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FDA approves belzutifan with lenvatinib for ccRCC following anti-PD-1/PD-L1 therapy

On September 24, 2026, the U.S. Food and Drug Administration (FDA) approved belzutifan and lenvatinib for the treatment of advanced clear cell renal cell carcinoma (ccRCC) which has progressed on anti-PD-1 or anti-PD-L1 therapy.1 Renal cell carcinoma is the most common type of kidney cancer, with ccRCC the most common subtype. 30% of cases are diagnosed at an advanced or metastatic stage. Whilst there are established first-line therapies, there are no globally accepted standard of care second- or later-line strategies, which depend on prior treatment and often involves immune checkpoint inhibitors (ICIs) or tyrosine kinase inhibitors (TKIs).2 Belzutifan, a HIF-2α inhibitor, has already shown efficacy in advanced RCC and is approved as a monotherapy following progression on anti-PD-1/PD-L1 and anti-VEGFR therapy. It is hypothesized that in combination with a VEGFR inhibitor, HIF-2α inhibition may help prevent or delay resistance to VEGFR inhibition, which patients inevitably develop.3

Approval was supported by data from the Phase III LITESPARK-011 trial (NCT04586231), which evaluated the combination against cabozatinib in patients who had been treated with anti-PD-1/anti-PD-L1 therapy within 6 months prior to randomization. Dual primary outcomes were progression-free survival (PFS), assessed by blinded independent central review, and overall survival (OS). Median follow-up was 19.6 months at first interim analysis (IA1) and 29.0 months at second interim analysis (IA2). Improved median PFS was seen at both analyses (HR 0.74, 95% CI: 0.61-0.89 at IA1 and HR 0.70, 95% CI: 0.59-0.84 at IA2) with PFS at IA2 14.6 months in the belzutifan/lenvatinib arm versus 10.6 months in the cabozatinib arm. An increased overall response rate was also found at the first interim analysis. No significant OS benefit was observed, however OS favored the combination arm and additional follow-up is ongoing. The safety profile was consistent with that of the individual drugs and a similar rate of grade 3 or higher treatment-emergent adverse events was observed (84.1% in the combination arm vs 82.7% in the cabozatinib arm). 4

Tian Zhang, MD, UT Southwestern Medical Center, Dallas, TX, discusses the results and their impact on treatment approaches:

“This is the first trial that has shown a progression-free survival benefit, that statistically and clinically significant benefit of the combination over cabozantinib. And so I do think this represents a way for us to understand sequencing approaches, for us to use lenvatinib and belzutifan in the refractory setting. Personally, I think we should probably be thinking about using cabozantinib sooner so that we can actually switch out those mechanisms in the later line for lenvatinib and belzutifan.”

This approval marks the first for a HIF-2α inhibitor and VEGFR tyrosine kinase inhibitor combination and represents a growing role for HIF-2α inhibitors in the treatment of advanced renal cell carcinoma. Belzutifan had previously been approved as a monotherapy for RCC following progression on anti-PD-1/PD-L1 and anti-VEGFR therapy, and this approval brings it forward to sit as a second-line treatment option in combination with lenvatinib.4

References

  1. U.S. Food and Drug Administration. FDA approves belzutifan in combination with lenvatinib for advanced renal cell carcinoma with a clear cell component. Available here. (Last Accessed 25/09/2026).
  2. Esterberg E, Iyer S, Nagar SP, et al. Real-World Treatment Patterns and Clinical Outcomes Among Patients with Advanced Renal Cell Carcinoma. Clin Genitourin Cancer. 2024 Apr; 22(2):115-125.
  3. Motzer RJ, Schmidinger M, Eto M, Suarez C, Figlin R, Liu Y, et al. LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy. Future Oncol, 2023 Jan;19(2).113-121
  4. Motzer RJ, 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. Abstract LBA417. Presented at the 2026 ASCO Annual Meeting; May 29-June 02, 2026; Chicago, IL.