casdatifan

Shows activity

Also known as:

AB521

Cancer types include:

kidney cancer

HealthScout AI Analysis

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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)

Active trials using casdatifan

Found 3 active trials using this drug:

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

Sponsor: Arcus Biosciences, Inc. (industry) Phase: 3 Start date: Sept. 8, 2025

HealthScout AI summary: Adults with unresectable or metastatic clear cell RCC who progressed on prior PD‑1/PD‑L1 therapy are randomized to casdatifan (AB521, a selective allosteric HIF‑2α inhibitor) plus cabozantinib versus cabozantinib plus placebo. Excludes prior HIF‑2α inhibitor or cabozantinib exposure; key goal is to improve PFS with the HIF‑2α/VEGFR–TKI combination.

ClinicalTrials.gov ID: NCT07011719

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)

Sponsor: AstraZeneca (industry) Phase: 3 Start date: July 28, 2025

HealthScout AI summary: Untreated adults with advanced/metastatic clear cell RCC (KPS ≥70%) are randomized to volrustomig (a PD‑1/CTLA‑4 bispecific designed to preferentially inhibit CTLA‑4 on PD‑1+ T cells) plus casdatifan (oral HIF‑2α inhibitor), volrustomig alone, or standard nivolumab/ipilimumab. Key exclusions include symptomatic CNS disease and active autoimmune disorders; endpoints focus on PFS/OS versus nivo/ipi.

ClinicalTrials.gov ID: NCT07000149

A Phase 1, Open-label, Dose Escalation and Dose Expansion Study, to Investigate the Safety, Tolerability, and Pharmacokinetic Profile of AB521 Monotherapy and Combination Therapies in Participants With Clear Cell Renal Cell Carcinoma and Other Solid Tumors

Sponsor: Arcus Biosciences, Inc. (industry) Phase: 1 Start date: Oct. 26, 2022

HealthScout AI summary: Adults with ECOG 0–1: dose escalation enrolls any advanced solid tumor lacking standard options; expansion enrolls histologically confirmed ccRCC. Treatments include the oral HIF-2α inhibitor casdatifan (AB521) as monotherapy or combined with cabozantinib or the anti–PD-1 antibody zimberelimab.

ClinicalTrials.gov ID: NCT05536141