Next-generation HIF-2α inhibitor shows promise in kidney cancer translational clinical trial
· Medical Xpressby Victoria Warren, Dana-Farber Cancer Institute
edited by Stephanie Baum, reviewed by Robert Egan
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The first-in-patient, single-arm ARC-20 clinical trial, led by Dana-Farber Cancer Institute's Toni K. Choueiri, MD, has evaluated casdatifan, a next-generation HIF-2α inhibitor, as monotherapy for metastatic clear cell renal cell carcinoma (ccRCC), the most common subtype of kidney cancer. Patients eligible for the study were previously treated with standard therapies.
Most ccRCC tumors accumulate HIF-2α, which drives tumor growth and metastasis. Casdatifan is a next-generation HIF-2α inhibitor designed for high potency and selectivity. A total of 127 patients enrolled and received a range of escalating doses.
Results showed that the treatment was well tolerated, with manageable side effects consistent with expectations for HIF-2α inhibitors. Casdatifan also showed promising signs of efficacy, with objective responses in 35% of patients receiving a 100 mg dose, the selected dose for future trials.
Extensive blood and tissue biomarkers of HIF-2α inhibition and downstream pathway activation paralleled clinical benefit, suggesting that the therapy is hitting its target and working as expected mechanistically. Choueiri collaborates closely with William G. Kaelin Jr. at Dana-Farber, who shared the Nobel Prize in 2019 for discovering how cells sense and adapt to oxygen. An understanding of that biology ultimately led to HIF-2α targeting in kidney cancer.
Evidence from this trial supports continued study of casdatifan for ccRCC, including the PEAK-1 international randomized phase 3 trial comparing casdatifan plus cabozantinib with cabozantinib alone in patients with metastatic ccRCC whose cancer progressed after immunotherapy.
Publication details
Toni Choueiri, Casdatifan shows durable response linked to HIF-2α biology in kidney cancer, Nature (2026). DOI: 10.1038/s41586-026-10718-x. www.nature.com/articles/s41586-026-10718-x
Journal information: Nature
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