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

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. 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 [Tcell GEP]/non-Tcell GEP 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. 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-Tcell GEP/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). 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.