Trial: MEDI5752 in Combination With Carboplati…

Trial Details

Sponsor: AstraZeneca (industry)

Phase: 3

Start date: Nov. 9, 2023

Planned enrollment: 825

Trial ID: NCT06097728

More trial details at ClinicalTrials.gov

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Investigational Drug AI Analysis

Show for: Volrustomig (MEDI5752, PD-1/CTLA-4 DuetMab, MEDI-5752)

Overview

Volrustomig (MEDI5752) is an investigational, humanized, monovalent bispecific IgG1 antibody that targets PD‑1 and CTLA‑4. It is being studied across multiple tumor types, including renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), pleural mesothelioma, hepatobiliary cancers, and head and neck cancer, in phases 1–3. Early clinical data show antitumor activity, with ongoing efforts to optimize dose to balance efficacy and immune‑related toxicities. (aacrjournals.org)

Mechanism of action

Volrustomig binds PD‑1 and CTLA‑4 with a “DuetMab” monovalent bispecific format engineered to fully block PD‑1 while preferentially inhibiting CTLA‑4 on activated PD‑1–positive T cells within tumors. This design enhances CTLA‑4 engagement in the tumor microenvironment and reduces activity on PD‑1–negative peripheral T cells. Tethering CTLA‑4 to PD‑1 also drives rapid internalization and degradation of PD‑1, providing a distinct mechanism from conventional separate PD‑1 and CTLA‑4 monoclonal antibodies. The Fc region is engineered to reduce effector function. (aacrjournals.org)

Efficacy

Advanced clear‑cell RCC (first‑line, monotherapy): In a phase 1 expansion (NCT03530397), volrustomig 1,500 mg Q3W produced an ORR of 38.5% in all expansion patients (n=26) and 58.3% in the first‑line ccRCC subset (n=12); median duration of response, PFS, and OS were not reached at 14.6 months’ follow‑up in the first‑line subset. Subsequent first‑line cohorts tested lower fixed doses. At ESMO 2023, ORR was 46.9% with 750 mg (n=32) and 45.5% with 500 mg (n=33); complete responses 9.4% and 6.1%, respectively; median PFS 11.1 and 9.9 months. (ascopubs.org)
Metastatic non‑squamous NSCLC (first‑line, with chemotherapy): In ESMO 2022 LBA56 (phase 1b/2, NCT03530397), volrustomig 1,500 mg + carboplatin/pemetrexed improved median PFS (15.1 vs 8.9 mo), DOR (20.5 vs 9.9 mo), and OS (not reached vs 16.5 mo) versus pembrolizumab + chemotherapy in a small randomized signal‑finding cohort (n=41). A separate single‑arm cohort using 750 mg + chemotherapy showed emerging ORR 44% overall and 48% in PD‑L1 <1% with improved tolerability at ~3.9 months’ follow‑up. A phase 3 trial (eVOLVE‑Lung02) is comparing volrustomig + chemotherapy vs pembrolizumab + chemotherapy in PD‑L1 <50% mNSCLC. (oncologypro.esmo.org)
Ongoing phase 3 programs: Volrustomig + carboplatin/pemetrexed is being compared against platinum/pemetrexed or nivolumab/ipilimumab in unresectable pleural mesothelioma; additional phase 3 evaluation is underway as consolidation after chemoradiotherapy in locally advanced head and neck squamous cell carcinoma. Results are pending. (mayo.edu)
Other tumor settings under study: Master protocols include combinations in hepatocellular and biliary tract cancers (e.g., volrustomig ± bevacizumab or lenvatinib; volrustomig + gemcitabine/cisplatin). RCC combinations with VEGF‑TKIs (e.g., lenvatinib/axitinib) are also in early‑phase evaluation. (mskcc.org)

Safety

Class‑consistent immune‑related adverse events (irAEs) occur and increase with higher dosing/intensity of CTLA‑4 engagement. In RCC expansion at 1,500 mg Q3W, grade 3–4 treatment‑related AEs occurred in 74.1% with discontinuations in 70.4%; hepatotoxicity was a common reason for discontinuation. In the dose‑escalation/expansion RCC cohorts overall, grade 5 TRAEs occurred in 1 patient per cohort. (ascopubs.org)
In NSCLC (ESMO 2022), volrustomig 1,500 mg + chemotherapy had grade ≥3 TRAEs and discontinuations of 70% each; lowering to 750 mg + chemotherapy reduced grade ≥3 TRAEs to 32% and discontinuations to 20%, while maintaining antitumor activity signals. (oncologypro.esmo.org)
Across first‑line RCC mini‑oral cohorts (ESMO 2023), grade 3–4 immune‑related AEs were more frequent at 750 mg than 500 mg (46.9% vs 24.2%), but most non‑endocrine irAEs resolved and about half did not require steroids; overall disease control remained high. (oncologypro.esmo.org)

TrialFetch AI Analysis

Goal: Evaluate whether adding volrustomig (MEDI5752) to carboplatin plus pemetrexed improves survival and clinical outcomes compared with current first-line standards—platinum plus pemetrexed or nivolumab plus ipilimumab—in unresectable pleural mesothelioma.

Patients: Adults ≥18 years with histologically confirmed unresectable pleural mesothelioma (epithelioid or non-epithelioid), measurable disease by modified RECIST 1.1, ECOG 0–1, and adequate organ function. Key exclusions include active or prior significant autoimmune/inflammatory disease, uncontrolled infections (including uncontrolled HBV/HCV/HIV, TB), another active malignancy with limited exceptions, untreated or progressive CNS metastases, and concurrent anticancer therapies.

Design: Global, multicenter, phase III, randomized, open-label study with 1:1 allocation to experimental therapy versus investigator’s choice control, stratified by histology. Planned enrollment is 825 participants. Primary intent is treatment with overall survival as the primary endpoint; follow-up up to approximately 61 months.

Treatments: Experimental: Volrustomig plus carboplatin and pemetrexed. Volrustomig (MEDI5752) is a monovalent bispecific antibody targeting PD-1 and CTLA-4, designed to fully inhibit PD-1 and preferentially inhibit CTLA-4 on activated PD-1–positive T cells in tumors, potentially enhancing intratumoral activity while reducing peripheral toxicity versus separate checkpoint antibodies. The bispecific format promotes PD-1 internalization and degradation. Early-phase studies in solid tumors, notably first-line renal cell carcinoma, showed objective response rates around 45% to 48% at doses of 500–750 mg every 3 weeks, with dose-dependent immune-related toxicity higher at ≥1500 mg; development focuses on sub-1500 mg dosing to balance efficacy and safety. Control: Investigator’s choice of standard of care—platinum (carboplatin or cisplatin) plus pemetrexed for epithelioid histology, or nivolumab plus ipilimumab; for non-epithelioid histology, nivolumab plus ipilimumab is mandated.

Outcomes: Primary: Overall survival. Secondary: Overall survival (additional analyses), progression-free survival by mRECIST 1.1 and/or RECIST 1.1, landmark OS (12, 18, 24, 36 months), landmark PFS (6, 12, 18, 24 months), overall response rate, duration of response, PFS2, patient-reported outcomes including physical function (PROMIS PF SF 8c), disease-related symptoms (EORTC IL305 and PRO-CTCAE items), role functioning and global health/HRQoL (EORTC QLQ-C30 subscales), safety by CTCAE v5.0, immunogenicity (anti-drug antibodies), and volrustomig pharmacokinetics (AUC, Cmax, Tmax).

Burden on patient: Moderate. As a phase III study with intravenous therapies, participants will undergo regular clinic visits for infusions, safety labs, and imaging at intervals typical for first-line mesothelioma care. Added burden arises from investigational agent-specific assessments, including immunogenicity sampling and pharmacokinetic timepoints, which increase blood draw frequency, particularly in early cycles. Patient-reported outcome questionnaires at multiple visits add brief time commitments. No mandated additional invasive procedures beyond standard-of-care biopsies are described. Travel and time demands align with standard chemoimmunotherapy schedules, with modest incremental visits for PK/ADA collections and study assessments over approximately 5 years of follow-up.

Last updated: Oct 2025

Eligibility

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London, Ontario, N6A 5W9, Canada

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Berlin, 14109, Germany

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Bochum, 44791, Germany

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Cologne, 51109, Germany

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Essen, 45122, Germany

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Gauting, 82131, Germany

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Georgsmarienhütte, 49124, Germany

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Großhansdorf, 22927, Germany

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Hamburg, 21075, Germany

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Heidelberg, 69126, Germany

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Kiel, 24105, Germany

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Münster, 48153, Germany

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Berlin, 13125, Germany

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Olsztyn, 10-357, Poland

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Poznan, 60-569, Poland

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Warsaw, 02-781, Poland

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Ulsan, 44033, South Korea

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Seoul, 06591, South Korea

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Seoul, 06351, South Korea

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Oviedo, 33011, Spain

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Taoyuan District, 333, Taiwan

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Santa Rosa, California, 95403, United States

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Chicago, Illinois, 60637, United States

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Commack, New York, 11725, United States

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Valhalla, New York, 10595, United States

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Columbus, Ohio, 43210, United States

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Portland, Oregon, 97213, United States

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Portland, Oregon, 97225, United States

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Philadelphia, Pennsylvania, 19104, United States

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Houston, Texas, 77030, United States

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Fairfax, Virginia, 22031, United States

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