Dr Heng on Treatment Sequencing With Belzutifan Plus Lenvatinib in Advanced RCC

Overall, we should make sure that we use the best therapies up-front, so I wouldn’t choose our [first-line] therapy based on second-line, third-line sequencing.

Daniel Heng, MD, MPH, FRCPC, a clinical professor at the University of Calgary and head of medical oncology at the Arthur J.E. Child Comprehensive Cancer Centre, discussed how the FDA approval of belzutifan (Welireg) plus lenvatinib (Lenvima) in the pretreated setting could influence treatment sequencing in advanced renal cell carcinoma (RCC).

In September 2026, the FDA approved belzutifan plus lenvatinib for the treatment of adult patients with advanced RCC with a clear cell component following a PD-1 or PD-L1 inhibitor. The combination received FDA approval based on results from the phase 3 LITESPARK-011 trial (NCT04586231), which compared the regimen with cabozantinib (Cabometyx) monotherapy after prior PD-1/PD-L1 inhibitor therapy. Findings supporting the approval showed that the median progression-free survival was 14.6 months (95% CI, 11.1-16.6) with belzutifan plus lenvatinib vs 10.6 months (95% CI, 9.2-11.1) with cabozantinib (HR, 0.74; 95% CI, 0.61-0.89; 1-sided P = .00095).

Heng explained that prior lenvatinib exposure is relevant when considering the combination in subsequent lines. If a patient’s disease has already progressed on a lenvatinib-containing first-line regimen, he would avoid reusing lenvatinib in the second-line setting. He raises the possibility that the second-line approval of a lenvatinib-containing combination could increase the use of other first-line combination options, including cabozantinib plus nivolumab (Opdivo) or ipilimumab (Yervoy) plus nivolumab.

However, Heng emphasized that clinicians should prioritize the most appropriate initial treatment for each patient rather than select first-line therapy primarily to preserve later options. Patients who need a substantial response should receive a regimen suited to that goal, whereas those best served by dual immunotherapy should receive that approach.

Looking ahead, Heng anticipates belzutifan plus lenvatinib becoming a new second-line standard. He highlighted response rates exceeding 50% as an encouraging development compared with the approximately 20% to 30% rates associated with other subsequent-line options.