(UroToday.com) The 2026 American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL, will host the Kidney and Bladder Cancer - Posters Session. Dr. Toni K. Choueiri will present Abstract TPS4636: PEAK-1: A randomized, double-blind, active-control, multicenter phase 3 trial of casdatifan and cabozantinib versus placebo and cabozantinib in patients with advanced clear cell RCC.
Treatment options remain limited for patients with advanced or metastatic clear cell RCC who progress following anti–PD-1/PD-L1 therapy, with second-line management still largely reliant on TKI monotherapy. He noted that hypoxia-inducible factor 2 alpha (HIF-2α) inhibition has emerged as a promising therapeutic strategy in ccRCC, with a mechanism of action distinct from VEGFR-targeted TKIs and without overlapping toxicities. Casdatifan is an orally bioavailable, selective HIF-2α inhibitor with a potentially improved pharmacodynamic profile relative to other agents within the class. Additionally, preliminary efficacy data from the phase 2 ARC-20 study previously demonstrated encouraging antitumor activity with the combination of casdatifan plus cabozantinib.
The design of PEAK-1 (NCT07011719), an ongoing phase 3, randomized, active-controlled, double-blind, global multicenter trial evaluating casdatifan in combination with cabozantinib in patients with advanced or metastatic ccRCC who progressed on or after prior anti–PD-1/PD-L1 therapy.
Approximately 720 patients are planned for enrollment and will be randomized in a 2:1 fashion to receive either:
- Casdatifan 100 mg once daily plus cabozantinib 60 mg once daily
- Placebo plus cabozantinib 60 mg once daily
Importantly, crossover between treatment arms is not permitted.
Eligible patients must have confirmed advanced or metastatic ccRCC and prior exposure to anti–PD-1 or anti–PD-L1 therapy as part of their most recent regimen, either in the adjuvant setting or first-line metastatic setting in combination with anti–CTLA-4 therapy or a VEGFR-TKI. Patients may have received no more than one prior metastatic regimen. Additional eligibility criteria include Karnofsky Performance Status ≥80%, measurable disease per RECIST 1.1, and adequate organ and marrow function.
Key exclusion criteria include prior treatment with a HIF-2α inhibitor or cabozantinib, ongoing treatment with moderate or strong CYP3A4 inducers, and uncontrolled hypertension despite the use of ≥3 antihypertensive agents.
Patients will be stratified according to:
- Geographic region (North America vs Western Europe vs the rest of the world)
- Prior VEGFR-TKI exposure
- IMDC risk category (favorable vs intermediate/poor)
The primary endpoint is progression-free survival by blinded independent central review per RECIST 1.1. Secondary endpoints include overall survival, objective response rate, duration of response, disease control rate, safety, and patient-reported outcomes using the NFKSI-DRS instrument.
PEAK-1 is currently the only phase 3 study evaluating the combination of a HIF-2α inhibitor plus a TKI in ccRCC and may help define a novel post-immunotherapy treatment strategy in this disease space.
Presented by: Toni K. Choueiri, MD, Dana Farber Cancer Institute, Boston, MA
Written by: Julian Chavarriaga, MD, Clinical Assistant Professor, Urologic Oncologist, Department of Urology at Penn State Health @chavarriagaj on X during the American Society of Clinical Oncology Genitourinary (ASCO) Annual Meeting held in Chicago, IL between May 29th and June 1st, 2026