Phase 1 casdatifan selective HIF-2α transcription-factor inhibitor pilot in refractory ccRCC

Vanderbilt-Ingram Cancer Center is running a single-institution, open-label pilot study of oral casdatifan (AB521), a small-molecule, allosteric inhibitor of HIF-2α–dependent transcription, in metastatic clear cell renal cell carcinoma (ccRCC) that has progressed after prior immune checkpoint therapy and VEGF-targeted therapy. Casdatifan is supplied by Arcus Biosciences, and patients take a fixed 100 mg once-daily continuous dose with protocol-defined dose reductions allowed for toxicity. The core purpose is translational: serial tumor biopsies (baseline, on-treatment, and at progression) undergo RNA sequencing to measure predefined HIF-2–regulated target-gene changes and broader adaptive/resistance expression programs, with blood collected for future correlative work. This is attractive commercially/scientifically because it ties a next-generation HIF-2α program to on-treatment pathway engagement in a setting where today’s care is sequential systemic therapy after IO+VEGF failure (commonly VEGFR TKIs and/or mTOR inhibitors, and in some sequences HIF-2 inhibition in later lines), and it aims to identify biomarkers and mechanisms that could guide expansion strategies and combinations.