Key Clinical Summary: 

• Design/Population: The phase 3 LITESPARK-011 trial randomized 747 patients with advanced clear cell renal cell carcinoma who progressed after anti-PD-L1 therapy to receive belzutifan plus lenvatinib or cabozantinib. Dual primary end points were progression-free survival and overall survival.
• Key Outcomes: Belzutifan plus lenvatinib significantly improved progression-free survival and objective response rate compared with cabozantinib. Overall survival numerically favored the combination but did not reach statistical significance at interim analyses.
• Clinical Relevance: These findings support belzutifan plus lenvatinib as a potential new treatment option for patients with advanced clear cell renal cell carcinoma following immunotherapy. Final overall survival analysis will further clarify long-term benefit.

Interim results from the phase 3 LITESPARK-011 trial demonstrate that belzutifan, a hypoxia-inducible factor 2 alpha (HIF2α) inhibitor, plus lenvatinib significantly improved progression-free survival (PFS) compared with cabozantinib among previously treated patients with advanced clear cell renal cell carcinoma (ccRCC).

These findings were presented by Robert Motzer, MD, Memorial Sloan Kettering Cancer Center, New York, New York, at the 2026 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium in San Francisco, California.

In this study, 747 patients who experienced disease progression on or after first- or second-line anti–PD-L1 therapy, or within ≤ 6 months of adjuvant anti-PD-L1 therapy, were randomized 1:1 to receive either 120 mg of belzutifan plus 20 mg of lenvatinib 20 (n = 371) or 60 mg of cabozantinib (n = 376). The dual primary end points were PFS and overall survival (OS). Secondary end points included objective response rate (ORR), duration of response, and safety.

At the first interim analysis, median PFS was 14.6 months in the belzutifan plus lenvatinib arm and 10.6 months in the cabozantinib arm (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.61 to 0.89; P = .00095). Median OS was not reached in the belzutifan plus lenvatinib arm and was 27.4 months in the cabozantinib arm (HR, 0.90; 95% CI, 0.70 to 1.15; P = .19322). Median ORR was 52.6% and 39.6%, respectively (P = .0002).

At the second interim analysis, median PFS was 14.8 months in the belzutifan plus lenvatinib arm and 10.7 months in the cabozantinib arm (HR, 0.70; 95% CI, 0.59 to 0.84; P = .00007). Median OS was 34.9 months and 27.6 months, respectively (HR, 0.85; 95% CI, 0.68 to 1.05; P = .06075). Median duration of response was 23 months in the belzutifan plus lenvatinib arm and 12.3 months in the cabozantinib arm.

Grade ≥ 3 treatment-emergent adverse events were reported in 84.1% of patients in the belzutifan plus lenvatinib arm and 82.7% of patients in the cabozantinib arm. Treatment-related deaths occurred in 2 patients receiving belzutifan plus lenvatinib, and in 1 patient receiving cabozantinib.

As Dr Motzer concluded, “LITESPARK-011 is the first phase 3 study of a HIF-2α inhibitor combined with a [vascular endothelial growth factor] (VEGFR) [tyrosine kinase inhibitors] (TKIs) and the first phase 3 study in RCC to demonstrate improved outcomes versus a contemporary VEGFR TKI.”

Source: 

Motzer R, Park SH, McDermott RS, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. Presented at ASCO GU. February 26-28, 2026. San Francisco, California. LBA417.