Genomic biomarkers of response to nivolumab/ipilimumab (nivo/ipi) and nivolumab (nivo) monotherapy in 108 patients with advanced renal cell carcinoma.

Abstract

641 Background: Both the combination of nivo/ipi and nivo monotherapy have shown efficacy across multiple malignancies including clear cell Renal Cell Carcinoma (ccRCC). Biomarkers such as tumor mutation burden (TMB) are prognostic in other malignancies, however, remain unvalidated in ccRCC. This study investigates genomic biomarkers associated with nivo/ipi and nivo clinical response. Methods: Whole exome sequencing (WES) was performed on pretreatment tumor derived DNA from nivo/ipi and nivo treated patients from MSKCC and publicly available WES datasets (Miao D, Science, 2018, 359: 6377). Somatic mutations, TMB, neoantigen load (NA), and HLA zyogosity were correlated to objective response rate (ORR), progression free survival (PFS), and Overall Survival (OS). Alterations occurring in < 10% of the cohort were considered non-evaluable (NE). Results: 108 patients had tumors studied; 32 patients with nivo/ipi and 76 patients with nivo therapy. No individual factors showed significant correlations to ORR or both PFS and OS. In the combined cohort, homozygosity at HLA-C was associated with shorter OS (HR=2.55 95% CI 1.17-5.57; P=0.02). In the nivo/ipi cohort, TMB (HR=0.36 95% CI 0.16-0.84; P=0.02) and NA (HR=0.43 95% CI 0.19-0.98; P=0.04) were associated with longer PFS. Conclusions: Increased TMB and NA load may predict for improved outcomes, and homozygosity at HLA loci may predict for worse outcomes. The predictors of response to nivo may not be generalizable to nivo/ipi. To rule out artifacts of multiple testing in a small cohort, validation in a larger dataset is necessary. [Table: see text]