Treatment options after progression on immune checkpoint inhibitor therapy remain an important unmet need in advanced clear-cell renal cell carcinoma, particularly because many established targeted therapies were developed before immunotherapy became widely integrated into the treatment landscape.
On August 12, 2026, The Lancet published the phase 3 LITESPARK-011 trial titled “Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial.”
Authors: Robert J. Motzer, Ray McDermott, Se Hoon Park, Mauricio Burotto, Roberto Iacovelli, Elena Verzoni, Cristina Suárez, Masatoshi Eto, Hernan J. Cutuli, Camillo Porta, Ray Manneh Kopp, Sylvie Rottey, Guillermo de Velasco, Begoña P. Valderrama, Arun A. Azad, Ugo De Giorgi, Michel Pavic, Piotr Tomczak, Robert Figlin, Hans M. Westgeest, Annalisa Guida, Andrea Necchi, Fabio A. Schutz, Britt B. M. Suelmann, John B. A. G. Haanen, Sammy Shuai Yuan, Rodolfo F. Perini, Ding Wang, Daniel Y. C. Heng, and Manuela Schmidinger, on behalf of the LITESPARK-011 Investigators.
Testing a New Strategy After PD-1/PD-L1 Therapy
LITESPARK-011 was a global, phase 3, open-label, randomized, active-controlled study conducted at 184 centers across 25 countries. The trial enrolled adults with unresectable locally advanced or metastatic stage IV clear-cell renal cell carcinoma who had experienced disease progression on or after previous anti-PD-1 or anti-PD-L1 therapy. Patients could have received previous VEGFR tyrosine kinase inhibitor therapy, but previous treatment with belzutifan, cabozantinib, or lenvatinib was not permitted.
Between March 2021 and September 2023, 747 patients were randomly assigned 1:1 to receive either oral belzutifan 120 mg plus lenvatinib 20 mg once daily or cabozantinib 60 mg once daily.
Of the 371 patients assigned to belzutifan plus lenvatinib, 43% had not previously received a VEGFR tyrosine kinase inhibitor and 55% had received one. Corresponding proportions in the cabozantinib group were 44% and 55%. The dual primary endpoints were progression-free survival assessed by masked independent central review according to RECIST 1.1 and overall survival. Objective response rate was a key secondary endpoint. The study was funded by Merck Sharp & Dohme, a subsidiary of Merck & Co. Lenvatinib was provided by Eisai.
Previous Results of the LITESPARK-011 Trial
On October 28, 2025, Merck reported that the phase 3 LITESPARK-011 trial had met one of its dual primary endpoints, progression-free survival. At the prespecified interim analysis, belzutifan plus lenvatinib demonstrated a statistically significant and clinically meaningful improvement in PFS compared with cabozantinib, as well as a statistically significant improvement in objective response rate. A trend toward improved overall survival was also observed, although the difference was not statistically significant at that analysis.
The subsequent Lancet publication reported results from the second interim analysis: median PFS was 14.8 months with belzutifan plus lenvatinib versus 10.7 months with cabozantinib (HR 0.70; 95% CI 0.59–0.84; one-sided p<0.0001), while ORR was 53% versus 40%, respectively. Median OS was 34.9 versus 27.6 months (HR 0.85; 95% CI 0.68–1.05; one-sided p=0.061) and remained not statistically significant.
PFS Improved With Belzutifan Plus Lenvatinib
At the second interim analysis, with an April 9, 2025 data cutoff and a median follow-up of 29.0 months, 232 patients in the belzutifan–lenvatinib group and 273 in the cabozantinib group had experienced disease progression or died.
Median progression-free survival was 14.8 months with belzutifan plus lenvatinib versus 10.7 months with cabozantinib, corresponding to a 30% reduction in the hazard of disease progression or death:
- HR 0.70; 95% CI 0.59–0.84; one-sided p<0.0001.
At 12 months, an estimated 55% of patients receiving belzutifan plus lenvatinib remained alive and progression-free compared with 41% receiving cabozantinib. At 24 months, the corresponding estimates were 36% and 19%.
The progression-free survival results were generally consistent across the key subgroups examined, although the investigators cautioned that some subgroup analyses were based on small numbers of events and were exploratory.
Higher and More Durable Response Rates
Belzutifan plus lenvatinib also produced a higher objective response rate. At the second interim analysis, confirmed objective responses were observed in 53% of patients receiving belzutifan plus lenvatinib compared with 40% receiving cabozantinib.
Complete responses were reported in 5% and 1% of patients, respectively. The objective response rate endpoint had already crossed the prespecified boundary for statistical significance at the first interim analysis, with an estimated between-group difference of 13%:
- 53% vs 40%; difference 13%; 95% CI 6–20; one-sided p=0.0002.
Responses were also more durable with the combination. Median duration of response was 23.0 months with belzutifan plus lenvatinib versus 12.3 months with cabozantinib.
An estimated 67% of responses in the combination group lasted at least 12 months, compared with 50% in the cabozantinib group.
Overall Survival Not Yet Significantly Different
At the second interim analysis, 162 patients in the belzutifan–lenvatinib group and 192 in the cabozantinib group had died. Median overall survival was 34.9 months with belzutifan plus lenvatinib and 27.6 months with cabozantinib. However, the difference did not meet the prespecified threshold for statistical significance:
- HR 0.85; 95% CI 0.68–1.05; one-sided p=0.061.
The estimated 24-month overall survival rate was 63% with belzutifan plus lenvatinib and 55% with cabozantinib. Overall survival will undergo further formal testing at the planned final analysis after additional follow-up.
Combining HIF-2α and VEGFR Inhibition
Belzutifan and lenvatinib target different components of pathways involved in renal cell carcinoma biology. Belzutifan is a selective inhibitor of hypoxia-inducible factor 2-alpha, or HIF-2α, whereas lenvatinib is a multitargeted VEGFR tyrosine kinase inhibitor.
The investigators described the combination as providing orthogonal inhibition of angiogenesis pathways, with belzutifan acting at the HIF-2α transcription factor level and lenvatinib providing potent multitargeted VEGFR inhibition.
The phase 3 findings provide clinical support for this mechanistic rationale, with the combination producing superior progression-free survival and antitumor activity compared with VEGFR tyrosine kinase inhibitor monotherapy.
Safety Profiles Were Different Between the Regimens
Almost all treated patients experienced at least one treatment-emergent adverse event. Grade 3 or worse treatment-emergent adverse events occurred in 84% of patients receiving belzutifan plus lenvatinib and 83% receiving cabozantinib.
The most common adverse event with belzutifan plus lenvatinib was anemia, occurring in 69% of patients, including grade 3 or worse anemia in 19%. In the cabozantinib group, the most common adverse event was diarrhea, reported in 70%, including grade 3 or worse events in 11%.
Hypertension was the most common grade 3 or worse adverse event in both groups, occurring in 31% of patients receiving belzutifan plus lenvatinib and 29% receiving cabozantinib.
Hypoxia, a known adverse reaction associated with belzutifan, occurred in 15% of patients receiving the combination and was grade 3 or worse in 12%. No cases of hypoxia were reported in the cabozantinib group. Cardiac dysfunction events occurred in 7% of patients receiving belzutifan plus lenvatinib compared with 1% receiving cabozantinib.
Treatment-related adverse events led to any treatment discontinuation in 19% of patients in the combination group and 5% in the cabozantinib group. Treatment-related deaths occurred in two patients receiving belzutifan plus lenvatinib and one receiving cabozantinib.
Patient-Reported Outcomes
Despite differences in the toxicity profiles, time to worsening of disease-related symptoms and global health status or quality of life was generally similar between the treatment groups.
For disease-related symptoms measured using the FKSI-DRS, the hazard ratio for time to confirmed worsening was 1.02 (95% CI 0.82–1.28). For global health status and quality of life measured using the EORTC QLQ-C30, the corresponding hazard ratio was 1.07 (95% CI 0.86–1.34).
The investigators noted that these findings suggest that adding belzutifan to lenvatinib did not negatively affect patients’ experience of disease-related symptoms or global health status/quality of life compared with cabozantinib.
A Potential New Option After Immunotherapy
According to the investigators, LITESPARK-011 is, to their knowledge, the first positive phase 3 trial in advanced renal cell carcinoma previously treated with anti-PD-1 or anti-PD-L1 therapy to include patients both with and without previous VEGFR tyrosine kinase inhibitor exposure. The authors also noted that the study is the first phase 3 trial in renal cell carcinoma to demonstrate superior efficacy of an investigational regimen over a contemporary VEGFR tyrosine kinase inhibitor, cabozantinib.
Several limitations were acknowledged. The trial was open-label, although progression-free survival was assessed by masked independent central review. Subgroup analyses were not adjusted for multiplicity and were hypothesis-generating. Differences in subsequent therapies could also influence the ongoing overall survival assessment, and Black patients represented less than 1% of the study population.
In addition, because the trial did not include belzutifan-alone or lenvatinib-alone groups, it cannot directly determine the individual contribution of each drug to the efficacy of the combination.
With a significant improvement in progression-free survival, a higher response rate, and more durable responses compared with cabozantinib, LITESPARK-011 establishes belzutifan plus lenvatinib as a potential treatment option for patients with advanced clear-cell renal cell carcinoma progressing after PD-1 or PD-L1 inhibitor therapy.
Overall survival, however, was not significantly different at the current analysis and remains under follow-up. The investigators concluded that belzutifan plus lenvatinib might represent a potential new standard of care in this difficult-to-treat setting.
The full article is available in The Lancet.