{"entity":{"id":"litespark-005","kind":"trial","name":"LITESPARK-005","aka":[],"tldr":"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.","status":"positive","asOf":"2026-09-07","links":[{"label":"ClinicalTrials.gov NCT04195750","url":"https://clinicaltrials.gov/study/NCT04195750"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["hif2a"],"drugs":["belzutifan","everolimus"],"companies":["merck"],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":["laurence-albiges","toni-choueiri"],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"nct":"NCT04195750","phase":"3","setting":"Advanced clear-cell RCC after PD-1/PD-L1 and VEGF-TKI: belzutifan vs everolimus","sponsor":"Merck","participation":[{"nct":"NCT04195750","source":"https://clinicaltrials.gov/study/NCT04195750","fetchedAt":"2026-10-07T16:53:16.124Z","studySha256":"1ff69b567ff6dea94ddceb887dd96cfa3c882e3b2ca8a2f45627936da7b60fcd","overallStatus":"ACTIVE_NOT_RECRUITING","lastUpdatePosted":"2026-05-14","leadSponsor":"Merck Sharp & Dohme LLC","collaboratorCount":0,"minimumAge":"18 Years","sex":"ALL","healthyVolunteers":false,"hasEligibility":true,"enrolment":755,"enrolmentType":"ACTUAL","siteCount":172,"recruitingSiteCount":0,"countries":["Brazil","Canada","Chile","Colombia","Czechia","Denmark","Finland","France","Germany","Hong Kong","Hungary","Italy","Japan","Norway","Russia","South Korea","Spain","Sweden","Taiwan","Turkey (Türkiye)","Ukraine","United Kingdom","United States"]}],"result":"PFS HR 0.75; ORR 22.7% vs 3.5%; OS not significant.","started":"2020-02-27","startedType":"actual","yearReported":2023,"enrolled":755,"enrolledBasis":"registry","outcomes":[{"endpoint":"Progression-free survival","primary":true,"arms":[{"name":"Belzutifan","n":374},{"name":"Everolimus","n":372}],"hr":0.75,"ci":[0.63,0.9],"source":"https://www.nejm.org/doi/full/10.1056/NEJMoa2313906"},{"endpoint":"Objective response rate","unit":"%","arms":[{"name":"Belzutifan","value":22.7},{"name":"Everolimus","value":3.5}],"source":"https://doi.org/10.1056/NEJMoa2313906"}],"replication":"Belzutifan activity replicated in VHL disease (LITESPARK-004); first-line combination (LITESPARK-012) did not meet its goal in 2026."},"route":"/trials/litespark-005/","neighbours":{"cancer":[{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"hif2a","kind":"target","name":"HIF-2α","route":"/targets/hif2a/"}],"drug":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"},{"id":"everolimus","kind":"drug","name":"Everolimus","route":"/drugs/everolimus/"}],"company":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}],"person":[{"id":"laurence-albiges","kind":"person","name":"Laurence Albiges","route":"/people/laurence-albiges/"},{"id":"toni-choueiri","kind":"person","name":"Toni K. Choueiri","route":"/people/toni-choueiri/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}