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

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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 (< 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.