Investigational Drug
Volrustomig
TrialFetch AI Analysis
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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
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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)
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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)
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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)
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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
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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)
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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)
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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)
Further reading
- Design/mechanism and translational evidence for MEDI5752 (volrustomig). Cancer Discovery (2021). (aacrjournals.org)
- Phase 1 RCC expansion (monotherapy) — ASCO 2022 abstract 107. (ascopubs.org)
- First‑line RCC (dose‑finding mini‑oral) — ESMO 2023 abstract 1883MO. (oncologypro.esmo.org)
- First‑line NSCLC with chemotherapy — ESMO 2022 LBA56; overview article. (oncologypro.esmo.org)
- Phase 3 programs: eVOLVE‑Lung02 (NSCLC) and mesothelioma study listings. (ascopubs.org)
Notes: All efficacy and safety data above are from early‑phase or conference abstracts with limited patient numbers and follow‑up; confirmatory phase 3 results are pending.
Last updated: Oct 2025
Active trials using Volrustomig
Found 9 active trials using this drug:
TrialFetch AI summary: This trial enrolls adults with metastatic, pMMR/MSS colorectal adenocarcinoma (no liver or CNS metastases, ECOG 0-1, no prior systemic therapy for metastatic disease) to evaluate the addition of volrustomig—a bispecific anti-PD-1/CTLA-4 antibody—to FOLFIRI and bevacizumab versus standard FOLFIRI plus bevacizumab. Volrustomig is designed to enhance immune response by targeting CTLA-4 selectively on PD-1+ T cells.
ClinicalTrials.gov ID: NCT06792695
TrialFetch AI summary: This trial enrolls treatment-naïve patients with stage IV non-squamous NSCLC (ECOG 0–1, no EGFR or other driver mutations) and randomizes them to one of two volrustomig priming regimens (a novel PD-1/CTLA-4 bispecific antibody) in combination with carboplatin and pemetrexed. Patients with stable, asymptomatic brain metastases may also be eligible.
ClinicalTrials.gov ID: NCT06448754
TrialFetch AI summary: Adults with advanced/metastatic solid tumors in three cohorts: recurrent/metastatic cervical cancer after 1–2 prior lines; recurrent/metastatic HNSCC (including PD-L1–positive, systemic-therapy–naive or platinum-refractory); and untreated R/M HNSCC receive volrustomig, a bispecific PD-1/CTLA-4 antibody, as monotherapy or combined with chemo (carboplatin/paclitaxel or 5-FU plus platinum). Excludes prior checkpoint inhibitor exposure and requires ECOG 0–1 and PD-L1 testing; endpoints include ORR and safety per RECIST 1.1.
ClinicalTrials.gov ID: NCT06535607
TrialFetch AI summary: Adults with unresectable pleural mesothelioma (epithelioid or non-epithelioid), ECOG 0–1, are randomized to volrustomig (a bispecific PD-1/CTLA-4 antibody) plus carboplatin/pemetrexed versus investigator’s choice of platinum/pemetrexed (epithelioid) or nivolumab plus ipilimumab (either histology; standard for non-epithelioid). Key exclusions include significant autoimmune disease and uncontrolled infections; primary endpoint is overall survival.
ClinicalTrials.gov ID: NCT06097728
TrialFetch AI summary: Adults with advanced hepatobiliary cancers: HCC cohorts receive volrustomig (PD-1/CTLA-4 bispecific) or rilvegostomig (PD-1/TIGIT bispecific) as monotherapy or combined with bevacizumab or lenvatinib, including a triple-immunotherapy/bevacizumab arm; BTC cohort (first-line) receives volrustomig or rilvegostomig with gemcitabine/cisplatin. Aims to assess response/PFS and safety of dual-checkpoint bispecifics, leveraging PD-1–anchored CTLA-4 or TIGIT blockade to enhance intratumoral T-cell activity.
ClinicalTrials.gov ID: NCT05775159
TrialFetch AI summary: First-line, unresectable/metastatic gastric or GEJ adenocarcinoma (ECOG 0–1), predominantly HER2-negative; some substudies require Claudin18.2-positive tumors. Non-randomized cohorts test bispecific checkpoint antibodies—PD-1/CTLA-4 (volrustomig), PD-1/TIGIT (rilvegostomig), or PD-1/TIM-3 (sabestomig)—alone with FOLFOX/XELOX or combined with a Claudin18.2-targeted MMAE ADC (AZD0901, sonesitatug vedotin) plus fluoropyrimidine.
ClinicalTrials.gov ID: NCT05702229
TrialFetch AI summary: Adults with advanced/metastatic solid tumors (endometrial, gastric, mCRPC, ovarian, colorectal, urothelial, biliary) receive datopotamab deruxtecan (anti‑TROP2 antibody–drug conjugate delivering a topoisomerase I inhibitor) as monotherapy or combined with agents such as capecitabine/5‑FU, bevacizumab ± platinum, prednisone (mCRPC), platinum in urothelial cancer, or bispecific PD‑1/CTLA‑4 (volrustomig) or PD‑1/TIGIT (rilvegostomig) immunotherapies. Key exclusions include active/untreated CNS disease, prior TROP2- or deruxtecan-based ADCs, significant ILD/pneumonitis history, and uncontrolled infections/comorbidities.
ClinicalTrials.gov ID: NCT05489211
TrialFetch AI summary: This trial enrolls adults with previously untreated advanced or metastatic non-squamous NSCLC with HER2 overexpression (no EGFR/ALK alterations), testing trastuzumab deruxtecan (HER2-directed antibody-drug conjugate) in combination with investigational bispecific checkpoint inhibitors (volrustomig [PD-1/CTLA-4] or rilvegostomig [PD-1/TIGIT]), with or without platinum chemotherapy. Patients must have good performance status and no major comorbidities.
ClinicalTrials.gov ID: NCT04686305
TrialFetch AI summary: Adults with unresectable/metastatic HER2-expressing gastric/GEJ/esophageal adenocarcinoma (HER2-positive or HER2-low) receive trastuzumab deruxtecan (anti‑HER2 antibody–drug conjugate delivering a topoisomerase I inhibitor) as monotherapy or combined with fluoropyrimidines and/or checkpoint inhibitors (durvalumab, pembrolizumab, or investigational bispecifics volrustomig [PD‑1/CTLA‑4] and rilvegostomig [PD‑1/TIGIT]); first-line cohorts include a comparator of trastuzumab plus fluoropyrimidine/platinum. Prior trastuzumab exposure is required only for a post-trastuzumab cohort, with key exclusions including active ILD/pneumonitis and untreated CNS metastases.
ClinicalTrials.gov ID: NCT04379596
