LITESPARK-003 Trial

Design - Phase 2 open-label belzutifan (Welireg, HIF-2a inhibitor) + cabozantinib (Cabometyx) in advanced ccRCC, including a first-line cohort (NCT03634540; Merck).

ORR (cohort 1, 1L) - 70% ORR (95% CI 55-82%): 8% complete responses, 62% partial responses (investigator-assessed, RECIST v1.1).

PFS / OS - Median PFS 30.3 months; median OS not reached; 12-month OS 96%, 24-month OS 86% (cohort 1).

Safety - All 50 patients had at least one any-grade AE and 60% had at least one grade >=3 AE; common events included anemia, diarrhea, fatigue and hypertension.

Regulatory - Investigational first-line combination. Belzutifan (Welireg) monotherapy and cabozantinib are separately FDA-approved in advanced RCC; this combination is not.

Sponsor / drugs - Merck; belzutifan (Welireg) + cabozantinib (Cabometyx).

Compiled and reviewed by the KOL Pulse research team, led by Brian Shields, Founder, KOL Pulse. Last updated July 21, 2026.

Confirmed Objective Response Rate (RECIST v1.1) — Primary Endpoint (Investigator-Assessed)

Median: 70 % ORR (95% CI 55-82%) (belzutifan 120mg + cabozantinib 60mg (1L, treatment-naive)). Cohort 1 (treatment-naive) ORR rate: 70% (ORR) vs. 8% (CR) vs. 62% (PR). IMDC poor/intermediate risk (n=22) ORR rate: 59% (ORR) vs. 5% (CR) vs. 55% (PR). Cohort 1 median PFS rate: 30.3% (PFS months) vs. 16.6-NR% (95% CI). Cohort 1 12-month rates rate: 69% (PFS) vs. 96% (OS). Cohort 1 24-month rates rate: 57% (PFS) vs. 86% (OS). Phase 2 open-label, single-arm, multi-center study. Cohort 1: 50 treatment-naive evaluable patients (median age 64, 80% male, 96% White, 66% ECOG PS 0, 56% favorable IMDC risk, 80% prior nephrectomy). Intervention: belzutifan 120mg + cabozantinib 60mg orally daily. Primary endpoint ORR 70% (95% CI 55-82%) with 8% CR + 62% PR. IMDC poor/intermediate (n=22): ORR 59% (95% CI 36-79%) with 5% CR + 55% PR. Median PFS 30.3 months (95% CI 16.6-NR). Median OS not reached (95% CI NR-NR). 12-mo PFS 69%, 24-mo PFS 57%. 12-mo OS 96%, 24-mo OS 86%. Choueiri et al., Lancet Oncol 2025;26(1):64-73.

Overall Survival (OS)

Median OS not reached in cohort 1 (treatment-naive). 12-month OS 96% (95% CI 84.2-98.9%); 24-month OS 86% (95% CI 68.2-94.0%). 5 (10%) deaths at data cutoff. Cohort 2 (previously treated with prior IO, N=52) previously reported separately. Strong signal supports further investigation; combination under evaluation in Phase 3 trials.

Safety & Tolerability

Key AEs: Grade 1/2: anemia (76%), diarrhea (74%), fatigue (58%), ALT increase (52%), nausea (52%), Grade 3/4: hypertension (12%), anemia (10%), fatigue (8%), hypoxia (6%), palmar-plantar erythrodysesthesia (6%). All 50 patients had at least 1 any-grade AE, 60% experienced ≥1 Grade ≥3 AE. Serious treatment-related AEs 14%. NO TREATMENT-RELATED DEATHS. Belzutifan dose reductions 28%, interruptions 48%. Treatment-emergent hypoxia (6% G3/4) is a known belzutifan class effect (HIF-2α inhibition).

Clinical Implications

🔄 Phase 2 signal supports Phase 3 development in 1L ccRCC. LITESPARK-003 cohort 1 demonstrated promising antitumor activity of belzutifan + cabozantinib in treatment-naive advanced ccRCC (ORR 70%, mPFS 30.3 mo, 24-mo OS 86%). The HIF-2α + multikinase inhibitor combination offers a novel 1L option but requires Phase 3 validation against established IO-based SOC (nivo+cabo, ipi+nivo, pembro+axi, pembro+lenva). Combination currently under evaluation in Phase 3 LITESPARK-011 and LITESPARK-012. Strong efficacy in IMDC poor/intermediate subgroup (59% ORR) is notable. Known class effects: anemia, hypertension, hypoxia. No new safety signals.

What is the LITESPARK-003 trial?

LITESPARK-003 (NCT03634540) is a Phase 2, open-label, Merck-sponsored trial of belzutifan (Welireg), a HIF-2-alpha inhibitor, combined with the multikinase inhibitor cabozantinib (Cabometyx) in advanced clear-cell renal cell carcinoma, including a treatment-naive (first-line) cohort and a previously treated cohort.

What did LITESPARK-003 show?

In the treatment-naive first-line cohort, belzutifan plus cabozantinib produced an objective response rate of 70% (8% complete and 62% partial responses), a median progression-free survival of 30.3 months, and a 24-month overall survival of 86% (12-month overall survival 96%). Median overall survival was not reached at the data cutoff.

Is belzutifan plus cabozantinib FDA approved for kidney cancer?

No - the specific first-line belzutifan plus cabozantinib combination studied in LITESPARK-003 is investigational and not an FDA-approved regimen. Belzutifan (Welireg) is separately FDA-approved as monotherapy for advanced renal cell carcinoma after a PD-1/PD-L1 inhibitor and a VEGF-targeted tyrosine kinase inhibitor, and cabozantinib (Cabometyx) is separately approved in advanced RCC.

What is the safety profile of the combination?

All 50 patients in the reported cohort experienced at least one adverse event of any grade, and 60% had at least one grade 3 or higher event. Common any-grade events included anemia, diarrhea, fatigue, ALT increase and nausea; grade 3/4 events included hypertension, anemia and fatigue. The profile reflects the combined toxicities of a HIF-2-alpha inhibitor and a multikinase inhibitor.

What is the significance of the LITESPARK-003 results?

The Phase 2 signal - a 70% response rate with a median progression-free survival exceeding two years in first-line clear-cell RCC - supports further Phase 3 development of the HIF-2-alpha plus multikinase inhibitor combination as a potential novel first-line option. Results were reported by Choueiri and colleagues (Lancet Oncology 2025).