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 renal cell carcinoma.

Abstract

TPS4636 Background: For patients (pts) with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have relapsed post anti-PD-1/PD-L1 treatment, second line treatment options remain limited, consisting primarily of tyrosine kinase inhibitors (TKI) monotherapy. Hypoxia-inducible factor 2 alpha (HIF-2α) inhibition represents a promising target as its mechanism of action has been clinically validated in ccRCC and is distinct from that of TKIs without overlapping toxicities. Casdatifan (cas) is an orally bioavailable, selective HIF-2α inhibitor that has a potentially improved pharmacodynamic profile relative to other members of the therapeutic class (Ghasemi 2025). Combining cas with a TKI (cabozantinib [cabo]) that targets VEGFR, MET, and AXL may yield enhanced antitumor activity beyond the individual agents. Preliminary efficacy data from the Phase 2 ARC-20 Study demonstrated promising antitumor activity with the combination (cas + cabo; Choueiri 2025). PEAK-1 is currently the only Phase 3 that examines the efficacy and safety of a HIF-2α inhibitor in combination with a TKI in ccRCC. Methods: PEAK-1 (NCT07011719) is an ongoing Phase 3, randomized, active-control, double-blind, 2-arm, global, multicenter study in adult pts with confirmed advanced or metastatic ccRCC who have experienced progression on or after anti-PD1 or anti-PD-L1 treatment. Approximately 720 pts will be enrolled and randomized 2:1 to treatment with 100 mg QD cas + 60 mg QD cabo (experimental arm) or placebo + 60 mg QD cabo (comparator arm). Crossover is not allowed. Stratification factors include by region (North America vs Western Europe vs rest of world); prior VEGFR-TKI (yes vs no); and International Metastatic RCC Database Consortium risk score (favorable vs intermediate/poor). Key eligibility requirements include adults (≥ 18 years) who have received anti-PD-1 or anti-PD-L1 treatment as part of the most recent regimen (either adjuvant monotherapy or first line in combination with anti-CTLA-4 or VEGFR-TKI), with ≤ 1 prior regimens in the metastatic setting. Pts must have a Karnofsky Performance Status score ≥ 80%, at least 1 target lesion measurable by computed tomography/magnetic resonance imaging per RECIST 1.1, and adequate organ and marrow function. Key exclusion criteria include prior treatment with a HIF-2α inhibitor or cabo, receiving ongoing concomitant treatment with moderate or strong CYP3A4 inducers, and uncontrolled or poorly controlled hypertension (sustained blood pressure >140/90 mm Hg on ≥ 3 antihypertensives). The primary endpoint of the study is PFS BICR according to RECIST 1.1. Secondary endpoints include safety, overall survival, overall response rate, duration of response, and disease control rate. Pt reported outcomes using NFKSI-DRS will also be assessed. Enrolment is ongoing as of 1 Oct 2025. Clinical trial information: NCT07011719 .