Updated ARC-20 data showed casdatifan activity as monotherapy and in combinations across treatment lines in advanced clear cell RCC.
Casdatifan demonstrated antitumor activity across first-line, second-line, and later-line clear cell renal cell carcinoma (ccRCC) cohorts in the open-label phase 1/1b ARC-20 trial (NCT05536141), according to updated data announced by Arcus Biosciences.1
Findings showed that at the September 4, 2026, cutoff, and a median follow-up of 11.5 months, treatment with casdatifan plus zimberelimab in the first-line setting (n = 30) produced a confirmed objective response rate (ORR) of 50%'; the 6- and 12-month progression-free survival (PFS) rates were 86% and 69%, respectively.
At a median follow-up of 21.3 months, treatment in the second line with casdatifan plus cabozantinib (Cabometyx; n = 30) yielded a median PFS of 14.5 months, a confirmed ORR of 44%, and an 18-month overall survival (OS) rate of 77%.
At a median follow-up of 28 months, patients treated in later-line monotherapy cohorts (n = 121) achieved a median OS of 35 months, a median PFS of 13 months, and a confirmed ORR of 36%.
"We are executing on a plan to develop casdatifan as a backbone therapy for all [patients with] ccRCC," Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, stated in the news release. “The disease control that has been observed for casdatifan plus anti–PD-1 in the first line, the remarkable benefit that has been observed for patients in the second line, even after progressing on prior TKI treatment, and unprecedented 3-year median OS from casdatifan monotherapy in patients who had progressed on multiple prior therapies reveal for the first time the potential associated with deep and durable HIF-2α inhibition. We are on track to initiate our second registrational trial in ccRCC, the first-line PEAK-20 study, by the end of this year. This study is enabled by the strong dataset we have generated in the first-line setting.”
Casdatifan is an investigational, orally administered small-molecule HIF-2α inhibitor.1,2 In ccRCC, loss of von Hippel-Lindau tumor-suppressor function can stabilize HIF-2α, driving transcriptional programs that fuel tumor growth and angiogenesis; casdatifan is designed to block this pathway.2
A prior peer-reviewed ARC-20 analysis linked deeper serum erythropoietin suppression, a pharmacodynamic marker of HIF-2α inhibition, with clinical benefit. Higher expression of a tumor HIF-2α transcriptional signature was associated with longer PFS with monotherapy (HR, 0.43; 95% CI, 0.21-0.86; P = .018). This exploratory biomarker finding supports further investigation rather than an established patient-selection test.
ARC-20 is a nonrandomized, multicenter study with dose-escalation and -expansion phases and an estimated enrollment of 362 patients across its cohorts.3 Eligible patients need to be at least 18 years of age with at least 1 measurable lesion and an ECOG performance status of 0 or 1; patients entering dose expansion also needed histologically confirmed ccRCC and a creatinine clearance of at least 40 mL/min.
Patients were ineligible if they had serious cardiac, respiratory, medical, or psychiatric conditions that could jeopardize their safety or ability to take part, or if they had undergone major surgery or experienced trauma in the 28 days before the first dose. None of the expansion cohorts permitted previous HIF-2α inhibitor therapy. Patients in the cabozantinib combination cohort could not have received cabozantinib before, and those in the zimberelimab-containing cohorts could not have received prior systemic therapy for active disease.
Casdatifan was given orally, either alone or with cohort-specific agents. The updated pooled monotherapy analysis included doses of 50 mg once daily, 50 mg twice daily, 100 mg once daily, and 150 mg once daily.1 The earlier dose-escalation analysis evaluated daily doses ranging from 20 to 200 mg and identified 100 mg once daily as the recommended phase 3 dose.2
The registered primary outcomes are dose-limiting toxicities and adverse effects. Secondary outcomes include ORR per RECIST 1.1 criteria and pharmacokinetic measures.
No unexpected safety signals emerged across the updated cohorts.1 In the earlier monotherapy dose-escalation analysis, no dose-limiting toxicities occurred at doses up to 150 mg once daily; grade 3 hypoxia at 200 mg resolved after treatment interruption.2
These data came from separate cohorts with different treatment histories. The ongoing phase 3 PEAK-1 trial (NCT07011719) is comparing casdatifan plus cabozantinib with cabozantinib alone.1 Randomized testing will be needed to establish comparative benefit; the third-party benchmarks cited in the release represent cross-trial observations.
