# LITESPARK-005

Source: https://onco.cc/trials/litespark-005/  
OnCo record `litespark-005` (Trial). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The HIF-2α inhibitor beat the old standard everolimus after immunotherapy and targeted therapy had failed, with durable responses in a subset.

## Summary

LITESPARK-005, trial NCT04195750 sponsored by Merck and reported in 2023, showed that the HIF-2-alpha inhibitor belzutifan beats the old standard everolimus in advanced clear-cell renal cell carcinoma after immunotherapy and a VEGF kinase inhibitor have failed, with durable responses in a subset. It randomised 746 patients, met its primary progression-free survival endpoint with a much higher response rate, did not significantly improve overall survival, and led to FDA approval in December 2023, with anaemia and low oxygen as on-mechanism toxicities. OnCo links it to renal cell carcinoma, HIF-2-alpha as a target, belzutifan, everolimus, Laurence Albiges and Toni K. Choueiri, and belzutifan's activity was also shown in VHL disease in LITESPARK-004 while the first-line combination LITESPARK-012 failed in 2026. Whether the responders can be identified in advance is the open question.

## Fields

- Kind: Trial
- Status: positive
- Last checked: 2026-09-07
- Registry id: NCT04195750
- Phase: 3
- Setting: Advanced clear-cell RCC after PD-1/PD-L1 and VEGF-TKI: belzutifan vs everolimus
- Sponsor: Merck
- Enrolled: 755
- Result: PFS HR 0.75; ORR 22.7% vs 3.5%; OS not significant.
- Outcomes: Progression-free survival: Belzutifan vs Everolimus, HR 0.75; Objective response rate: Belzutifan 22.7% vs Everolimus 3.5%
- Replication: Belzutifan activity replicated in VHL disease (LITESPARK-004); first-line combination (LITESPARK-012) did not meet its goal in 2026.

## Sources

- ClinicalTrials.gov NCT04195750: https://clinicaltrials.gov/study/NCT04195750

## Connected records

- cancers: [Renal cell carcinoma](https://onco.cc/cancers/rcc/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [HIF-2α](https://onco.cc/targets/hif2a/)
- drugs: [Belzutifan](https://onco.cc/drugs/belzutifan/), [Everolimus](https://onco.cc/drugs/everolimus/)
- companies: [Merck & Co. (MSD)](https://onco.cc/companies/merck/)
- people: [Laurence Albiges](https://onco.cc/people/laurence-albiges/), [Toni K. Choueiri](https://onco.cc/people/toni-choueiri/)
- roadmaps: [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

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