Biomarker analyses from the phase 3 randomized CLEAR trial: Lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma.

IF 56.7 1区 医学 Q1 ONCOLOGY
R J Motzer, C Porta, M Eto, T E Hutson, S Y Rha, J R Merchan, E Winquist, H Gurney, V Grünwald, S George, J Markensohn, J E Burgents, R Cristescu, P Sachdev, Y Narita, J Huang, Z Zhao, C E Okpara, Y Minoshima, T K Choueiri
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引用次数: 0

Abstract

Background: In CLEAR, lenvatinib + pembrolizumab (L+P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (RCC). We report results from CLEAR biomarker analyses.

Methods: PD-L1 immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA-sequencing) were performed on archival tumor specimens. For IHC-derived/RNA-sequencing analyses, a continuous analysis was performed adjusting by Karnofsky performance status (KPS) score for: PD-L1 CPS versus best overall response (BOR)/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 pre-specified.

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 mutant or wildtype 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 ORR 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.

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来源期刊
Annals of Oncology
Annals of Oncology 医学-肿瘤学
CiteScore
63.90
自引率
1.00%
发文量
3712
审稿时长
2-3 weeks
期刊介绍: Annals of Oncology, the official journal of the European Society for Medical Oncology and the Japanese Society of Medical Oncology, offers rapid and efficient peer-reviewed publications on innovative cancer treatments and translational research in oncology and precision medicine. The journal primarily focuses on areas such as systemic anticancer therapy, with a specific emphasis on molecular targeted agents and new immune therapies. We also welcome randomized trials, including negative results, as well as top-level guidelines. Additionally, we encourage submissions in emerging fields that are crucial to personalized medicine, such as molecular pathology, bioinformatics, modern statistics, and biotechnologies. Manuscripts related to radiotherapy, surgery, and pediatrics will be considered if they demonstrate a clear interaction with any of the aforementioned fields or if they present groundbreaking findings. Our international editorial board comprises renowned experts who are leaders in their respective fields. Through Annals of Oncology, we strive to provide the most effective communication on the dynamic and ever-evolving global oncology landscape.
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