# LITESPARK-011

Source: https://onco.cc/trials/nct04586231/  
OnCo record `nct04586231` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

In LITESPARK-011, belzutifan plus lenvatinib held advanced clear-cell kidney cancer in check for about four months longer than cabozantinib in people whose cancer had grown after immunotherapy, but at the interim look it had not been shown to help them live longer; a final survival analysis is still to come.

## Summary

LITESPARK-011 (NCT04586231; MK-6482-011) is an open-label, randomised, active-controlled phase 3 trial at 184 centres in 25 countries, sponsored by Merck Sharp & Dohme with Eisai. Adults with advanced unresectable, locally advanced or metastatic clear-cell renal cell carcinoma whose disease had progressed after anti-PD-1 or anti-PD-L1 therapy, with or without a prior VEGFR tyrosine kinase inhibitor, were randomly assigned 1:1 to belzutifan 120 mg plus lenvatinib 20 mg or to cabozantinib 60 mg, all taken by mouth once daily until progression or unacceptable toxicity. Randomisation was stratified by IMDC prognostic score, line of previous immunotherapy and region. The dual primary endpoints were progression-free survival by masked independent central review and overall survival in all randomised participants; the study counted as positive if either was met.

Between March 2021 and September 2023, 955 people were screened and 747 randomised (371 to belzutifan plus lenvatinib, 376 to cabozantinib). At the second interim analysis (data cutoff 9 April 2025; median follow-up 29.0 months), which was the final analysis for progression-free survival, median progression-free survival was 14.8 months (95 percent CI 11.2 to 16.6) with belzutifan plus lenvatinib against 10.7 months (9.2 to 11.1) with cabozantinib (hazard ratio 0.70, 0.59 to 0.84; one-sided p less than 0.0001). Overall survival, an interim result, was not significantly different: median 34.9 months (27.5 to not reached) against 27.6 months (24.0 to 31.4), hazard ratio 0.85 (0.68 to 1.05), one-sided p 0.061. Grade 3 or worse treatment-emergent adverse events occurred in 311 of 370 (84 percent) and 307 of 371 (83 percent) treated participants, most often hypertension (31 and 29 percent); treatment-related adverse events led to two deaths on belzutifan plus lenvatinib and one on cabozantinib (Lancet, 12 August 2026).

The investigator presentation at ASCO GU 2026 (same cutoff) reported descriptive figures that the abstract does not: confirmed objective response by central review 52.6 percent against 40.2 percent (a key secondary endpoint that was statistically significant at the first interim analysis, 52.6 against 39.6 percent, one-sided p 0.0002, and not retested), median duration of response 23.0 against 12.3 months among 195 and 151 responders, grade 3 or worse treatment-related adverse events 71.6 against 65.8 percent, and discontinuation of all study drugs for adverse events 11.1 against 11.3 percent. The authors conclude that belzutifan plus lenvatinib is an efficacious option and may become a new standard after immunotherapy, while noting that overall survival was not significantly different. The registry lists the trial as active, not recruiting, with primary completion recorded on 2 February 2026 and study completion expected in February 2027; no regulatory decision on the combination had been announced when this record was written.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-09-24
- Also known as: LITESPARK 011; MK-6482-011; A Study of Belzutifan (MK-6482) in Combination With Lenvatinib Versus Cabozantinib for Treatment of Renal Cell Carcinoma (MK-6482-011)
- Tags: pipeline; issue-98
- Registry id: NCT04586231
- Phase: 3
- Setting: Advanced clear-cell renal cell carcinoma that has progressed after anti-PD-1 or anti-PD-L1 therapy: belzutifan 120 mg plus lenvatinib 20 mg versus cabozantinib 60 mg, all oral once daily, open label, randomised 1:1
- Sponsor: Merck Sharp & Dohme LLC
- Enrolled: 747
- Result: Final progression-free survival 14.8 vs 10.7 months (hazard ratio 0.70, 95% CI 0.59 to 0.84; one-sided p<0.0001). Interim overall survival 34.9 vs 27.6 months (hazard ratio 0.85, 0.68 to 1.05; one-sided p 0.061), not statistically significant. Data cutoff 9 April 2025.
- Outcomes: Progression-free survival by masked independent central review (final analysis at the second interim analysis, data cutoff 9 April 2025): Belzutifan + lenvatinib 14.8 months vs Cabozantinib 10.7 months, HR 0.7; Overall survival (interim analysis at the second interim analysis, data cutoff 9 April 2025): Belzutifan + lenvatinib 34.9 months vs Cabozantinib 27.6 months, HR 0.85; Grade 3 or worse treatment-emergent adverse events (treated participants): Belzutifan + lenvatinib 84% vs Cabozantinib 83%; Confirmed objective response rate by masked independent central review (key secondary; second interim analysis, descriptive): Belzutifan + lenvatinib 52.6% vs Cabozantinib 40.2%; Median duration of response by masked independent central review (second interim analysis, descriptive): Belzutifan + lenvatinib 23 months vs Cabozantinib 12.3 months; Grade 3 or worse treatment-related adverse events (as-treated population, descriptive): Belzutifan + lenvatinib 71.6% vs Cabozantinib 65.8%
- Replication: First phase 3 of a HIF-2 alpha inhibitor combination after immunotherapy in kidney cancer; no independent trial has tested the pair. LITESPARK-012 (first-line triplet) fell short and LITESPARK-022 (adjuvant belzutifan plus pembrolizumab) was positive, so the drug's benefit depends on setting and partner. The final overall survival analysis is awaited.

## Sources

- ClinicalTrials.gov NCT04586231: https://clinicaltrials.gov/study/NCT04586231
- Lancet 2026: https://doi.org/10.1016/S0140-6736(26)01089-5
- ASCO GU 2026 investigator presentation (Eisai medical information): https://www.eisaimedicalinformation.com/-/media/Files/EisaiMedicalInformation/Oncology/Congress-Materials/ASCO-GU-2026/Motzer_LS011_ASCO-GU-2026_Presented.pdf

## Connected records

- cancers: [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- technologies: [Anti-angiogenic therapy](https://onco.cc/technologies/antiangiogenic/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- drugs: [Belzutifan](https://onco.cc/drugs/belzutifan/), [Cabozantinib](https://onco.cc/drugs/cabozantinib/), [Lenvatinib](https://onco.cc/drugs/lenvatinib/)
- companies: [Eisai](https://onco.cc/companies/eisai/), [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- people: [Robert J. Motzer](https://onco.cc/people/robert-motzer/)
- key papers: [Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial](https://onco.cc/key-papers/paper-litespark-011-motzer-lancet-2026/)

---
JSON: https://onco.cc/api/v1/entities/nct04586231.json