Subsequent Therapy May Have Narrowed the Overall Survival Gap in LITESPARK-011

In the wake of the 2026 European Society for Medical Oncology (ESMO) Congress, Daniel Y.C. Heng, MD, MPH, FRCPC, head of medical oncology at the Arthur J.E. Child Comprehensive Cancer Centre and clinical professor of medicine at the University of Calgary in Alberta, Canada, discussed in an interview with CancerNetwork® why the overall survival (OS) benefit with belzutifan plus lenvatinib in advanced renal cell carcinoma (RCC) has not yet reached statistical significance.

In the final analysis of the phase 3 LITESPARK-011 trial (NCT04586231), which Heng presented at ESMO, belzutifan plus lenvatinib was compared with cabozantinib in patients with advanced clear cell RCC after anti–PD-(L)1 therapy. The combination improved the objective response rate (53.1% vs 40.2%) and median progression-free survival (PFS; 14.8 vs 10.8 months; HR, 0.74; 95% CI, 0.62-0.88), and median duration of response was 22.0 vs 11.9 months. Median OS was 33.7 vs 28.6 months (HR, 0.85; 95% CI, 0.70-1.03), which did not cross the prespecified boundary for statistical significance. In an exploratory analysis, median PFS2 (progression-free survival on next-line therapy) was 28.7 vs 23.4 months (HR, 0.80; 95% CI, 0.67-0.96).

Transcript:

CancerNetwork: In LITESPARK-011, more patients in the cabozantinib arm went on to later treatments, and PFS2 favored belzutifan plus lenvatinib. How much do you think subsequent treatment narrowed the OS difference?

Heng: That is a great question. To set some background, the LITESPARK-011 clinical trial enrolled patients in the second- or third-line setting with metastatic disease or progression after adjuvant immunotherapy, randomly assigning them to lenvatinib plus belzutifan vs cabozantinib. There was a large difference in objective response rate, 53% vs 40%, and a PFS difference of 14.8 months vs 10.8 months. There was an OS difference, but it was not statistically significant. The delta was 5 months, but it is not statistically significant—maybe not yet.

As for why it could be related to subsequent therapy, you are right. There were more progressions in the cabozantinib arm, so more patients in that arm went on to subsequent therapies than in the lenvatinib/belzutifan arm, which can dilute the OS benefit. I also feel that belzutifan has a disease-stabilizing quality, and the duration of response doubled, at 22 months vs [11.9] months. Because of that difference, I wonder whether the OS difference will take a little longer to see. We have to wait for the curves to separate after a year, and then they start separating because that response is quite durable. I look forward to seeing whether we can see that. That is how I explain the data.

Reference

Heng DYC, Schmidinger M, McDermott R, et al. Final prespecified analysis of the phase 3 LITESPARK-011 study: belzutifan plus lenvatinib versus cabozantinib for advanced renal cell carcinoma after anti–PD-(L)1 therapy. Ann Oncol. Published online October 25, 2026. doi:10.1016/j.annonc.2026.10.109