Casdatifan shows durable activity in metastatic clear cell renal cell carcinoma

Results from the phase 1 ARC-20 study (NCT05536141) have been published in Nature, showing that the investigational hypoxia-inducible factor 2-alpha (HIF-2α) inhibitor casdatifan yielded durable antitumor activity in patients with heavily pretreated metastatic clear cell renal cell carcinoma (ccRCC).¹

In addition to demonstrating objective responses and promising progression-free survival (PFS), the study identified translational biomarkers—including serum erythropoietin (EPO) suppression and tumor HIF-2α pathway activity—that correlated with clinical benefit, potentially informing future biomarker-driven development of HIF-2α inhibition.

“This is the first study to comprehensively assess the relationship between HIF-2a inhibitor-associated suppression of serum EPO production with tumor biology and clinical outcomes,” said principal investigator Toni K. Choueiri, MD, director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg chair and professor of medicine at Harvard Medical School, in a news release on the results.² “These findings were elucidated in parallel with demonstrating the meaningful clinical benefit of casdatifan, an investigational, HIF-2a inhibitor in development for the treatment of kidney cancer. Patients treated with casdatifan had a median progression-free survival of over 1 year despite half of patients having progressed on 3 or more prior treatments with other standard therapies.”

About ARC-20

The Nature publication encompasses dose expansion data from the ARC-20 trial. Investigators enrolled 127 patients with metastatic ccRCC who had progressed following prior treatment with both VEGF receptor tyrosine kinase inhibitors and anti-PD-1/PD-L1 therapy. Patients had received a median of 3 prior systemic therapies, and approximately 71% had intermediate- or poor-risk disease according to International Metastatic RCC Database Consortium (IMDC) criteria.

Investigators reported efficacy for both the recommended phase 3 dose of 100 mg once daily (n = 32) and the pooled monotherapy population (n = 127), which included the 50 mg QD, 50 mg BID, 100 mg QD and 150 mg QD cohorts.

Among efficacy-evaluable patients, the confirmed objective response rate (ORR) was 35% (95% CI, 19 to 55) in the 100-mg cohort and 31% (95% CI, 23 to 40) across all dose cohorts. One complete response was observed in the pooled population, with the remaining confirmed responses consisting of partial responses. The median time to response was 2.6 months (range, 1.2 to 9.5) and 2.8 months (range, 1.2 to 13.0), respectively.

Disease control rates reached 84% (95% CI, 66 to 95) in the 100-mg cohort and 81% (95% CI, 73 to 88) overall.

With median follow-up of 12.4 months in the recommended-dose cohort and 15.5 months overall, the median PFS was not yet estimable in the 100-mg cohort and reached 12.2 months (95% CI, 9.4 to 20.6) in the pooled analysis. At 12 months, an estimated 60% of patients receiving the recommended phase 3 dose and 50% of patients in the total population remained progression free.

According to the authors, the safety data were generally consistent with the known class effects of HIF-2α inhibition. The most common treatment-emergent adverse events were anemia, fatigue, headache, and dyspnoea.

Treatment-related anemia occurred in 89% of patients overall and was grade 3 or higher in 41%. Treatment-related hypoxia occurred in 16% of patients, with grade-related management including treatment interruption (14%), dose reduction (7%), supplemental oxygen (70%), and treatment discontinuation (2%). Treatment discontinuation because of treatment-emergent adverse events occurred in 9% of patients overall. Investigators reported 3 treatment-emergent deaths in the pooled population, none of which were considered related to casdatifan.

Biomarker analyses

Beyond the clinical efficacy findings, the study emphasized translational analyses linking pharmacodynamic effects to treatment outcomes. Patients experienced rapid and sustained reductions in circulating serum EPO, with 71% of patients reaching their maximal sEPO reduction during the first cycle of treatment. Most patinets (68%) experienced a maximal sEPO reduction of over 80%. Greater reductions in serum EPO were associated with a significantly higher likelihood of complete response or partial response (OR, 1.09; 95% CI, 1.04 to 1.16, per percent difference; P = .001), a lower likelihood of progressive disease (OR, 0.94; 95% CI , 0.89 to 0.98, per percent difference; P = .003), and longer PFS (HR, 0.97, 95% CI, 0.95 to 0.99, per percent difference; Cox regression, P = .006).

According to the authors, “Each 10% deeper reduction in maximal sEPO would predict a 140% increase in the relative odds of tumor response and a 28% decrease in the relative risk of tumor progression or death.”

Tumor-based analyses further supported these observations. Higher baseline tumor EPO messenger RNA expression, greater HIF-2α protein expression by immunohistochemistry, and enrichment of HIF-2α transcriptional signatures were each associated with improved clinical outcomes. By contrast, common genomic alterations frequently observed in ccRCC—including VHL and PBRM1 mutations—did not independently predict response. The authors noted that these results suggest that mutation status alone is not sufficient to predict response to casdatifan.

Interpretations and next steps

Enrollment is ongoing in PEAK-1 (NCT07011719), a global phase 3 trial comparing casdatifan plus cabozantinib (Cabometyx) with cabozantinib alone in patients with immunotherapy-pretreated metastatic ccRCC (NCT06516965). Arcus Biosciences plans to complete enrollment in PEAK-1 and initiate a phase 3 study in the first-line metastatic ccRCC setting by the end of 2026.

Results from PEAK-1 will help determine whether the promising activity observed in ARC-20 translates into improved outcomes in a randomized setting.

“The comprehensive translational work published in Nature validates EPO as a biomarker for HIF-2a suppression and correlates dramatic and sustained EPO suppression to durable response with monotherapy casdatifan,” said Richard Markus, MD, PhD, chief medical officer at Arcus Biosciences, in the news release.² “We believe this new research provides unambiguous evidence that casdatifan is a best-in-class HIF-2a inhibitor, and we are rapidly advancing a comprehensive development strategy so that every ccRCC patient has the opportunity to benefit from casdatifan across each line of therapy.”

REFERENCES

1. Choueiri TK, Merchan J, Patnaik A, et al. Casdatifan shows durable response linked to HIF-2α biology in kidney cancer. Nature. 2026. doi:10.1038/s41586-026-10718-x

2. New research published in Nature links clinical activity with HIF‑2a biology in advanced kidney cancer patients treated with casdatifan. News release. Arcus Biosciences. July 1, 2026. Accessed July 6, 2026. https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2026/New-Research-Published-in-Nature-Links-Clinical-Activity-with-HIF2a-Biology-in-Advanced-Kidney-Cancer-Patients-Treated-with-Casdatifan/default.aspx