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
Planned enrollment: 720
Show Summary from Sponsor
Show for: casdatifan (AB521)
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)
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)
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)
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)
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
Goal: Evaluate whether adding casdatifan to cabozantinib improves progression-free survival versus cabozantinib plus placebo in adults with advanced or metastatic clear cell renal cell carcinoma previously treated with anti–PD-1/PD-L1 therapy.
Patients: Adults with unresectable, measurable locally advanced or metastatic renal cell carcinoma with a primary clear cell component, prior progression on or after PD-1/PD-L1–based immunotherapy, KPS ≥80%, adequate organ function, and at least one RECIST 1.1 target lesion outside prior radiation fields. Key exclusions include prior HIF-2α inhibitor or cabozantinib, active second malignancy within 1 year, unresolved ≥Grade 3 toxicities, uncontrolled hypertension, and history of leptomeningeal disease or spinal cord compression.
Design: Randomized, double-blind, active-controlled, multicenter phase 3 trial enrolling approximately 720 participants. Allocation is 1:1 to experimental versus comparator arms with blinded independent central review of imaging per RECIST 1.1.
Treatments: Experimental arm: oral casdatifan plus oral cabozantinib. Comparator arm: oral placebo plus oral cabozantinib. Casdatifan (AB521) is an investigational, selective, allosteric HIF‑2α inhibitor targeting HIF‑2α–dependent transcription, a validated pathway in ccRCC. Early phase 1/1b data (ARC‑20) demonstrated antitumor activity as monotherapy and higher response rates when combined with cabozantinib, with a safety profile consistent with the HIF‑2α class (notably anemia and occasional hypoxia). Cabozantinib is an approved VEGFR/MET/AXL tyrosine kinase inhibitor commonly used in previously treated RCC.
Outcomes: Primary: progression-free survival by blinded independent central review per RECIST 1.1. Secondary: overall survival; objective response rate, duration of response, and disease control rate by blinded independent central review; incidence and severity of TEAEs and SAEs; time to first symptom deterioration on the NFKSI-DRS (items 1–9). Time horizons extend to approximately 33 months for disease control endpoints and safety, and up to 64 months for overall survival.
Burden on patient: Expected burden is moderate and similar to other phase 3 oral therapy studies in metastatic RCC. Treatment and placebo are oral without mandated intensive pharmacokinetic sampling typical of phase 1 trials. Patients will undergo regular clinic visits for safety labs, vitals, and adverse event monitoring, plus periodic cross-sectional imaging per RECIST with blinded central review, likely every 8–12 weeks, consistent with standard practice. No routine research biopsies are specified, but baseline and on-treatment assessments will require standard hematology/chemistry panels and pregnancy testing where applicable. Travel burden corresponds to scheduled imaging and follow-up visits typical for second-line RCC management; added burden relates mainly to vigilance for class-related toxicities such as anemia, hypoxia, hypertension, and cabozantinib-associated adverse events requiring monitoring and potential dose modifications.
Last updated: Nov 2025
Show Criteria
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.
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