A Phase Ib/III Randomized, Multicenter, Global Study of Volrustomig Plus Casdatifan or Volrustomig Monotherapy Versus Nivolumab Plus Ipilimumab as First-line Treatment for Participants With Advanced Clear Cell Renal Cell Carcinoma (ccRCC)

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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

• 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)

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

Overview

Casdatifan (AB521) is an oral, small‑molecule hypoxia‑inducible factor‑2 alpha (HIF‑2α) inhibitor in development for clear cell renal cell carcinoma (ccRCC) and other tumors. Clinical activity has been reported from the ongoing Phase 1/1b ARC‑20 trial in previously treated metastatic ccRCC, and a Phase 3 study (PEAK‑1) of casdatifan plus cabozantinib has been initiated. (ascopubs.org)

Mechanism of action

Casdatifan selectively and allosterically inhibits HIF‑2α–dependent transcription, with minimal activity against HIF‑1α in preclinical models. In vitro and xenograft studies demonstrated inhibition of HIF‑2α–driven tumor biology, reductions in pharmacodynamic markers, and tumor regressions; activity was also observed in endothelial cells and M2‑polarized macrophages. (pubmed.ncbi.nlm.nih.gov)

Clinical development

• Phase 1/1b ARC‑20 (NCT05536141): dose‑escalation and expansion evaluating casdatifan as monotherapy and in combination (cabozantinib; zimberelimab) in ccRCC and other solid tumors. (clinicaltrials.ucbraid.org)
• Phase 3 PEAK‑1: randomized, double‑blind study of casdatifan + cabozantinib vs placebo + cabozantinib in advanced ccRCC (IO‑experienced). Site listings indicate initiation in 2025. (dana-farber.org)

Efficacy

Monotherapy (ARC‑20; heavily pretreated metastatic ccRCC; data cutoff January 3, 2025 unless noted) - 50 mg BID (n=32): confirmed ORR 25% (95% CI 11.5–43.4); median PFS 9.7 months (95% CI 5.5–NE). Disease control rate (DCR) 81%. (investors.arcusbio.com)
- 50 mg QD (n=28): confirmed ORR 32% (95% CI 15.9–52.4); median PFS not reached at 12‑month median follow‑up. DCR 86%. (investors.arcusbio.com)
- 100 mg QD tablet (go‑forward dose; n=27): confirmed ORR 33% (95% CI 16.5–54.0); median PFS not reached at ~5‑month median follow‑up. DCR 85%. (investors.arcusbio.com)

ASCO GU 2025 abstract reported safety/efficacy across multiple monotherapy doses in ARC‑20 (Rapid Oral, Abstract 441). (ascopubs.org)

Combination with cabozantinib (ARC‑20 expansion; IO‑experienced ccRCC; ASCO 2025) - Casdatifan 100 mg QD + cabozantinib 60 mg QD: confirmed ORR 46% (11/24; 95% CI 26–67) at 5.3‑month median follow‑up; CR 4%, PD 4%. (investors.arcusbio.com)

More recent sponsor updates (August–October 2025) describe pooled monotherapy analyses across four cohorts (n=121) with confirmed ORR 35% and median PFS 12.2 months (cohort‑pooled), with mPFS not reached in the 100‑mg QD cohort (DCO August 15, 2025). Interpret with caution pending peer‑reviewed presentation/publication. (investors.arcusbio.com)

Safety

The emerging safety profile is consistent with the HIF‑2α inhibitor class. In ARC‑20 monotherapy cohorts, no unexpected safety signals were observed; class‑typical anemia and hypoxia occurred, with few discontinuations attributed to these events. In the cabozantinib combination cohort (n=42 safety population), grade ≥3 treatment‑related AEs included anemia (24% attributable to casdatifan) and hypoxia (7% attributable to casdatifan); no casdatifan‑related grade 4/5 events were reported, and only two patients discontinued any drug, none discontinuing both. (investors.arcusbio.com)

Further reading

• Preclinical characterization of casdatifan/AB521 (BJP, 2025). (pubmed.ncbi.nlm.nih.gov)
• ARC‑20 ASCO GU 2025 abstract page (JCO 43:5_suppl, Abstract 441). (ascopubs.org)
• ARC‑20 monotherapy data press release (Feb 15, 2025). (investors.arcusbio.com)
• ARC‑20 cabozantinib combination data (ASCO 2025). (investors.arcusbio.com)
• Trial listings: ARC‑20 (NCT05536141) and PEAK‑1 Phase 3 site information. (clinicaltrials.ucbraid.org)

Notes: Casdatifan remains investigational; efficacy and safety have not been established by regulators. Reported outcomes are from early‑phase studies with relatively short follow‑up for some cohorts and should be interpreted accordingly. (investors.arcusbio.com)

Last updated: Oct 2025

Inclusion Criteria:

* Histologically or cytologically confirmed RCC with clear cell component.

* Advanced/metastatic RCC or recurrent disease that has not previously been treated with systemic therapy in the 1L setting.

* Karnofsky Performance Status ≥ 70%.

* Provision of acceptable tumor sample.

* At least one lesion that can be accurately measured at baseline as ≥ 10 mm in the longest diameter (except lymph nodes, which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for accurate repeated measurements.

Exclusion Criteria:

* History of leptomeningeal disease or spinal cord compression.

* Symptomatic brain metastases.

* Medical history of severe chronic obstructive pulmonary disease.

* Active or prior documented autoimmune or inflammatory disorders.

* Prior systemic therapy for advanced/metastatic RCC. Note - Other inclusion and exclusion criteria may apply as stated in the protocol.