Clear cell renal cell carcinoma is strongly linked to HIF-2α biology, and HIF-2α inhibition is a therapeutic option for patients with advanced clear cell RCC after prior PD-1/PD-L1 inhibitor and VEGFR tyrosine kinase inhibitor treatment.
On July 1, 2026, Nature published results from ARC-20, evaluating casdatifan, an oral HIF-2α inhibitor, in patients with refractory metastatic clear cell renal cell carcinoma.
The article, titled “Casdatifan shows durable response linked to HIF-2α biology in kidney cancer,” reported dose-expansion data from casdatifan monotherapy and examined associations between serum erythropoietin reduction, tumor HIF-2α biology, and clinical outcomes.
Authors: Toni K. Choueiri, Jamie Merchan, Amita Patnaik, Alexandra Drakaki, Brian I. Rini, Sun Young Rha, Jae Lyun Lee, Moshe C. Ornstein, Rohit Kumar, Clara Hwang, Yusra Shao, Se Hoon Park, Pedro C. Barata, Bradley A. McGregor, Paul Foster, Jianfen Chen, Melissa Eisen, Hunter Cole, Ben Weeder, Yinghui Guan, Jaskirat Singh, Angelo Kaplan, Soonweng Cho, Richard Markus, Omar Kabbarah, and Rana R. McKay.
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ARC-20 Study Design
ARC-20 is an ongoing, multicenter, phase 1, open-label dose-escalation and dose-expansion study registered as NCT05536141.
The dose-escalation stage evaluated casdatifan monotherapy across total daily doses ranging from 20 mg to 200 mg in patients with advanced solid tumors. No dose-limiting toxicities were observed up to 150 mg once daily. One dose-limiting toxicity, grade 3 hypoxia, occurred in the 200 mg once-daily cohort and resolved after treatment interruption.
For the dose-expansion stage, casdatifan was evaluated in patients with refractory metastatic clear cell RCC. This report focused on the 100 mg once-daily cohort, selected as the recommended phase 3 dose, and the total monotherapy population across the 50 mg once-daily, 50 mg twice-daily, 100 mg once-daily, and 150 mg once-daily cohorts.
In total, 127 patients were enrolled in the dose-expansion monotherapy population, including 32 patients in the 100 mg once-daily cohort. All patients had previously received a VEGFR tyrosine kinase inhibitor and anti-PD-1 or anti-PD-L1 therapy. Patients were HIF-2α inhibitor-naive and had ECOG performance status 0 or 1.
At the data cutoff of August 15, 2025, median follow-up was 12.4 months in the 100 mg once-daily cohort and 15.5 months in the total monotherapy population.
Efficacy Results
Among efficacy-evaluable patients, the confirmed objective response rate was 35% in the 100 mg once-daily cohort, with all responses reported as partial responses. In the total monotherapy population, the confirmed objective response rate was 31%, including one complete response and 37 partial responses.
The disease control rate was 84% in the 100 mg cohort and 81% in the total population. Median time to response was 2.6 months and 2.8 months, respectively. Median progression-free survival was not estimable in the 100 mg once-daily cohort and was 12.2 months in the total monotherapy population.
At 12 months, the PFS rate was 60% in the 100 mg cohort and 50% in the total population.
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Safety
The most common treatment-emergent adverse events included anemia, fatigue, headache, and dyspnea. Treatment-related anemia occurred in 84% of patients in the 100 mg cohort and 89% in the total population. Grade 3 or higher treatment-related anemia occurred in 25% and 41%, respectively. No treatment-related anemia led to treatment discontinuation.
Treatment-related hypoxia occurred in 13% of patients in the 100 mg cohort and 16% in the total population. Hypoxia led to treatment discontinuation in 3% and 2%, respectively.
Treatment-emergent adverse events leading to death occurred in 2 patients in the 100 mg cohort and 3 patients in the total population. None were considered related to casdatifan.
Biomarker Findings
The study also examined whether HIF-2α pathway markers were linked with benefit from casdatifan. Greater maximal reductions in serum erythropoietin were associated with improved outcomes, including a higher likelihood of response, lower rates of progressive disease, and longer progression-free survival.
Across biomarker-evaluable patients, 68% had a maximal serum erythropoietin reduction of more than 80%.
Tumor EPO mRNA expression was higher in patients with disease control than in those with progressive disease. EPO expression was mainly seen in carcinoma cells, suggesting a connection between tumor HIF-2α activity and circulating erythropoietin. Patients with at least 25% tumor HIF-2α staining had higher tumor EPO expression and longer progression-free survival than those with lower HIF-2α staining.
Limitations
ARC-20 was a single-arm, early-phase study, so the efficacy results should be interpreted without direct comparison to another treatment. The study included patients with ECOG performance status 0 or 1 and adequate organ and marrow function, which may limit generalizability. Biomarker analyses also used archival tissue samples.
Conclusion
Casdatifan showed durable antitumor activity and a manageable safety profile in heavily pretreated metastatic clear cell RCC. The biomarker findings support a link between HIF-2α pathway inhibition, serum erythropoietin reduction, tumor HIF-2α biology, and clinical benefit. Further evaluation is ongoing, including the phase 3 PEAK-1 study of casdatifan plus cabozantinib in previously treated advanced clear cell RCC.