Arcus Biosciences presented encouraging initial data from its ARC-20 study at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, showing that the combination of casdatifan and cabozantinib achieved a 46% confirmed overall response rate in patients with clear cell renal cell carcinoma (ccRCC) who had progressed on prior immunotherapy.
The Phase 1/1b dose-escalation and expansion study evaluated once-daily 100mg of casdatifan, a HIF-2α inhibitor, plus 60mg of cabozantinib, a tyrosine kinase inhibitor, in patients with ccRCC. At the March 14, 2025 data cutoff, 42 participants were evaluable for safety and 24 reached at least 12 weeks of follow-up for efficacy evaluation.
Strong Efficacy Signal in Challenging Patient Population
Among the 24 efficacy-evaluable patients, nearly half (46%) achieved a confirmed response per RECIST 1.1 criteria, with only one patient experiencing primary progressive disease. The vast majority of patients in the efficacy-evaluable population remain on treatment. Most participants (79%) in the safety-evaluable population had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors of intermediate or poor.
"I was very encouraged to see that nearly half of patients had a confirmed response to the casdatifan plus cabozantinib combination despite short follow-up," said Dr. Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and lead investigator of ARC-20. "Casdatifan plus cabozantinib was well tolerated, and the safety profile was consistent with that of either agent alone, supporting their potential as a combination therapy."
Favorable Safety Profile Supports Combination Approach
The combination demonstrated an acceptable safety profile with no meaningful overlapping toxicity between the two drugs. No unexpected safety risks were identified, and only two patients discontinued any drug while no patients discontinued treatment with both drugs. The incidence of treatment-emergent adverse events with casdatifan, particularly anemia and hypoxia, was similar to those observed with casdatifan monotherapy. There were no casdatifan-related Grade 4 or 5 adverse events.
Advancing to Phase 3 Development
Terry Rosen, chief executive officer of Arcus, noted that "the initial data for casdatifan plus cabozantinib in the ARC-20 study have already exceeded the historic benchmarks for either agent alone, as well as that of another HIF-2α inhibitor plus cabozantinib in the same second-line setting."
These results support the initiation of PEAK-1, a Phase 3 study that will evaluate casdatifan plus cabozantinib versus cabozantinib monotherapy as first- or second-line treatment in patients with metastatic ccRCC who have previously received anti-PD-1/PD-L1 therapy. The primary endpoint will be progression-free survival with overall survival as a key secondary endpoint.
Comprehensive Development Program
Arcus is pursuing a broad development program for casdatifan in both immunotherapy-naive and post-immunotherapy settings. Additional studies include eVOLVE-RCC02, a Phase 1b/3 study sponsored by AstraZeneca evaluating casdatifan plus volrustomig as first-line treatment, and additional ARC-20 cohorts examining casdatifan in earlier-line settings.
Addressing Unmet Medical Need
According to the American Cancer Society, an estimated 80,980 Americans will be diagnosed with kidney cancer in 2025. Clear cell RCC is the most common type of kidney cancer in adults. While early-stage RCC has a high five-year survival rate, patients with advanced or late-stage metastatic RCC face a five-year survival rate of only 18%. In 2022, approximately 32,200 patients with advanced kidney cancer required systemic therapy in the U.S.
Casdatifan is designed to selectively bind HIF-2α, a transcription factor responsible for activating multiple tumor growth pathways in hypoxic environments. Clear cell renal cell carcinoma is almost universally associated with HIF-2α dysregulation, making this pathway an attractive therapeutic target.
