Latest LITESPARK-003 data highlight antitumor activity of belzutifan plus cabozantinib

Durable antitumor activity continued to be seen with combination treatment with belzutifan (Welireg) plus cabozantinib (Cabometyx) for patients with advanced clear cell renal cell carcinoma (RCC), according to the latest data from the phase 3 LITESPARK-003 (NCT03634540) study.¹

Toni K. Choueiri, MD

The results were presented at the 2025 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium by investigators led by Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, Massachusetts.

In their poster, the investigators explained that previously reported LITESPARK-003 data indicated that belzutifan combined with cabozantinib was associated with antitumor activity in patients with advanced clear cell RCC who were either treatment naïve (cohort 1) or previously treated (cohort 2). According to the initial analysis, objective response rate (ORR, the primary end point) was 57% in cohort 1 (n = 35) 31% in cohort 2 (n = 52) at a median follow-up of 14.0 months and 24.6 months, respectively.^2,3 The treatment combination’s antitumor activity was found to be durable after a median follow-up of 24.3 moths in cohort 1 and 39.8 months in cohort 2.^4,5

At ASCO GU, the investigators presented updated results for belzutifan plus cabozantinib in LITESPARK-003 cohorts 1 and 2 at a median follow-up of 34.4 months for cohort 1 and 49.9 months for cohort 2.

Patients were eligible for inclusion if they had locally advanced or metastatic clear cell RCC, were treatment naïve (cohort 1), had received prior immunotherapy and 2 or fewer regimens for metastatic RCC (cohort 2) had measurable disease per RECIST v.1.1, and had ECOG Performance Status of 0 or 1. Patients in both cohorts received belzutifan 120 mg/day by mouth plus cabozantinib 60 mg/day by mouth.

The primary end point was ORR per RECIST v1.1 by investigator assessment; secondary end points included duration of response (DOR), time to response (TTR), progression-free survival (PFS), overall survival (OS), and safety.

A total of 50 patients were enrolled and treated in cohort 1, and 52 patients were enrolled and treated in cohort 2. In cohort 1, treatment is ongoing in 23 patients; 27 patients discontinued treatment. In cohort 2, treatment is ongoing in 5 patients; 47 patients discontinued treatment.

Median patient age was similar in the 2 cohorts. In cohort 1, 23 (46%) patients were 65 years of age or older, and in cohort 2, 24 (46%) patients were 65 years of age or older.

ORR was 70% (95% CI, 55-82) in cohort 1 compared with 31% (95% CI, 19-45) in cohort 2. Complete responses were observed in 6 (12%) patients in cohort 1 and 2 (4%) patients in cohort 2.

ORR was 32% in cohort 2 in patients who had previously received immunotherapy only (n = 28) and 29% in patients who had previously received immunotherapy as well as an anti-VEGF therapy (n = 24).

Median PFS was 30.3 (95% CI, 19.4-not reached) months in cohort 1 and 13.8 (95% CI, 9.2-19.4) months in cohort 2. Median OS was not reached in cohort 1 and was 26.7 (95% CI, 20.0-41.1) months in cohort 2.

Regarding safety, more than half of patients in each cohort experienced a grade 3 or higher treatment-related adverse event (TRAE, 54% in cohort 1 and 65% in cohort 2). No patients in cohort 1 died as a result of a TRAE; in cohort 2, 1 (2%) patient died as a result of a treatment-related respiratory failure.

“With updated follow-up, belzutifan plus cabozantinib continued to show durable antitumor activity in both first-line (cohort 1) and subsequent-line (cohort 2) treatment of participants with clear cell RCC…These results support further investigation of a HIF-2α inhibitor in combination with a VEGF(R) tyrosine kinase inhibitor for advanced clear cell RCC in both first-line and subsequent-line settings,” the authors wrote in their conclusion.

REFERENCES

1. Choueiri T, Bauer T, Merchan J, et al. Updated results from the phase 2 LITESPARK-003 study of belzutifan plus cabozantinib in patients with advanced clear cell renal cell carcinoma (ccRCC). J Clin Oncol 43, 2025 (suppl 5; abstr 549). doi:10.1200/JCO.2025.43.5_suppl.549

2. Choueiri TK, Bauer T, Merchan J, et al.1447O Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): Cohort 1 of LITESPARK-003. Ann Oncol. 2022;33(suppl_7):S1204

3. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 2023;24(5):553-562. doi:10.1016/S1470-2045(23)00097-9

4. Choueiri TK, Merchan JR, Figlin R, et al. Belzutifan plus cabozantinib as first-line treatment for patients with advanced clear-cell renal cell carcinoma (LITESPARK-003): an open-label, single-arm, phase 2 study. Lancet Oncol. 2025;26(1):64-73. doi:10.1016/S1470-2045(24)00649-1

5. Choueiri TK, Bauer T, Merchan JR, et al. LBA87 Phase II LITESPARK-003 study of belzutifan in combination with cabozantinib for advanced clear cell renal cell carcinoma (ccRCC). Ann Oncol. 2023;34(suppl_2):S1328-S1329