Dr Heng on Role of Belzutifan Across Lines of Therapy in Advanced RCC

Daniel Heng, MD, MPH, FRCPC, of the University of Calgary discusses where belzutifan (Welireg) fits in the treatment sequence for advanced renal cell carcinoma (RCC), drawing on data from 2 phase 3 studies: the final analysis of LITESPARK-011 (Abstract 3587O) and the first-line LITESPARK-012 study (Abstract 3586O). These findings were shared at the the European Society for Medical Oncology (ESMO) Congress 2026.

LITESPARK-011 evaluated belzutifan plus lenvatinib (Lenvima) versus cabozantinib (Cabometyx) in patients with advanced clear cell RCC (ccRCC) whose disease progressed after anti-PD-(L)1 therapy. Heng describes the belzutifan and lenvatinib combination as a new standard of care in the second-line setting. He notes that its regulatory status varies by jurisdiction. The combination was approved by the FDA in September 2026, while approval from the European Medicines Agency was pending at the time of the ESMO presentation. Other jurisdictions are also reviewing the combination.

According to Heng, the shift to doublet therapy in the second-line setting is very exciting for patients. He points to an objective response rate of approximately 53% with the combination, which he describes as considerably better than the 20% to 30% response rates he referenced previously. In the final analysis, the objective response rate was 53.1% with belzutifan plus lenvatinib versus 40.2% with cabozantinib. Although the combination demonstrated significant improvements in progression-free survival and response rate, the final overall survival analysis did not meet the prespecified threshold for statistical significance.

The picture is different in the frontline setting. LITESPARK-012 was a randomized, open-label phase 3 study evaluating the addition of belzutifan or quavonlimab to first-line pembrolizumab (Keytruda) plus lenvatinib in patients with advanced ccRCC. Heng explains that the trial showed the addition of belzutifan could not improve upon the current first-line regimen of lenvatinib plus pembrolizumab. Based on these results, he does not see a place for belzutifan in the first-line setting.

Heng sees a definite place for belzutifan in the second-line setting. For patients who did not have the opportunity to receive it in that line, he notes it remains an option in subsequent treatment settings. Belzutifan is also FDA-approved as monotherapy for advanced ccRCC following treatment with both a PD-1/PD-L1 inhibitor and a VEGF-targeted therapy.

Taken together, the findings from LITESPARK-011 and LITESPARK-012 help define belzutifan's position across the treatment continuum in advanced ccRCC.