Casdatifan Shows Activity Across Treatment Lines in ccRCC

The investigational hypoxia-inducible factor 2α (HIF-2α) inhibitor casdatifan (AB521) showed antitumor activity alone and in combination in patients with clear cell renal cell carcinoma (ccRCC) treated in the first-, second-, and later-line settings, according to updated data from the ARC-20 study (NCT05536141) reported by Arcus Biosciences at an investor event.^1,2

In the ARC-20 platform study, patients with heavily pretreated disease who received casdatifan monotherapy had a median overall survival (OS) of 34.7 months (95% CI, 32.8-not estimable). In the second-line setting, casdatifan plus cabozantinib (Cabometyx) yielded a median progression-free survival (PFS) of 14.5 months, and in the first-line setting, casdatifan plus the investigational anti–PD-1 antibody zimberelimab resulted in a 12-month PFS rate of 69%. All cohorts had a data cutoff of September 4, 2026.

“Across the RCC treatment continuum, and in every setting in which it has been studied, casdatifan has shown rapid disease control, a meaningful impact on survival, and was tolerable, both alone and in combination with standard-of-care therapies,” said Rana R. McKay, MD, professor of medicine, urology, and radiation medicine and associate director of clinical sciences at the UC San Diego Moores Cancer Center, in the news release.¹

Late-Line Monotherapy

The pooled monotherapy analysis included 121 efficacy-evaluable patients treated at 4 dose levels (50 mg once daily, 50 mg twice daily, 100 mg once daily, and 150 mg once daily), with a median follow-up of 28 months. Prior treatment included both an anti–PD-1 agent and a VEGFR tyrosine kinase inhibitor (TKI), and 52% of patients had received 3 or more prior lines of therapy.

The confirmed objective response rate (ORR) was 36% (95% CI, 26%-45%), and median PFS was 13.0 months (95% CI, 9.4-16.4). The 12- and 24-month OS rates were 82% and 67%, respectively. The investor presentation compared the PFS duration favorably with the outcomes with belzutifan (Welireg), the only FDA-approved HIF-2α inhibitor, in the phase 3 LITESPARK-005 trial (NCT04195750). Arcus also reported that PFS with casdatifan did not differ by the number of prior TKI-containing regimens.

Among 127 patients evaluable for safety, 71% had grade 3 or higher treatment-emergent adverse events (TEAEs); 55% were considered related to casdatifan. Anemia occurred in 95% of patients and was grade 3 or higher and treatment related in 47%. Hypoxia occurred in 21%, including treatment-related grade 3 or higher events in 11%. Serious TEAEs were related to casdatifan in 9% of patients.

Arcus stated its plans to launch a registrational trial of casdatifan plus tivozanib (Fotivda) vs tivozanib alone in the late-line setting.

Second-Line Combination With Cabozantinib

In 43 immunotherapy-exposed patients, casdatifan plus cabozantinib showed a confirmed ORR of 44%, a disease control rate of 95%, and a primary progression rate of 5% at a median follow-up of 21.3 months. The 12- and 18-month OS rates were 84% and 77%, respectively. Arcus noted that historical median PFS with cabozantinib alone in this setting is approximately 10 months. The company compared this outcome with the phase 3 LITESPARK-011 trial (NCT04586231) of belzutifan plus lenvatinib (Lenvima).

Efficacy was similar regardless of whether patients had received a prior TKI, including lenvatinib, according to the company. Among 44 patients evaluable for safety, treatment-related grade 3 or higher adverse events occurred in 77%, most commonly anemia (52%). Grade 3 or higher hypoxia related to casdatifan occurred in 14%, no grade 4 or 5 casdatifan-related events were reported, and 4 patients (9.1%) discontinued casdatifan because of TEAEs.

The combination is under evaluation in the phase 3 PEAK-1 trial (NCT07011719), which plans to randomly assign approximately 720 patients 2:1 to casdatifan 100 mg plus cabozantinib or placebo plus cabozantinib, with PFS as the primary end point.

First-Line TKI-Free Combinations

Among 30 patients receiving casdatifan plus zimberelimab, the 6- and 12-month PFS rates were 86% and 69%, respectively, at a median follow-up of 11.5 months. The confirmed ORR was 50%, including 2 responses confirmed after the data cutoff, and 2 patients (6.7%) had primary progression. Arcus compared these results favorably vs those seen with ipilimumab (Yervoy) plus nivolumab (Opdivo) in CheckMate 214 (NCT02231749), and vs pembrolizumab (Keytruda) monotherapy in KEYNOTE-427 (NCT02853344).

A triplet cohort of casdatifan plus zimberelimab and ipilimumab enrolled 31 patients with a median follow-up of 3.0 months. Only 1 of 24 patients with at least 1 scan had primary progression. Grade 3 or higher immune-mediated events included hepatitis in 3 patients and colitis in 2, and 1 patient had myositis, myocarditis, and myasthenia gravis. No grade 5 TEAEs occurred.

These data support the phase 3 PEAK-20 trial, which will randomly assign patients with previously untreated advanced ccRCC 1:1 to casdatifan 100 mg plus nivolumab and ipilimumab or nivolumab and ipilimumab alone. PFS is the primary end point and OS the key secondary end point. Arcus expects to begin the trial by the end of 2026.

REFERENCES

1. Arcus presents new data from ARC-20 that demonstrate the opportunity for Ccsdatifan to become a foundational treatment across all kines of therapy in kidney cancer. News release. Arcus Biosciences. October 20, 2026. Accessed October 20, 2026. https://tinyurl.com/y2sepw3p

2. Casdatifan Investor Day - New monotherapy and combination data in first-line, second line and late-line kidney cancer. News release. Arcus Biosciences. October 20, 2026. Accessed October 20, 2026. https://tinyurl.com/yva796eb