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, also known as MEDI5752 or PD-1/CTLA-4 DuetMab, is an investigational bispecific monoclonal antibody targeting both PD-1 and CTLA-4 immune checkpoints. It is designed to fully inhibit PD-1 while preferentially inhibiting CTLA-4 on activated PD-1–positive T cells, aiming to enhance antitumor immune responses. (oncologypro.esmo.org)

Mechanism of Action

Volrustomig's bispecific nature allows it to simultaneously block PD-1 and CTLA-4 pathways. This dual inhibition is intended to restore and amplify T-cell activity against tumor cells, potentially leading to improved therapeutic outcomes compared to targeting either checkpoint alone. (aacrjournals.org)

Efficacy

In a Phase 1 study involving treatment-naïve patients with advanced clear cell renal cell carcinoma (ccRCC), volrustomig demonstrated promising efficacy:

• 750 mg dose cohort (V750):
• Objective response rate (ORR): 48.4%
• Complete response (CR) rate: 9.7%
• Disease control rate (DCR): 90.3%
• Median duration of response (DOR): 17.0 months

• Median progression-free survival (PFS): 12.3 months

• 500 mg dose cohort (V500):

• ORR: 45.5%
• CR rate: 6.1%
• DCR: 69.7%
• Median DOR: 11.5 months
• Median PFS: 9.7 months

These results suggest that volrustomig has the potential to improve outcomes in patients with advanced RCC. (onclive.com)

Safety

The safety profile of volrustomig is consistent with dual checkpoint inhibition:

• 750 mg dose cohort (V750):
• Treatment-related adverse events (TRAEs) occurred in 96.9% of patients, with grade 3 or 4 TRAEs in 62.5%.
• Common TRAEs included pruritus (50%), hyperthyroidism (34.4%), and diarrhea (25%).

• 46.9% of patients discontinued treatment due to TRAEs.

• 500 mg dose cohort (V500):

• TRAEs occurred in 93.9% of patients, with grade 3 or 4 TRAEs in 42.4%.
• Common TRAEs included pruritus (39.4%), hyperthyroidism (21.2%), and diarrhea (21.2%).
• 30.4% of patients discontinued treatment due to TRAEs.

One treatment-related death occurred in the V500 cohort due to bronchopulmonary aspergillosis with immune neutropenia. (onclive.com)

Further Reading

• Volrustomig Demonstrates Activity in Treatment-Naive Advanced ccRCC
• MEDI5752 (volrustomig), a novel PD-1/CTLA-4 bispecific antibody, in the first-line treatment of 65 patients with advanced clear cell renal cell carcinoma
• Abstract 3627: Volrustomig a novel PD-1/CTLA-4 bispecific antibody leads to robust increase in peripheral and intra-tumoral pharmacodynamic biomarkers in solid tumors from FTiH study

Last updated: Apr 2025

Overview

Casdatifan (AB521) is an investigational, oral hypoxia‑inducible factor 2 alpha (HIF‑2α) inhibitor being developed for clear cell renal cell carcinoma (ccRCC). Early clinical data from the phase 1/1b ARC‑20 study show antitumor activity as monotherapy in previously treated ccRCC and in combination with cabozantinib, with a safety profile consistent with the HIF‑2α inhibitor class. As of September 2, 2025, casdatifan is not approved for any indication. (ascopubs.org, investors.arcusbio.com)

Mechanism of action

Casdatifan is a potent, selective, allosteric small‑molecule inhibitor of HIF‑2α–dependent transcription. Preclinical studies demonstrated selective inhibition of HIF‑2α (with no HIF‑1α activity), suppression of pharmacodynamic markers, and tumor regressions in ccRCC xenografts; activity was enhanced when combined with cabozantinib or anti–PD‑1 therapy. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Monotherapy (ARC‑20, phase 1/1b; previously treated ccRCC) - ASCO GU 2025 meeting abstract (NCT05536141) reported confirmed ORR of 25% in the 50 mg BID cohort (n≈32) and 21% in the 50 mg QD cohort (n≈28); disease‑control rates were 81% and 86%, respectively. The abstract identified 100 mg QD as the dose moving forward based on pharmacodynamic data. (ascopubs.org) - Independent conference coverage of the same presentation noted, with shorter follow‑up for 100 mg QD, a confirmed ORR of 33%; 25% and 29% in the 50 mg BID and 50 mg QD cohorts, respectively. (urotoday.com) - Earlier data presented at the 2024 EORTC‑NCI‑AACR Symposium (100 mg daily expansion cohort; n=32) showed ORR 34% unconfirmed (25% confirmed), disease‑control rate 81%, and median PFS not reached at data cutoff. (investors.arcusbio.com)

Combination with cabozantinib (ARC‑20 expansion cohort) - ASCO 2025 oral presentation (Abstract 4506) and contemporaneous reports described a confirmed ORR of 41% among efficacy‑evaluable patients (n=22; early follow‑up), including 1 complete response; common AEs included anemia and fatigue. (kidneycancer.org, kidney-cancer-journal.com) - Company presentation at ASCO 2025 (more mature cut) reported a confirmed ORR of 46% among patients with ≥12 weeks of follow‑up, with manageable safety. (investors.arcusbio.com)

Ongoing/planned trials - PEAK‑1: phase 3 study of casdatifan (100 mg QD) + cabozantinib (60 mg) vs cabozantinib in IO‑experienced metastatic ccRCC, initiated in 2025. (investors.arcusbio.com) - eVOLVE program: planned AstraZeneca‑sponsored study evaluating casdatifan + volrustomig (PD‑1/CTLA‑4 bispecific) in first‑line ccRCC. (investors.arcusbio.com) - ARC‑20 remains open with multiple expansion cohorts, including monotherapy and combinations. (ichgcp.net)

Safety

Monotherapy (ASCO GU 2025 abstract; previously treated ccRCC) - Grade ≥3 treatment‑emergent adverse events (TEAEs): 42% (50 mg BID) and 36% (50 mg QD). No grade ≥4 TEAEs reported in these cohorts. - Class‑typical events included anemia (grade 3: 36% overall across doses) and hypoxia (grade 3: 9% at 50 mg BID; 6% at 50 mg QD). (ascopubs.org) - Conference coverage reported anemia in 80–90% of patients across doses and grade ≥3 anemia in 17–42% depending on dose; grade ≥3 hypoxia in ~7–10%. Therapy‑related discontinuations were uncommon (2/93). (urotoday.com)

Combination with cabozantinib (ASCO 2025) - Early reports: all‑grade AEs in 89% (most common anemia 59%, fatigue 56%); grade ≥3 anemia 26%, hypoxia 11%; discontinuation due to AE in 4% (hypoxia). No notable overlapping toxicities beyond expected class effects. (kidneycancer.org) - Company summary: manageable safety with no meaningful overlapping toxicity; supports phase 3 evaluation. (investors.arcusbio.com)

Further reading

• ASCO GU 2025 meeting abstract: casdatifan monotherapy in previously treated ccRCC (ARC‑20). Journal of Clinical Oncology (abstract 441). (ascopubs.org)
• Independent summary of ASCO GU 2025 monotherapy data (UroToday). (urotoday.com)
• ASCO 2025 oral abstract on casdatifan + cabozantinib (Abstract 4506) – clinical community summaries. (kidneycancer.org, kidney-cancer-journal.com)
• Preclinical characterization of casdatifan (AB521) as a selective, allosteric HIF‑2α inhibitor. British Journal of Pharmacology (2025). (pubmed.ncbi.nlm.nih.gov)
• EORTC‑NCI‑AACR 2024 presentation press summary for 100 mg cohort (early clinical activity). (investors.arcusbio.com)
• ARC‑20 clinical trial listing (NCT05536141). (ichgcp.net)
• Development updates including PEAK‑1 phase 3 and AZ collaboration (volrustomig) press materials. (investors.arcusbio.com)

Notes - Reported response rates and safety reflect early‑phase, evolving datasets with varying follow‑up; values may change with maturity of data and across cohorts. Preference was given to peer‑reviewed and scientific‑meeting sources where available. (ascopubs.org, pubmed.ncbi.nlm.nih.gov)

Last updated: Sep 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.