Biomarker analyses in patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial.
Authors: Robert J. Motzer, Camillo Porta, Masatoshi Eto, Thomas E. Hutson, Sun Young Rha, Jaime R. Merchan, Eric Winquist, Howard Gurney, Viktor Grünwald, Saby George, Julia Markensohn, Joseph E. Burgents, Razvan Cristescu, Yudai Narita, Cixin S. He, Ziming Zhao, Chinyere E Okpara, Yukinori Minoshima, Toni K. CHOUEIRI
Journal: Journal of Clinical Oncology (2024)

4504 Background: In the primary analysis of CLEAR, lenvatinib + pembrolizumab (L+P) significantly improved efficacy vs sunitinib (S) in treatment-naïve patients with aRCC (Motzer 2021). Results were confirmed at the final prespecified OS analysis (Motzer 2024). We report biomarker analyses from CLEAR. Methods: PD-L1 IHC 22C3 pharmDx and NGS assays (ImmunoID NeXT platform: WES and RNA-Seq) were performed on archival tumor specimens. To identify somatic alterations including mutations and copy-number variations, paired PBMC samples were used as reference. For RNA-Seq/IHC-derived analyses, a continuous value analysis was performed adjusting by KPS score for: each gene-signature score (T-cell inflamed gene-expression profile [GEP], and non-GEP signatures including proliferation, angiogenesis, hypoxia, MYC, WNT, and other signatures [Cristescu 2022]) vs best overall response (BOR); non-GEP signatures vs BOR adjusted by GEP; and PD-L1 CPS vs BOR. Cutoff analyses were performed for biomarkers that showed significant association in the continuous value analysis. Cutoff values (1st tertile of GEP, or median of non-GEP, signatures) were determined based on combined L+P and S arms. WES analyses were descriptively summarized if TMB/INDEL burden and mutation status of key RCC driver genes were associated with BOR. Results: There were no notable differences in baseline characteristics and tumor responses in biomarker analysis sets vs the ITT population. In the L+P arm, the continuous GEP signature score was not associated with BOR. The MYC signature score was negatively associated with BOR (2-sided test, significance criteria 0.1; FDR-adjusted p=0.013/0.012 with/without adjustment by GEP signature score, respectively). The ORRs (95% CI) for the MYC-high and -low groups were 66.3% (56.1-75.6) and 84.0% (75.0-90.8), respectively. In the S arm, the continuous GEP signature score was positively associated with BOR (2-sided test, significance criteria 0.05; p=0.010). The ORRs (95% CI) for the GEP-high and -low groups were 46.9% (38.1-55.9) and 28.8% (18.3-41.3), respectively. The angiogenesis signature was positively associated with BOR (2-sided test, significance criteria 0.1; FDR-adjusted p=0.046/0.088 with/without adjustment by GEP signature score, respectively). The ORRs (95% CI) for the angiogenesis-high and -low groups were 52.1% (41.6-62.5) and 30.4% (21.7-40.3), respectively. PD-L1 CPS and TMB/INDEL burden were not associated with BOR in L+P or S arms. ORR was higher with L+P vs S, regardless of the deleterious mutation status of BAP1, VHL, PBRM1, SETD2, and KDM5C—frequently mutated genes in RCC. Conclusions: The superiority of L+P vs S in ORR does not appear to be impacted by gene-expression signatures for tumor-induced proliferation, angiogenesis, hypoxia, MYC, or WNT, or by PD-L1 status, TMB/INDEL burden or mutation status of RCC driver genes. Clinical trial information: NCT02811861 .