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Publications

Journal Article Clinical Trial, Phase III Randomized Controlled Trial Multicenter Study Comparative Study Ppublish 7 citations

PubMed: 42586114 DOI: 10.1016/S0140-6736(26)01089-5

Belzutifan plus lenvatinib versus cabozantinib in patients with previously treated advanced renal cell carcinoma (LITESPARK-011): an open-label, randomised, controlled, phase 3 trial.

Lancet 408(10557):808-820

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, Manuela Schmidinger

Affiliations

  • Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • St Vincent's University Hospital, Cancer Trials Ireland, Dublin, Ireland.
  • Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
  • Bradford Hill Clinical Research Center, Santiago, Chile.
  • Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Rome, Italy.
  • Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Genitourinary Medical Oncology, Milan, Italy.
  • Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
  • Kyushu University, Graduate School of Medical Sciences, Fukuoka, Japan.
  • Hospital Sirio Libanés, Buenos Aires, Argentina.
  • Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari and University of Bari A Moro, Bari, Italy.
  • Sociedad de Oncología y Hematología del Cesar, Valledupar, Colombia.
  • Ghent University Hospital, Ghent, Belgium.
  • Department of Medical Oncology, University Hospital 12 de Octubre, Instituto de Investigación (imas12), Madrid, Spain.
  • Hospital Universitario Virgen del Rocío, Seville, Spain.
  • Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
  • IRCCS Istituto Romagnolo per lo Studio dei Tumori, Dino Amadori, Meldola, Italy.
  • CIUSSS de l Estrie-CHUS-Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
  • University of Medical Sciences, Poznań, Poland.
  • Cedars Sinai Medical Center, Los Angeles, CA, USA.
  • Amphia Hospital, Breda, Netherlands.
  • Azienda Ospedaliera S Maria di Terni, Terni, Italy.
  • Department of Medical Oncology, IRCCS San Raffaele Hospital, Comprehensive Cancer Center, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
  • BP-A Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil.
  • Universitair Medisch Centrum Utrecht, Utrecht, Netherlands.
  • Netherlands Cancer Institute, Antoni van Leeuwenhoek, Amsterdam, Netherlands; Leiden University Medical Center, Leiden, Netherlands; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
  • Merck & Co, Rahway, NJ, USA.
  • Arthur J E Child Comprehensive Cancer Centre, Calgary, AB, Canada.
  • Medical University of Vienna, Vienna, Austria.

Abstract

BACKGROUND

The identification of a clear standard of care for patients with advanced clear-cell renal cell carcinoma following anti-PD-1 or anti-PD-L1 therapy warrants study as an unmet need. We aimed to investigate belzutifan plus lenvatinib versus cabozantinib in participants with clear-cell renal cell carcinoma previously treated with immune checkpoint inhibitors.

METHODS

LITESPARK-011 is a phase 3, open-label, randomised, active-controlled study conducted at 184 medical centres in 25 countries in Asia, Australia, Europe, North America, and South America. Participants were aged 18 years or older with advanced unresectable, locally advanced or metastatic stage IV clear-cell renal cell carcinoma, with disease progression following anti-PD-1 or anti-PD-L1 therapy with or without previous VEGFR-tyrosine-kinase inhibitors. Participants were randomly assigned (1:1) to receive 120 mg belzutifan plus 20 mg lenvatinib (belzutifan-lenvatinib) or 60 mg cabozantinib orally once daily until disease progression or unacceptable adverse events occurred. Randomisation was done using a web-based interactive response system (block size four) and stratified by International Metastatic Renal-Cell Carcinoma Database Consortium prognostic score (0 vs 1-2 vs 3-6), line of previous immunotherapy (adjuvant, neoadjuvant-adjuvant, or first-line vs second-line), and geographical region (North America vs western Europe vs rest of the world). The dual primary endpoints were progression-free survival by masked independent central review and overall survival, assessed in all randomly assigned participants. Safety was assessed in all randomly assigned participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04586231, and has completed participant recruitment and is ongoing with treatment and follow-up.

FINDINGS

Between March 5, 2021, and Sept 1, 2023, 955 individuals were screened for eligibility, 747 of whom were randomly assigned to belzutifan-lenvatinib (n=371) or cabozantinib (n=376). 565 (76%) participants were male and 182 (24%) were female; 651 (87%) were White (table 1). At second interim analysis (data cutoff April 9, 2025; median follow-up 29·0 months [IQR 23·7-34·9]), progression-free survival was significantly longer in the belzutifan-lenvatinib group compared with the cabozantinib group (median 14·8 months [95% CI 11·2-16·6] vs 10·7 months [9·2-11·1]; hazard ratio [HR] 0·70 [95% CI 0·59-0·84]; one-sided p<0·0001). Overall survival was not significantly different between the groups (median 34·9 months [95% CI 27·5-not reached] vs 27·6 months [24·0-31·4]; HR 0·85 [95% CI 0·68-1·05]; one-sided p=0·061). Grade 3 or worse treatment-emergent adverse events occurred in 311 (84%) of 370 participants in the belzutifan-lenvatinib group and 307 (83%) of 371 participants in the cabozantinib group, most commonly hypertension in both groups (114 [31%] participants in the belzutifan-lenvatinib group and 107 [29%] in the cabozantinib group). Treatment-related adverse events led to two deaths in the belzutifan-lenvatinib group and one death in the cabozantinib group.

INTERPRETATION

Belzutifan-lenvatinib represents a novel and efficacious treatment option. Although overall survival was not significantly different between the groups, belzutifan-lenvatinib might be a new standard of care for patients with advanced clear-cell renal cell carcinoma with disease progression after previous anti-PD-1 or anti-PD-L1 therapy. The safety profile of belzutifan-lenvatinib was consistent with those of the individual drugs.

FUNDING

Merck Sharp & Dohme, a subsidiary of Merck & Co.

MeSH

Cells, Progression-Free Survival, Disease Progression, Carcinoma, Renal Cell, Drug-Related Side Effects And Adverse Reactions, Therapeutics