A Randomized, Double-Blind, Active-Control, Multicenter Phase 3 Trial of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients With Advanced Clear Cell Renal Cell Carcinoma

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:

* Unresectable and measurable locally advanced or metastatic renal cell carcinoma with a primary clear cell component.

* A Karnofsky Performance Status (KPS) score ≥ 80%

* At least 1 target lesion measurable by computed tomography/magnetic resonance imaging per RECIST 1.1, not within a field of prior radiation therapy.

* Adequate organ and marrow function, ≤ 72 hours prior to randomization.

* Women of childbearing potential (WOCBP) must have a negative serum pregnancy test.

Exclusion Criteria:

* Received prior treatment with a HIF-2α inhibitor or cabozantinib.

* Other prior malignancy active within the previous year except for locally curable cancers that have been apparently cured.

* Clinically significant toxicities related to any prior anticancer treatment, or toxicities Grade ≥ 3 per National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI CTCAE v5.0) regardless of relatedness to prior anticancer therapies.

* Uncontrolled or poorly controlled hypertension, as defined by a sustained blood pressure \> 140/90 mm Hg on more than three antihypertensives

* History of leptomeningeal disease or spinal cord compression.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.