{"entity":{"id":"paper-litespark-011-motzer-lancet-2026","kind":"paper","name":"Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial","aka":[],"tldr":"In 747 people whose advanced clear-cell kidney cancer had grown after immunotherapy, belzutifan plus lenvatinib kept the cancer from progressing for a median of 14.8 months against 10.7 with cabozantinib, but at this interim look the survival difference was not statistically significant.","summary":"Primary publication of LITESPARK-011 (NCT04586231), an open-label, randomised, active-controlled phase 3 trial at 184 centres in 25 countries. Adults with advanced clear-cell renal cell carcinoma that 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 cabozantinib 60 mg, orally once daily, stratified by IMDC 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.\n\nBetween 5 March 2021 and 1 September 2023, 955 people were screened and 747 randomised (371 belzutifan plus lenvatinib, 376 cabozantinib); 76 percent were male and 87 percent White. At the second interim analysis (data cutoff 9 April 2025; median follow-up 29.0 months, IQR 23.7 to 34.9), progression-free survival was significantly longer with belzutifan plus lenvatinib (median 14.8 months, 95 percent CI 11.2 to 16.6, versus 10.7 months, 9.2 to 11.1; hazard ratio 0.70, 0.59 to 0.84; one-sided p less than 0.0001). Overall survival was not significantly different (median 34.9 months, 27.5 to not reached, versus 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 commonly hypertension (31 and 29 percent); treatment-related adverse events led to two deaths and one death respectively. The authors conclude that belzutifan plus lenvatinib is a novel and efficacious option that might become a new standard of care after immunotherapy, with a safety profile consistent with the individual drugs.","asOf":"2026-09-24","links":[{"label":"Lancet 2026","url":"https://doi.org/10.1016/S0140-6736(26)01089-5"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/42586114/"},{"label":"ClinicalTrials.gov NCT04586231","url":"https://clinicaltrials.gov/study/NCT04586231"}],"tags":[],"related":[],"cancers":["rcc"],"sections":[],"technologies":[],"targets":[],"drugs":["belzutifan","lenvatinib","cabozantinib"],"companies":["merck","eisai"],"institutions":[],"pathways":[],"terms":[],"trials":["nct04586231"],"people":["robert-motzer"],"bottlenecks":[],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2026,"doi":"10.1016/S0140-6736(26)01089-5","pmid":"42586114","authors":"Motzer RJ, McDermott R, Park SH, et al.","paperType":"rct","findings":["Progression-free survival (final analysis): median 14.8 vs 10.7 months; hazard ratio 0.70 (95 percent CI 0.59 to 0.84); one-sided p<0.0001.","Overall survival (interim analysis): median 34.9 vs 27.6 months; hazard ratio 0.85 (0.68 to 1.05); one-sided p 0.061; not statistically significant.","Grade 3 or worse treatment-emergent adverse events in 84 percent vs 83 percent; hypertension the commonest; treatment-related deaths 2 vs 1."],"whatItMeans":"There has been no clear standard for clear-cell kidney cancer that progresses after immunotherapy; this is the first phase 3 to show a HIF-2 alpha inhibitor combination beating a standard tyrosine kinase inhibitor on progression-free survival in that setting. Whether it changes practice depends on the final overall survival analysis and on regulators, since the interim survival difference did not reach significance and the combination brings the toxicity of two drugs.","caveats":["Overall survival, a dual primary endpoint, was not statistically significant at this interim analysis; a survival benefit is not established.","Open-label design; progression-free survival was assessed by masked central review to limit bias.","87 percent of participants were White, and the comparator was cabozantinib alone rather than the newer sequences some centres use.","Funded by Merck Sharp & Dohme; the objective response and duration-of-response figures were presented at ASCO GU 2026 and are not in the abstract."],"changedPractice":false,"participants":747},"route":"/key-papers/paper-litespark-011-motzer-lancet-2026/","neighbours":{"cancer":[{"id":"rcc","kind":"cancer","name":"Renal cell carcinoma","route":"/cancers/rcc/"}],"drug":[{"id":"belzutifan","kind":"drug","name":"Belzutifan","route":"/drugs/belzutifan/"},{"id":"cabozantinib","kind":"drug","name":"Cabozantinib","route":"/drugs/cabozantinib/"},{"id":"lenvatinib","kind":"drug","name":"Lenvatinib","route":"/drugs/lenvatinib/"}],"company":[{"id":"eisai","kind":"company","name":"Eisai","route":"/companies/eisai/"},{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"}],"trial":[{"id":"nct04586231","kind":"trial","name":"LITESPARK-011","route":"/trials/nct04586231/"}],"person":[{"id":"robert-motzer","kind":"person","name":"Robert J. Motzer","route":"/people/robert-motzer/"}],"journal":[{"id":"lancet","kind":"journal","name":"The Lancet","route":"/journals/lancet/"}]}}