Casdatifan shows safety, efficacy as monotherapy in late-line metastatic ccRCC

Arcus Biosciences has released new data from the phase 1 ARC-20 trial (NCT05536141), which is assessing the safety and efficacy of casdatifan (AB521) monotherapy in patients with late-line metastatic clear cell renal cell carcinoma (ccRCC).¹

Casdatifanis an investigational small molecule inhibitor of HIF-2a, according to Arcus Biosciences.

The analysis included data from the 100-mg tablet cohort (the phase 3 dose level), as well as pooled data across all 4 monotherapy cohorts of the agent (50 mg BID, 50 mg QD, 100 mg QD, 150 mg QD). Patients in the study were heavily pre-treated; in the pooled analysis, 55% of patients has received at least 3 prior lines of therapy, and 29% had received at least 4 prior lines of therapy. Overall, 71% of patients had an IMDC risk score of intermediate or poor.

The efficacy analysis included 31 patients in the 100 mg cohort and 121 patients total. The median follow-up was 12.4 months and 15.2 months, respectively.

“In the 100-mg tablet cohort, our phase 3 dose and formulation, casdatifan showed a 35% confirmed [objective response rate] (ORR), with 2 additional responses pending confirmation, and [median progression-free survival] (mPFS) had not been reached, even with a median follow-up of 1 year,” said Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, in the news release from the company.¹ “Even when we analyzed pooled data for the 121 patients treated with casdatifan monotherapy, casdatifan showed a confirmed ORR of 31% and a median PFS of 12.2 months, which is meaningfully longer than published data from studies with the only marketed HIF-2a inhibitor and for TKIs alone in a similar patient population and setting.”

Further, data from the 100 mg cohort showed an estimated 12-month PFS of 60% (95% CI, 40 to 75). The 18-month PFS was not estimable (NE) in this cohort. In the pooled analysis, the 12- and 18- month PFS rates were 50% (95% CI, 41 to 59) and 43% (95% CI, 33 to 53), respectively.

The overall ORR, including responses pending confirmation, was 42% in the 100-mg cohort and 33% in the pooled analysis. The median time to response was 2.6 months and 2.8 months, respectively. Data also showed a disease control rate of 84% (95% CI, 66 to 95) in the 100 mg cohort and 81% (95% CI, 63 to 88) across the pooled cohorts.

The safety analysis included 32 patients in the 100-mg cohort and 127 patients in the pooled analysis. At the time of data cutoff, no unexpected safety signals were observed, and casdatifan showed a manageable safety profile across all 4 dose levels.

Serious treatment-emergent adverse events (TEAEs) were reported in 31% of patients (n = 10) in the 100-mg cohort and 31% of patients (n = 39) overall. Grade 3 or higher TEAEs related to casdatifan included anemia (25% and 41%) and hypoxia (9% and 11%). TEAEs led to treatment discontinuation in 9% of patients (n = 3) in the 100-mg cohort and 9% of patients (n = 11) in the pooled analysis.

Additional Studies of Casdatifan

The ARC-20 trial also includes 3 cohorts evaluating casdatifan in earlier-line settings. Specifically, cohorts are assessing casdatifan in combination with zimberelimab in first-line ccRCC, casdatifan monotherapy in favorable-risk ccRCC, and casdatifan monotherapy in the immunotherapy experienced, TKI-naïve setting.

Beyond ARC-20, casdatifan is also being explored across various studies in both the immune-oncology (IO) naïve and post-IO settings in ccRCC. The phase 1b/3 eVOLVE-RCC02 trial (NCT07000149) is evaluating casdatifan in combination with volrustomig (MEDI5752) as first-line treatment for patients with ccRCC. In the phase 3 portion of the study, patients will be randomly assigned 1:1:1 to received casdatifan plus volrustomig, volrustomig monotherapy, or standard-of-care nivolumab (Opdivo) plus ipilimumab (Yervoy).

Additionally, the phase 3 randomized PEAK-1 trial (NCT07011719) is evaluating casdatifan plus cabozantinib (Cabometyx) vs cabozantinib alone as a first- or second-line therapy in patients with metastatic ccRCC who have previously received anti-PD-1/PD-L1 therapy. The primary end point for the trial is PFS, with overall survival as a key secondary end point. Primary completion of the trial is expected in April 2028.²

REFERENCES

1. Arcus Biosciences presents new data for its HIF-2a inhibitor casdatifan and discloses first inflammation programs at investor event. News release. Arcus Biosciences. October 6, 2025. Accessed October 6, 2025. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2025/Arcus-Biosciences-Presents-New-Data-for-its-HIF-2a-Inhibitor-Casdatifan-and-Discloses-First-Inflammation-Programs-at-Investor-Event/default.aspx

2. Study of casdatifan and cabozantinib versus placebo and cabozantinib in patients with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Last updated September 29, 2025. Accessed October 6, 2025. https://clinicaltrials.gov/study/NCT07011719