Toni K. Choueiri, MD, FASCO, on RCC: Biomarker Analysis From the CLEAR Trial

The KEYNOTE study is actually the study that established first-line combination VEGF-TKI, lenvatinib, and PD-1 inhibitor, pembrolizumab, as a standard therapy in metastatic renal cell cancer. The study has met several endpoint, progression-free survival, overall survival, and response rate showing that the combination of pembrolizumab and lenvatinib is superior to sunitinib. And here, what we did during the 2024 ASCO, great meeting by the way, we looked at baseline PD-L1 expression by immunohistochemistry, specific gene alteration by interrogating whole exome, and gene expression pattern using RNA-Seq. We did not have samples on all the patient from the full analysis, but the large subset we had on had similar baseline characteristic as the whole cohort. What we concluded is the combination of lenvatinib and pembrolizumab does work irrespective of PD-L1 immunohistochemistry. It showed that it worked and had a longer progression-free survival and improved response rate over sunitinib regardless of specific kidney cancer driver gene alteration, and these driver gene alteration are essentially the top mutated gene in kidney cancer, VHL, PBRM1, [inaudible 00:01:37], BAP1, KDM5C, but the combination is superior to sunitinib irrespective. And finally, we did look at a specific molecular subtype and gene expression, but the gene expression where the past several years reported specific to renal cell or not, but we looked at specific signature for renal cell cancer, the clusters, and universally, it showed that pembrolizumab-lenvatinib does work irrespective of any molecular subtypes, whether it's the angiogenesis subtype, the immune proliferative, et cetera. We will continue trying to find biomarkers specific to one therapy, and despite that this is a bit on the negative side, I think it's important to show that what doesn't work as biomarker as important show what does work.