| 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. © 2024 The Author(s) |
| Keywords: |
immunohistochemistry; adult; controlled study; human tissue; aged; middle aged; gene mutation; major clinical study; genetics; clinical trial; sunitinib; advanced cancer; cancer risk; cancer patient; antineoplastic agent; lymphocyte proliferation; t lymphocyte; biomarkers; progression free survival; multiple cycle treatment; gene expression profiling; randomized controlled trial; antineoplastic combined chemotherapy protocols; pathology; angiogenesis; retrospective study; tumor marker; renal cell carcinoma; kidney neoplasms; high risk patient; risk assessment; monoclonal antibody; karnofsky performance status; statistical significance; kidney tumor; carcinoma, renal cell; myc protein; stroma; hazard ratio; phase 3 clinical trial; vhl gene; drug therapy; tumor gene; von hippel lindau protein; oncogene myc; programmed death 1 ligand 1; progression-free survival; randomized controlled trial (topic); intermediate risk patient; phase 3 clinical trial (topic); quinolines; rcc; quinoline derivative; multicenter study (topic); bap1 gene; overall response rate; low risk patient; antibodies, monoclonal, humanized; high throughput sequencing; phenylurea compounds; pbrm1 gene; setd2 gene; lenvatinib; carbanilamide derivative; humans; human; male; female; article; rna sequencing; pembrolizumab; clear; whole exome sequencing; biomarkers, tumor; cd274 protein, human; b7-h1 antigen; kdm5c gene; microvascular density
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