive result would represent more than a step up from chemotherapy — it would mean a bispecific-antibody regimen outperformed the established dual-immunotherapy standard. A neutral or negative result would help define the ceiling of checkpoint-inhibitor benefit in mesothelioma and clarify whether the bispecific design's theoretical advantages translate into survival gains. Either way, the estimated primary-completion timeline points to a survival readout no earlier than late 2027, with regulatory review, if pursued, following thereafter.

How eVOLVE-Meso Differs from CheckMate 743

Feature	CheckMate 743	eVOLVE-Meso
Immunotherapy	Nivolumab + ipilimumab (Nivo+Ipi) — two separate antibodies	Volrustomig — one PD-1/CTLA-4 bispecific antibody
Chemotherapy	None (immunotherapy alone)	Yes — added carboplatin + pemetrexed
Control arm	Platinum + pemetrexed chemotherapy	Investigator's choice: Nivo+Ipi or platinum + pemetrexed
Status	Reported; FDA-approved October 2020	Recruiting; survival readout estimated 2027+
Design intent	Establish dual immunotherapy vs chemotherapy	Test whether a bispecific + chemo beats the current standard

Regulatory and Access Status (2026)

Volrustomig is investigational. It has not received FDA approval for mesothelioma or any other cancer as of 2026, and it is available only through participation in clinical trials such as eVOLVE-Meso. There is no expanded-access or off-label pathway for volrustomig in mesothelioma outside of a trial, because the molecule remains in Phase 3 testing.

Patients and families interested in eVOLVE-Meso should discuss eligibility with a thoracic oncology center, review the trial's listing on ClinicalTrials.gov under identifier NCT06097728, and confirm the nearest participating site. Enrollment decisions belong to the treating oncology team and the trial investigators.

Related Topics

• CheckMate 743 Trial — first-line nivolumab plus ipilimumab immunotherapy
• ATOMIC-Meso Trial — first-line pegargiminase for nonepithelioid mesothelioma
• NIPU Trial / UV1 Vaccine — telomerase peptide vaccine in pretreated mesothelioma
• MARS2 Trial — extended pleurectomy/decortication
• Immunotherapy for Mesothelioma — overview of checkpoint inhibition
• Clinical Trials for Mesothelioma — how to find and join a trial
• Pleural Mesothelioma — overview of disease subtypes
• Pemetrexed Chemotherapy — backbone combination partner

Glossary

• Bispecific antibody — A single engineered antibody that binds two different targets simultaneously.
• CTLA-4 — Cytotoxic T-lymphocyte antigen 4; an immune checkpoint that restrains T-cell activation; the target of ipilimumab.
• ECOG PS — Eastern Cooperative Oncology Group performance status; a 0–5 scale of functional status (0 = fully active).
• IgG1 — Immunoglobulin G subclass 1; the antibody backbone format of volrustomig.
• IV — Intravenous; administration directly into a vein.
• MEDI5752 — The development name for volrustomig.
• Monovalent bispecific — A bispecific antibody presenting a single binding site for each of its two targets.
• OS — Overall survival; time from randomization to death from any cause.
• PD-1 — Programmed death-1; an immune checkpoint on T cells; the target of nivolumab and pembrolizumab.
• PFS — Progression-free survival; time from randomization to documented progression or death.
• TRAE — Treatment-related adverse event; a side effect attributed to study treatment.
• Volrustomig — The PD-1/CTLA-4 bispecific antibody investigated in eVOLVE-Meso.

External Links

• eVOLVE-Meso (NCT06097728) — ClinicalTrials.gov registry record
• First-in-human study of volrustomig, a PD-1/CTLA-4 bispecific antibody — Tran et al., Clinical Cancer Research 2026