Lenvatinib/Everolimus or Lenvatinib/Pembrolizumab Versus Sunitinib Alone as Treatment of Advanced Renal Cell Carcinoma
Summary
The primary purpose of the study is to demonstrate that lenvatinib in combination with everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) in improving progression-free survival (PFS) (by independent imaging review \[IIR\] using Response Evaluation Criteria in Solid Tumors \[RECIST 1.1\]) as first-line treatment in participants with advanced renal cell carcinoma (RCC).
Timeline
- Start
- 2016-10-13
- Primary completion
- 2020-08-28
- Completion
- 2027-03-31
Outcome
Met primary endpoint
registry analysis (superiority test); Lenvatinib 18 mg Plus Everolimus 5 mg vs Sunitinib 50 mg; p <0.0001; Stratified Hazard Ratio 0.65 (95% CI 0.53 to 0.80) NCT02811861 ↗
registry analysis (superiority test); Lenvatinib 20 mg Plus Pembrolizumab 200 mg vs Sunitinib 50 mg; p <0.0001; Stratified Hazard Ratio 0.39 (95% CI 0.32 to 0.49) NCT02811861 ↗
release “Merck and Eisai announced the Phase 3 KEYNOTE-581/CLEAR trial (Study 307) met its primary endpoint of progression free survival (PFS)” merck.com ↗
release “CLEAR study (Study 307/KEYNOTE-581), in which LENVIMA plus KEYTRUDA demonstrated statistically significant improvements in PFS, OS and ORR versus sunitinib.” eisai.com ↗
release “Based on Phase 3 CLEAR/KEYNOTE-581 Trial, KEYTRUDA Plus LENVIMA Significantly Reduced Risk of Disease Progression or Death by 61% Versus Sunitinib” merck.com ↗
release “In the CLEAR/KEYNOTE-581 trial, KEYTRUDA plus LENVIMA reduced the risk of disease progression or death by 61% versus sunitinib” eisai.com ↗
release “Results from the final pre-specified OS analysis were consistent with the superior results versus sunitinib from the primary OS analysis of the CLEAR/KEYNOTE-581 trial.” merck.com ↗
Publications
- Fawsitt CG, Pan J, Orishaba P, Jackson CH, Thom H. Unanchored simulated treatment comparison on survival outcomes using parametric and Royston-Parmar models with application to lenvatinib plus pembrolizumab in renal cell carcinoma. BMC Med Res Methodol. 2025 Jan 30;25(1):26. doi: 10.1186/s12874-025-02480-x.
- Zheng H, Zhou J, Tong Y, Zhang J. Cost-Effectiveness Analysis of Lenvatinib plus Pembrolizumab or Everolimus as First-Line Treatment for Advanced Renal Cell Carcinoma. Clin Genitourin Cancer. 2025 Feb;23(1):102264. doi: 10.1016/j.clgc.2024.102264. Epub 2024 Nov 15.
- Motzer RJ, Choueiri TK, Hutson T, Young Rha S, Puente J, Lalani AA, Winquist E, Eto M, Basappa NS, Tannir NM, Vaishampayan U, Bjarnason GA, Oudard S, Grunwald V, Burgents J, Xie R, McKenzie J, Powles T. Characterization of Responses to Lenvatinib plus Pembrolizumab in Patients with Advanced Renal Cell Carcinoma at the Final Prespecified Survival Analysis of the Phase 3 CLEAR Study. Eur Urol. 2024 Jul;86(1):4-9. doi: 10.1016/j.eururo.2024.03.015. Epub 2024 Apr 6.
- Motzer RJ, Porta C, Eto M, Powles T, Grunwald V, Hutson TE, Alekseev B, Rha SY, Merchan J, Goh JC, Lalani AA, De Giorgi U, Melichar B, Hong SH, Gurney H, Mendez-Vidal MJ, Kopyltsov E, Tjulandin S, Gordoa TA, Kozlov V, Alyasova A, Winquist E, Maroto P, Kim M, Peer A, Procopio G, Takagi T, Wong S, Bedke J, Schmidinger M, Rodriguez-Lopez K, Burgents J, He C, Okpara CE, McKenzie J, Choueiri TK; CLEAR Trial Investigators. Lenvatinib Plus Pembrolizumab Versus Sunitinib in First-Line Treatment of Advanced Renal Cell Carcinoma: Final Prespecified Overall Survival Analysis of CLEAR, a Phase III Study. J Clin Oncol. 2024 Apr 10;42(11):1222-1228. doi: 10.1200/JCO.23.01569. Epub 2024 Jan 16.
- Grunwald V, Powles T, Eto M, Kopyltsov E, Rha SY, Porta C, Motzer R, Hutson TE, Mendez-Vidal MJ, Hong SH, Winquist E, Goh JC, Maroto P, Buchler T, Takagi T, Burgents JE, Perini R, He C, Okpara CE, McKenzie J, Choueiri TK. Phase 3 CLEAR study in patients with advanced renal cell carcinoma: outcomes in subgroups for the lenvatinib-plus-pembrolizumab and sunitinib arms. Front Oncol. 2023 Aug 16;13:1223282. doi: 10.3389/fonc.2023.1223282. eCollection 2023.
- Rha SY, Choueiri TK, Matveev VB, Alyasova A, Hong SH, Gordoa TA, Gurney H, Bjarnason GA, Buchler T, Pedrazzoli P, Takagi T, Park SH, Lee JL, Perini RF, He CS, McKenzie JA, Eto M. Efficacy and safety of lenvatinib plus pembrolizumab vs sunitinib in the East Asian subset of patients with advanced renal cell carcinoma from the CLEAR trial. Int J Cancer. 2023 Sep 15;153(6):1241-1250. doi: 10.1002/ijc.34608. Epub 2023 Jun 9.
- Aldin A, Besiroglu B, Adams A, Monsef I, Piechotta V, Tomlinson E, Hornbach C, Dressen N, Goldkuhle M, Maisch P, Dahm P, Heidenreich A, Skoetz N. First-line therapy for adults with advanced renal cell carcinoma: a systematic review and network meta-analysis. Cochrane Database Syst Rev. 2023 May 4;5(5):CD013798. doi: 10.1002/14651858.CD013798.pub2.
- Motzer R, George S, Merchan JR, Hutson TE, Song X, Perini RF, Xie R, Bapat U, Puente J. Characterization and Management of Adverse Reactions From the CLEAR Study in Advanced Renal Cell Carcinoma Treated With Lenvatinib Plus Pembrolizumab. Oncologist. 2023 Jun 2;28(6):501-509. doi: 10.1093/oncolo/oyac269.
- Choueiri TK, Eto M, Motzer R, De Giorgi U, Buchler T, Basappa NS, Mendez-Vidal MJ, Tjulandin S, Hoon Park S, Melichar B, Hutson T, Alemany C, McGregor B, Powles T, Grunwald V, Alekseev B, Rha SY, Kopyltsov E, Kapoor A, Alonso Gordoa T, Goh JC, Staehler M, Merchan JR, Xie R, Perini RF, Mody K, McKenzie J, Porta CG. Lenvatinib plus pembrolizumab versus sunitinib as first-line treatment of patients with advanced renal cell carcinoma (CLEAR): extended follow-up from the phase 3, randomised, open-label study. Lancet Oncol. 2023 Mar;24(3):228-238. doi: 10.1016/S1470-2045(23)00049-9.
- Motzer R, Porta C, Alekseev B, Rha SY, Choueiri TK, Mendez-Vidal MJ, Hong SH, Kapoor A, Goh JC, Eto M, Bennett L, Wang J, Pan JJ, Saretsky TL, Perini RF, He CS, Mody K, Cella D. Health-related quality-of-life outcomes in patients with advanced renal cell carcinoma treated with lenvatinib plus pembrolizumab or everolimus versus sunitinib (CLEAR): a randomised, phase 3 study. Lancet Oncol. 2022 Jun;23(6):768-780. doi: 10.1016/S1470-2045(22)00212-1. Epub 2022 Apr 27.
- Motzer R, Alekseev B, Rha SY, Porta C, Eto M, Powles T, Grunwald V, Hutson TE, Kopyltsov E, Mendez-Vidal MJ, Kozlov V, Alyasova A, Hong SH, Kapoor A, Alonso Gordoa T, Merchan JR, Winquist E, Maroto P, Goh JC, Kim M, Gurney H, Patel V, Peer A, Procopio G, Takagi T, Melichar B, Rolland F, De Giorgi U, Wong S, Bedke J, Schmidinger M, Dutcus CE, Smith AD, Dutta L, Mody K, Perini RF, Xing D, Choueiri TK; CLEAR Trial Investigators. Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma. N Engl J Med. 2021 Apr 8;384(14):1289-1300. doi: 10.1056/NEJMoa2035716. Epub 2021 Feb 13.
- Hofmann F, Hwang EC, Lam TB, Bex A, Yuan Y, Marconi LS, Ljungberg B. Targeted therapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 2020 Oct 14;10(10):CD012796. doi: 10.1002/14651858.CD012796.pub2.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Everolimus | Small molecule | 5 mg | Oral |
| Subject | Lenvatinib | Small molecule | 18 mg | Oral |
| Subject | Lenvatinib | Small molecule | 20 mg | Oral |
| Subject | Pembrolizumab | Monoclonal antibody | 200 mg | Intravenous |
| Comparator | Sunitinib | Small molecule | 50 mg | Oral |