Association between biomarkers and clinical outcomes of lenvatinib + pembrolizumab in advanced renal cell carcinoma (RCC): Results from Study 111/KEYNOTE-146.
Authors: Lee Chung-Han , Rasco Drew W. , Rao Arpit , Taylor Matthew H. , Hsieh James J , Pinto Alvaro , Vogelzang Nicholas J. , Cao Z. Alexander , Suttner Leah , Loboda Andrey , Vajdi Amir , Predoiu Raluca Andreia , Nebozhyn Michael , Lunceford Jared , Perini Rodolfo F. , Matsui Junji , Minoshima Yukinori , Dutcus Corina E. , Dutta Lea , Motzer Robert J. 
Published: February 2022

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Background: In the Study 111/KEYNOTE-146 trial (NCT02501096; N=147), lenvatinib (lenva) + pembrolizumab (pembro) showed encouraging antitumor activity and a manageable safety profile in treatment-naive (n=23) or previously treated metastatic RCC (n=105, previously treated with immune checkpoint inhibitor [ICI]; n=19, previously treated ICI naive); 145 had clear cell RCC and 2 had non-clear cell RCC. In this exploratory analysis, we evaluated the association between clinical outcomes and gene expression signatures and DNA variants for individual RCC-specific driver genes of interest based on published reports. Methods: Patients (pts) with metastatic RCC were treated with lenva 20 mg orally once daily + pembro 200 mg intravenously once every 3 weeks. The analysis population included pts with treatment-naive (n=10) and ICI pretreated (n=70) disease with evaluable RNA-sequencing data for the 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) and for 11 other signatures (angiogenesis; glycolysis; gMDSC; hypoxia; mMDSC; MVD; MYC; proliferation; RAS; stroma/EMT/TGFβ; WNT) and whole exome sequencing (WES) data for DNA variants for individual genes ( VHL, PBRM1, BAP1, and SETD2). Specimens were collected prior to the start of treatment. The associations between each signature score and ORR and PFS per immune-related RECIST were evaluated using logistic regression and Cox proportional hazards, respectively. One-sided P values for TcellinfGEP (hypothesized positive association) and two-sided P values for all other signatures (no hypothesized association) were adjusted for multiplicity using the Hochberg step-up procedure; significance was prespecified at α=0.05. The association between DNA variants for individual genes and ORR was evaluated descriptively. Clinical data cutoff was August 18, 2020. Results: Of 147 treated pts, RNA sequencing and WES data were available for 80 (54%) and 60 (41%), respectively. TcellinfGEP was not associated with ORR ( P=0.827) or PFS ( P=0.741), nor were the other 11 signatures before or after adjustment for TcellinfGEP. ORR for DNA variants reported in the table. Conclusions: In this exploratory analysis of pts with metastatic RCC enrolled in Study 111/KEYNOTE-146 treated with lenva + pembro, responses were observed regardless of biomarker status. There were no statistically significant associations between gene signatures and clinical outcomes. Clinical benefit was observed regardless of VHL, PBRM1, BAP1, or SETD2 mutation status. Analyses in larger randomized datasets will provide additional information on the role of biomarkers in RCC. Clinical trial information: NCT02501096. [Table: see text]