88 PEAK-1 (NCT07011719): A Randomized, Double-Blind, Active-Control Phase 3 Trial of Casdatifan and Cabozantinib Versus Placebo and Cabozantinib in Patients with Advanced Clear Cell Renal Cell Carcinoma

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Abstract Background For patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC) who have relapsed after anti-programmed death protein 1 (anti–PD-1) or anti-programmed death ligand-1 (anti–PD-L1) treatment, second-line treatment options remain limited, consisting primarily of tyrosine kinase inhibitor (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 TKI without overlapping toxicities. Casdatifan is an orally bioavailable, potent, and selective HIF-2α inhibitor that has a potentially improved pharmacodynamic profile relative to other members of the therapeutic class (Ghasemi 2025). Combining casdatifan with cabozantinib, a second-generation TKI which targets VEGF, MET, and AXL, may enhance antitumor activity beyond the individual agents. Preliminary data from the phase 1 ARC-20 study showed promising antitumor activity with the casdatifan plus cabozantinib combination (Choueiri 2025). PEAK-1 is a phase 3 study evaluating the efficacy and safety of casdatifan in combination with cabozantinib for the treatment of patients with ccRCC. Methods PEAK-1 (NCT07011719) is an ongoing, global, randomized, double-blind, phase 3 study in adults with confirmed advanced or metastatic ccRCC who have experienced progression on or after anti–PD-1 or anti–PD-L1 therapy. Approximately 720 patients will be randomly assigned (2:1) to casdatifan 100 mg plus cabozantinib 60 mg once daily or placebo plus cabozantinib 60 mg once daily; crossover is not permitted. Stratification factors include region (North America vs Western Europe vs rest of world), prior VEGFR-TKI use (yes vs no), International Metastatic RCC Database Consortium risk score category (favorable vs intermediate/poor). Eligible patients are adults (aged ≥ 18 years) with a most recent regimen that includes anti–PD-(L)1 therapy (adjuvant or first-line in combination with anti–CTLA-4 or VEGFR-TKI), ≤ 1 prior regimen in the metastatic setting, a Karnofsky Performance Status score ≥ 80%, ≥ 1 target lesion measurable by CT/MRI per RECIST v1.1, and adequate organ and marrow function. Key exclusion criteria include prior use of an HIF-2α inhibitor or cabozantinib, ongoing concomitant use of moderate or strong CYP3A4 inducers, and uncontrolled or poorly controlled hypertension (sustained blood pressure > 150 mmHg systolic or > 90 mmHg diastolic). The primary endpoint of the study is progression-free survival assessed by blinded independent central review per RECIST v1.1. Secondary endpoints include safety, overall survival, objective response rate, disease control rate, and duration of response. Patient-reported outcomes will also be assessed using the disease-related symptoms subscale of the National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy–Kidney Symptom Index. Results Enrollment is ongoing. Targeting HIF-2α with casdatifan in combination with the TKI cabozantinib may offer a complementary strategy to overcome resistance after prior immunotherapy. The casdatifan plus cabozantinib combination is a novel treatment approach for patients with ccRCC in the post–first-line setting. Conclusions N/A

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