A New Targeted Therapy Signal Emerges in Heavily Pretreated Kidney Cancer: 35% Response Rate in Phase 1 Casdatifan Trial

Treatment options gradually narrow for advanced kidney cancer after immunotherapy and anti-angiogenic drugs. The phase 1 ARC-20 trial now provides an early signal: the oral HIF-2α inhibitor casdatifan produced marked tumor shrinkage in about one-third of these patients whose disease had continued to progress after multiple treatments, with some responses lasting more than a year.

The study enrolled 127 patients with refractory metastatic clear-cell renal cell carcinoma who had received a median of three prior lines of systemic therapy. All had previously received a VEGF receptor tyrosine kinase inhibitor and PD-1 or PD-L1 immunotherapy. Across the four pooled monotherapy dose groups, the confirmed objective response rate among 121 evaluable patients was 31%. In the 100 mg once-daily group selected as the dose for a subsequent phase 3 trial, 35% of 31 evaluable patients achieved a partial response, with a 95% confidence interval of 19% to 55%.

As of the August 2025 data cutoff, median progression-free survival in the pooled population was 12.2 months, and the disease control rate was 81%. At that time, median progression-free survival could not yet be estimated in the 100 mg group because of the shorter follow-up period. A follow-up analysis subsequently announced by the company in January 2026 reported 15.1 months for that group, but this later figure was not part of the paper’s primary analysis and should be distinguished when interpreting the results.

The study’s greater scientific significance lies in the alignment between the efficacy signal and activity against the drug’s target. Following HIF-2α inhibition by casdatifan, greater reductions in serum erythropoietin were associated with a higher likelihood of tumor response and a lower risk of disease progression. Erythropoietin expression in tumors, HIF-2α protein levels, and related gene-expression signatures were likewise associated with clinical benefit or longer progression-free survival. These findings support that the drug is acting on its intended pathway and identify candidate biomarkers for future patient selection or monitoring of drug activity.

The trade-offs also reflected the mechanism of action of this drug class. In the pooled population, 89% of patients experienced investigator-assessed treatment-related anemia, including 41% with grade 3 or higher events; 16% developed treatment-related hypoxia. About one-quarter of patients had dose reductions because of related adverse events, and 3% discontinued treatment for this reason. Deaths during the treatment period reported in the study were not considered related to casdatifan, but anemia, oxygen requirements, and dose adjustments remain issues that must be carefully weighed in subsequent large trials.

HIF-2α has already been validated as a therapeutic target in kidney cancer by the drug belzutifan, which belongs to the same class. Whether casdatifan can provide greater or more durable benefit, however, cannot be determined through direct comparisons of response rates across different trials. ARC-20 had no randomized control group, the 100 mg group included only 32 patients, and the biomarker analyses covered only a subset of patients with available specimens. The paper’s authors also disclosed extensive relationships with the developer and other pharmaceutical companies. The current results are sufficient to support further validation, but they do not yet show that casdatifan is superior to existing therapies, nor do they establish changes in erythropoietin as a mature tool for treatment selection.