Updated results from the phase 2 LITESPARK-003 study of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC).
Authors: Toni K. Choueiri, Todd Michael Bauer, Jaime R. Merchan, David F. McDermott, Robert A. Figlin, Edward Arrowsmith, M. Dror Michaelson, Elisabeth I. Heath, Anishka D’Souza, Song Zhao, Laurent Kassalow, Rodolfo F. Perini, Donna Vickery, Scott S. Tykodi
Journal: Journal of Clinical Oncology (2025)

549 Background: In the phase 2 LITESPARK-003 study (NCT03634540), belzutifan plus cabozantinib showed antitumor activity in patients with advanced ccRCC who were treatment-naive (cohort 1) or previously treated (cohort 2). We present updated results from cohorts 1 and 2 with a median follow-up of 34.4 months and 49.9 months, respectively. Methods: Eligible patients had advanced or metastatic ccRCC and ECOG performance status of 0 or 1. Cohort 1 included patients with no prior systemic therapy. Cohort 2 included patients who had received prior immunotherapy and ≤2 systemic regimens. Starting doses for patients in both cohorts were belzutifan 120 mg PO QD + cabozantinib 60 mg PO QD. The primary end point was ORR per RECIST v1.1 by investigator assessment. Secondary end points included DOR, PFS, OS, and safety. Results: 50 patients were enrolled and treated in cohort 1 and 52 patients in cohort 2. Confirmed ORR was 70% (95% CI, 55-82; 6 CRs, 29 PRs) in cohort 1 and 31% (95% CI, 19-45; 2 CRs, 14 PRs) in cohort 2. In cohort 2, ORR was 32% (95% CI, 16-52; 1 CR, 8 PRs) in patients who received prior immunotherapy only (n = 28) and 29% (95% CI, 13-51; 1 CR, 6 PRs) in patients who received both prior immunotherapy and anti-VEGFR TKIs (n = 24). ORR by IMDC risk and baseline tumor burden subgroups is shown in the Table. Median DOR was 29.1 months (range, 1.9+ to 47.4; + indicates ongoing response at the last assessment) in cohort 1 and 30.4 months (range, 4.2+ to 45.6) in cohort 2. An estimated 62% of responders in cohort 1 and 52% in cohort 2 remained in response for ≥24 months. Median PFS was 30.3 months (95% CI, 19.4-not reached) in cohort 1 and 13.8 mo (95% CI, 9.2-19.4) in cohort 2. Median OS has not been reached in cohort 1 and was 26.7 months (95% CI, 20.0-41.1) in cohort 2. Overall, 27 (54%) patients in cohort 1 and 34 (65%) patients in cohort 2 had a grade 3 or higher treatment-related adverse event (TRAE). No patients died due to a TRAE in cohort 1 and 1 patient (2%) died due to treatment-related respiratory failure in cohort 2. Conclusions: With updated follow-up,belzutifan plus cabozantinib showed durable antitumor activity in both frontline and subsequent-line treatment of patients with RCC and a safety profile consistent with prior reports. These results support further investigation of a HIF-2α inhibitor in combination with a VEGFR-TKI as a treatment option for advanced ccRCC in both settings. Clinical trial information: NCT03634540 . Cohort 1 Cohort 2 IMDC risk category Favorable n = 33ORR, 73% (95% CI, 54-87); 5 CRs, 19 PRs n = 9ORR, 67% (95% CI, 30-93); 1 CR, 5 PRs Intermediate or poor n = 17ORR, 65% (95% CI, 38-86); 1 CR, 10 PRs n = 43ORR, 23% (95% CI, 12-39); 1 CR, 9 PRs Baseline tumor burden a Low (&lt; median) n = 25ORR, 80% (95% CI, 59-93);3 CRs, 17 PRs n = 26ORR, 27% (95% CI, 12-48); 2 CRs, 5 PRs High (≥ median) n = 25ORR, 60% (95% CI, 39-79); 3 CRs, 12 PRs n = 26ORR, 35% (95% CI, 17-56); 0 CRs, 9 PRs a Based on the sum of diameter of the target lesions at baseline.