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Biomarker analyses from the phase III randomized CLEAR trial: lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma.

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Title: Biomarker analyses from the phase III randomized CLEAR trial: lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma.
Authors: Motzer RJ; Memorial Sloan Kettering Cancer Center, New York, USA. Electronic address: motzerr@mskcc.org., Porta C; Interdisciplinary Department of Medicine, University of Bari 'A. Moro' and Division of Medical Oncology, Policlinico Consorziale di Bari, Bari, Italy., Eto M; Department of Urology, Kyushu University, Fukuoka, Japan., Hutson TE; Texas Tech University Health Science Center, Lubbock, USA., Rha SY; Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea., Merchan JR; University of Miami Sylvester Comprehensive Cancer Center, Miami, USA., Winquist E; Department of Oncology, Western University, London, Ontario, Canada., Gurney H; Department of Medical Oncology, Macquarie University, Sydney, New South Wales, Australia., Grünwald V; Interdisciplinary Genitourinary Oncology, Clinic for Urology, Clinic for Medical Oncology, University Hospital Essen, Essen, Germany., George S; Roswell Park Cancer Institute, Buffalo, USA., Markensohn J; Merck & Co., Inc., Rahway, USA., Burgents JE; Merck & Co., Inc., Rahway, USA., Cristescu R; Merck & Co., Inc., Rahway, USA., Sachdev P; Eisai Inc., Nutley, USA., Narita Y; Eisai Co., Ltd., Ibaraki, Japan., Huang J; Eisai Inc., Nutley, USA., Zhao Z; Eisai Inc., Nutley, USA., Okpara CE; Eisai Ltd., Hatfield, UK., Minoshima Y; Eisai Co., Ltd., Ibaraki, Japan., Choueiri TK; Dana-Farber Cancer Institute, Boston, USA.
Source: Annals of oncology : official journal of the European Society for Medical Oncology [Ann Oncol] 2025 Apr; Vol. 36 (4), pp. 375-386. Date of Electronic Publication: 2024 Dec 11.
Publication Type: Journal Article; Randomized Controlled Trial; Clinical Trial, Phase III; Comparative Study
Language: English
Journal Info: Publisher: Elsevier Country of Publication: England NLM ID: 9007735 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1569-8041 (Electronic) Linking ISSN: 09237534 NLM ISO Abbreviation: Ann Oncol Subsets: MEDLINE
Imprint Name(s): Publication: 2020- : London : Elsevier
Original Publication: Dordrecht ; Boston : Kluwer Academic Publishers, c1990-
MeSH Terms: Carcinoma, Renal Cell*/drug therapy , Carcinoma, Renal Cell*/genetics , Carcinoma, Renal Cell*/pathology , Carcinoma, Renal Cell*/mortality , Kidney Neoplasms*/drug therapy , Kidney Neoplasms*/genetics , Kidney Neoplasms*/pathology , Kidney Neoplasms*/mortality , Biomarkers, Tumor*/genetics , Biomarkers, Tumor*/metabolism , Antineoplastic Combined Chemotherapy Protocols*/therapeutic use, Sunitinib/administration & dosage ; Antibodies, Monoclonal, Humanized/administration & dosage ; Phenylurea Compounds/administration & dosage ; Quinolines/administration & dosage ; B7-H1 Antigen/metabolism ; B7-H1 Antigen/genetics ; Humans ; Female ; Male ; Middle Aged ; Aged ; Progression-Free Survival ; Adult
Abstract: Background: In CLEAR, lenvatinib + pembrolizumab (L + P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (aRCC). We report results from CLEAR biomarker analyses.
Patients and Methods: Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA sequencing) were carried out on archival tumor specimens. For IHC-derived/RNA sequencing analyses, a continuous analysis was carried out adjusting by Karnofsky performance status (KPS) score for: PD-L1 combined positive score (CPS) versus best overall response (BOR)/progression-free survival (PFS); and each gene signature score [T-cell inflamed gene expression profile (TcellinfGEP)/non-TcellinfGEP signatures including proliferation and angiogenesis] versus BOR/PFS. Association between mutation status of RCC driver genes and PFS were analyzed for genes for which ≥20 patients per arm had oncogenic alterations. Association of molecular subtypes with outcome was evaluated with baseline KPS adjustments. The set of biomarkers evaluated and statistical significance criteria for PD-L1 CPS, gene signature scores, and molecular subtypes were prespecified.
Results: Within-arm analyses using continuous values showed no association between PD-L1 levels and BOR/PFS for either treatment. PFS hazard ratios between arms were similar regardless of the mutant or wild-type subgroups of RCC driver genes (VHL, PBRM1, SETD2, BAP1, KDM5C). No associations between PFS and gene signature scores were observed for L + P. With sunitinib, high proliferation and MYC signature scores showed shorter PFS; high angiogenesis and microvessel density signature scores showed longer PFS. Six new molecular subtypes were defined. Tumors of patients with favorable/intermediate risk were enriched in angiogenesis and angiogenesis/stromal clusters; those with poor risk were enriched in proliferative and unclassified (low-TcellinfGEP/low-angiogenesis/low-proliferation) clusters. No association between molecular subtypes and PFS for L + P/sunitinib was observed (after adjustment for KPS and gene signatures that were individually associated with PFS).
Conclusions: Improvements in objective response rate and PFS for L + P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.
(Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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Grant Information: P30 CA006516 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; P50 CA101942 United States CA NCI NIH HHS
Contributed Indexing: Keywords: CLEAR; RCC; biomarkers; lenvatinib; pembrolizumab
Substance Nomenclature: V99T50803M (Sunitinib)
EE083865G2 (lenvatinib)
0 (Antibodies, Monoclonal, Humanized)
0 (Biomarkers, Tumor)
0 (Phenylurea Compounds)
DPT0O3T46P (pembrolizumab)
0 (Quinolines)
0 (CD274 protein, human)
0 (B7-H1 Antigen)
Entry Date(s): Date Created: 20241213 Date Completed: 20250326 Latest Revision: 20260625
Update Code: 20260626
PubMed Central ID: PMC12459081
DOI: 10.1016/j.annonc.2024.12.003
PMID: 39672382
Database: MEDLINE
Description
ISSN:1569-8041
DOI:10.1016/j.annonc.2024.12.003