Results from the phase 3 LITESPARK-011 trial (NCT04586231) showed that belzutifan (Welireg) plus lenvatinib (Lenvima) significantly improved disease control compared with cabozantinib (Cabometyx) in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC), according to a news release from the Vall d’Hebron Institute of Oncology (VHIO).¹
What did the phase 3 LITESPARK-011 trial show?
LITESPARK-011 randomly assigned 747 patients 1:1 to belzutifan at 120 mg plus lenvatinib at 20 mg orally once daily (n = 371) or cabozantinib at 60 mg orally once daily (n = 376).2 At a median follow-up of 29 months, belzutifan/lenvatinib reduced the risk of disease progression or death by 30% compared with cabozantinib, with a median progression-free survival (PFS) of 14.8 months vs 10.7 months.
Overall survival (OS) trended in favor of the combination but did not reach statistical significance, with a median OS of 34.9 months vs 27.6 months; OS follow-up is ongoing. Additionally, the objective response rate (ORR) was 53% with belzutifan plus lenvatinib vs 40% with cabozantinib.
What is belzutifan and how does it work with lenvatinib?
Belzutifan is a first-in-class, oral inhibitor of hypoxia-inducible factor 2α (HIF-2α), a transcription factor that also regulates VEGF expression and contributes to resistance to anti-VEGF therapy. Lenvatinib is a VEGFR-targeted tyrosine kinase inhibitor (TKI). By combining HIF-2α blockade with VEGFR inhibition, investigators hypothesized that the regimen would suppress VEGF signaling at both the transcriptional and receptor level.
LITESPARK-011 is the first phase 3 trial to evaluate a HIF-2α inhibitor combined with a VEGFR-TKI, and the first phase 3 trial in RCC in the post-immune checkpoint inhibitor setting to show improved outcomes vs a contemporary VEGFR-TKI.
“The results of the LITESPARK-011 study represent a significant advance because they demonstrate, for the first time, that a new combination of treatments can significantly improve disease control compared [with] current therapy in this patient population,” Cristina Suárez Rodríguez, Sr, MD, PhD, medical oncologist at the Vall d’Hebron University Hospital and head of VHIO’s Genitourinary (non-prostate), Central Nervous System Tumors (CNS), Sarcomas, and Tumors of Unknown Origin Group, stated in the news release.1
What quality-of-life data support the combination?
Exploratory patient-reported outcome (PRO) data from LITESPARK-011 were presented at the 2026 Kidney Cancer Research Summit (KCRS), which showed that time to deterioration in disease-specific symptoms per the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) was similar between arms (HR, 1.02; 95% CI, 0.82-1.28), at a median of 13.8 months (95% CI, 6.4-20.3) with belzutifan plus lenvatinib vs 10.6 months (95% CI, 7.4-20.2) with cabozantinib.3 The time to deterioration in global health status/quality of life per the EORTC QLQ-C30 was also comparable between arms (HR, 1.07; 95% CI, 0.86-1.34).
“Patient-reported outcomes were generally comparable between treatment arms and showed no additional [health-related quality of life] burden with belzutifan plus lenvatinib,” Manuela Schmidinger, MD, professor of medicine and program director of Renal Cell Carcinoma Research at the Medical University of Vienna, and coinvestigators wrote in the KCRS poster.3
What’s next for belzutifan plus lenvatinib in RCC?
The authors concluded that although OS was not significantly different between the groups, they asserted that belzutifan/lenvatinib could be a new standard of care for advanced ccRCC groups following disease progression after previous anti–PD-1 or anti–PD-L1 therapy. The FDA is currently reviewing a supplemental new drug application for belzutifan plus lenvatinib in this setting, with a target action date of October 4, 2026.4
Previous LITESPARK-011 efficacy findings, presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), showed the combination showed a similar PFS and ORR benefit at an earlier data cutoff.5
References
- Novel treatment combination improves disease control in previously treated advanced renal cancer compared with standard of care. News release. Vall d’Hebron Institute of Oncology. August 20, 2026. Accessed August 20, 2026. https://tinyurl.com/3srufwxe
- Motzer RJ, McDermott R, Park SH, et al. Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial. Lancet. Published online August 12, 2026. doi:10.1016/S0140-6736(26)01089-5
- Schmidinger M, Heng DYC, McDermott R, et al. Belzutifan plus lenvatinib versus cabozantinib in post–PD-(L)1 renal cell carcinoma: health-related quality-of-life outcomes in the phase 3 LITESPARK-011 study. Presented at: Kidney Cancer Research Summit (KCRS); July 23-24, 2026; Boston, MA. Abstract 23.
- WELIREG® (belzutifan) plus LENVIMA® (lenvatinib) reduced the risk of disease progression or death by 30% compared to cabozantinib in certain previously treated patients with advanced renal cell carcinoma (RCC). News release. Merck. February 28, 2026. Accessed August 20, 2026. https://tinyurl.com/yvy6pe62
- 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. J Clin Oncol. 2026;44(suppl 7):LBA417. doi:10.1200/JCO.2026.44.7_suppl.LBA417
