In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up.
This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group [not reported in this updated analysis]) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861.
Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 [26%] female, 796 [74%] male; median age 62 years [IQR 55-69]) were randomly assigned: 355 (33%) patients (255 [72%] male and 100 [28%] female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 [77%] male and 82 [23%] female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3-33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5-32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8-27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0-11·0) in the sunitinib group (stratified hazard ratio [HR] 0·42 [95% CI 0·34-0·52]). Median overall survival follow-up was 33·7 months (IQR 27·4-36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7-36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached [95% CI 41·5-not estimable]) versus sunitinib (median not reached [38·4-not estimable]; HR 0·72 [95% CI 0·55-0·93]).
Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma.
Eisai and Merck Sharp & Dohme.
The Lancet. Oncology. 2023 Mar [Epub]
Toni K Choueiri, Masatoshi Eto, Robert Motzer, Ugo De Giorgi, Tomas Buchler, Naveen S Basappa, María José Méndez-Vidal, Sergei Tjulandin, Se Hoon Park, Bohuslav Melichar, Thomas Hutson, Carlos Alemany, Bradley McGregor, Thomas Powles, Viktor Grünwald, Boris Alekseev, Sun Young Rha, Evgeny Kopyltsov, Anil Kapoor, Teresa Alonso Gordoa, Jeffrey C Goh, Michael Staehler, Jaime R Merchan, Ran Xie, Rodolfo F Perini, Kalgi Mody, Jodi McKenzie, Camillo G Porta
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: ., Department of Urology, Kyushu University, Fukuoka, Japan., Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy., Department of Oncology, First Faculty of Medicine, Charles University and Thomayer University Hospital, Prague, Czech Republic., Department of Medical Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada., Department of Medical Oncology, Hospital Universitario Reina Sofía, Maimonides Institute for Biomedical Research of Córdoba, Córdoba, Spain., Department of Clinical Pharmacology and Chemotherapy, N N Blokhin National Medical Research Center for Oncology, Ministry of Health of the Russian Federation, Moscow, Russia., Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea., Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic., Department of Medical Oncology, Texas Oncology-Baylor Charles A Sammons Cancer Center, Dallas, TX, USA., Department of Hematology and Oncology, AdventHealth Cancer Institute, Orlando, FL, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA., Department of Oncology, The Royal Free NHS Trust, London, England, UK; Department of Oncology, Barts Cancer Institute, Queen Mary Institute of London, London, UK., Clinic for Urology and Clinic for Medical Oncology, University Hospital Essen, Essen, Germany., Department of Onco-urology, P A Hertsen Moscow Cancer Research Institute, Moscow, Russia., Department of Medical Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea., State Institution of Healthcare "Regional Clinical Oncology Dispensary", Omsk, Russia., Division of Urology, Department of Surgery, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada., Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain., ICON Research, South Brisbane, QLD, Australia; Department of BioMedical Sciences, Queensland University of Technology, Brisbane, QLD, Australia., Department of Urology, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany., Department of Medicine, University of Miami Sylvester Comprehensive Cancer Center, Miami, FL, USA., Biostatistics, Eisai, Nutley, NJ, USA., Clinical Research, Merck, Rahway, NJ, USA., Clinical Research, Eisai, Nutley, NJ, USA., Interdisciplinary Department of Medicine, University of Bari 'A Moro', Bari, Italy.