Casdatifan shows durable response linked to HIF-2α biology in kidney cancer
Recommended Citation
Choueiri TK, Merchan J, Patnaik A, Drakaki A, Rini BI, Rha SY, Lee JL, Ornstein MC, Kumar R, Hwang C, Shao Y, Park SH, Barata PC, McGregor BA, Foster P, Chen J, Eisen M, Cole H, Weeder B, Guan Y, Singh J, Kaplan A, Cho S, Markus R, Kabbarah O, McKay RR. Casdatifan Shows Durable Response Linked to Hif-2α Biology in Kidney Cancer. Nature. 2026;656(8128):734-741.
Document Type
Article
Publication Date
8-1-2026
Publication Title
Nature
Keywords
Adult, Aged, Female, Humans, Male, Middle Aged, Basic Helix-Loop-Helix Proteins, Carcinoma, Renal Cell, Endothelial PAS Domain-Containing Protein 1, Erythropoietin, Gene Expression Regulation, Neoplastic, Kidney Neoplasms, Progression-Free Survival, Antineoplastic Agents, Aged, 80 and over
Abstract
Clear cell renal cell carcinoma (ccRCC) is largely driven by the transcription factor hypoxia-inducible factor 2α (HIF-2α)(1). Here we show that monotherapy with casdatifan-an orally bioavailable, potent and selective HIF-2α inhibitor(2)-produces meaningful, durable antitumour activity with manageable safety in individuals with refractory metastatic ccRCC. Dose-expansion data from the ARC-20 study ( NCT05536141 ) are presented, including for the 100 mg once daily (QD) cohort (n = 32) and the total cohort (n = 127). Treatment discontinuation from casdatifan-related adverse events was infrequent (3%), and class-effect toxicities included anaemia and hypoxia. The confirmed objective response rates (ORRs) were 35% (95% confidence intervals (CI) = 19-55%; 100 mg QD) and 31% (95% CI = 23-40%; total); median progression-free survival (PFS) was not estimable (95% CI = 5.7-not estimable; 100 mg QD) and 12.2 months (9.4-20.6; total). Greater maximal reductions in serum erythropoietin were associated with improved clinical outcomes, including a higher ORR (P = 0.001), lower rates of progressive disease (P = 0.003) and longer PFS (P = 0.006). Erythropoietin expression was restricted to cancer cells and was significantly higher at the mRNA level in patients with clinical benefit. Concordantly, HIF-2α protein expression and HIF-2α expression signature were associated with prolonged PFS. Overall, our findings show that casdatifan achieves meaningful, durable responses with manageable safety. These data establish a link between on-target HIF-2α pathway modulation, tumour biology and clinical efficacy.
Medical Subject Headings
Adult; Aged; Female; Humans; Male; Middle Aged; Basic Helix-Loop-Helix Proteins; Carcinoma, Renal Cell; Endothelial PAS Domain-Containing Protein 1; Erythropoietin; Gene Expression Regulation, Neoplastic; Kidney Neoplasms; Progression-Free Survival; Antineoplastic Agents; Aged, 80 and over
PubMed ID
42386974
ePublication
ePub ahead of print
Volume
656
Issue
8128
First Page
734
Last Page
741
