The VHL-HIF pathway is one of the most commonly activated pathways in clear cell renal cell carcinoma (ccRCC). Loss of von Hippel-Lindau (VHL) gene function leads to the stabilization of hypoxia-inducible factors HIF-1α and HIF-2α, driving tumor growth and progression. The development of HIF-2α inhibitors, including belzutifan and casdatifan, has introduced new therapeutic strategies for ccRCC.At the 2025 ASCO GU Annual Meeting, Professor Toni Choueiri from Dana-Farber Cancer Institute presented phase I study results on casdatifan, offering insights into its clinical activity and potential role in renal cell carcinoma treatment.

Key Findings from the Phase I ARC-20 Trial

The ongoing phase I ARC-20 clinical trial demonstrates that casdatifan monotherapy exhibits promising clinical activity in previously treated ccRCC patients, with manageable and predictable adverse effects such as anemia and hypoxia.

This study enrolled patients who had previously received PD-(L)1 inhibitors and VEGFR-tyrosine kinase inhibitors (TKIs). Participants were treated with casdatifan monotherapy across five dose-escalation cohorts and four dose-expansion cohorts. The trial’s primary endpoints include the incidence of treatment-emergent adverse events (TEAEs) and objective response rate (ORR).

Future research will explore the efficacy of casdatifan in frontline therapy, with plans for a pivotal phase III trial to further evaluate this novel agent.

Casdatifan Demonstrates Clinical Activity in ccRCC

“The patients tolerated casdatifan well,” said Professor Toni Choueiri, principal investigator of the study. “The toxicity profile is manageable, particularly in terms of ‘on-target’ adverse effects such as anemia and hypoxia. Additionally, casdatifan has demonstrated clinical activity, with several patients achieving durable responses.”

ccRCC is the most common histological subtype of renal cell carcinoma. Current standard treatments include immune checkpoint inhibitor (ICI) combinations targeting PD-1, CTLA-4, and VEGF pathways. However, ccRCC is also strongly associated with VHL pathway dysregulation, leading to HIF-2α overexpression and oncogene activation.

This has driven the development of HIF-2α inhibitors, such as belzutifan, which was granted accelerated FDA approval in August 2021 for patients with VHL-associated renal cell carcinoma, central nervous system hemangioblastomas, and pancreatic neuroendocrine tumors that did not require immediate surgery. In December 2023, belzutifan received full FDA approval for use in advanced RCC patients previously treated with PD-(L)1 and VEGF-targeted therapies.

Casdatifan is a novel oral small-molecule inhibitor that blocks HIF-2α-dependent gene transcription. “It is essentially a small-molecule HIF-2α inhibitor that has demonstrated strong antitumor activity in RCC xenograft models,” Professor Choueiri explained.

Study Design and Initial Results of the ARC-20 Trial

The ARC-20 study enrolled ccRCC patients aged 18 and older who had not received prior HIF-2α inhibitors and had previously undergone treatment with PD-(L)1 inhibitors and VEGFR-TKIs.

• 33 patients received 50 mg casdatifan twice daily, with a median follow-up of 11 months.
• 31 patients received 50 mg casdatifan once daily, with a median follow-up of 8 months.

No grade 4 TEAEs were observed in either cohort. Grade 3 TEAEs were reported in 42% of the twice-daily group and 36% of the once-daily group. The most common TEAE was anemia, affecting 36% of patients. Hypoxia occurred in 9% of patients in the twice-daily group and 6% in the once-daily group.

Confirmed objective response rates (ORRs) were 25% in the twice-daily cohort and 21% in the once-daily cohort.

Future Directions: Phase III PEAK-1 Trial

“We are planning a new trial, PEAK-1, which will be a randomized phase III trial comparing casdatifan plus cabozantinib versus cabozantinib alone in patients with metastatic ccRCC who have progressed after immunotherapy,” Professor Choueiri stated.

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About Professor Toni Choueiri

Toni K. Choueiri, MD

Dana-Farber Cancer Institute

Professor Toni Choueiri is the Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute (DFCI) and Co-Leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center. He holds the Jerome and Nancy Kohlberg Chair in Medicine at Harvard Medical School and serves as the Medical Director of International Strategic Initiatives at Dana-Farber.

Professor Choueiri has received numerous awards, including the George Canellos Award for Excellence in Clinical Research and Patient Care (2013, DFCI) and the Eugene Schonfeld Award from the Kidney Cancer Association (2016). He was also named a Cancer Care Giant in 2021.

A recognized leader in kidney cancer research, Professor Choueiri is a member of the National Comprehensive Cancer Network (NCCN) Kidney Cancer Panel, the KidneyCan Board of Directors, and the NCI Genitourinary Steering Committee. He previously served as the Chair of the Medical and Scientific Steering Committee of the Kidney Cancer Association (2015–2018) and is the principal investigator of multiple national and international phase I–III genitourinary oncology trials.