Integrative genomic profiling of RCC treated with second-line nivolumab.

Abstract

720 Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer comprising up to 80% of RCC. Anti-vascular endothelial growth factor receptor (VEGFR) is a common therapy. Immune checkpoint inhibitor therapy with anti-PD1 antibody Nivolumab is a standard second line option in mccRCC. Overall response rate with Nivolumab however is only 25%. Since there is a critical need to develop and refine predictive biomarkers for anti-PD1 checkpoint inhibitor immunotherapy, we undertook a genomics based approach to gain further insights. Methods: Archival pre-treatment tissues from 37 metastatic mccRCC patients who had received anti-VEGFR first and then Nivolumab were collected and profiled by integrated next generation sequencing (NGS) including whole exome sequencing and RNA sequencing. Integrative NGS analysis was used to discover somatic mutations, indels, copy-number alterations and gene expression changes among the samples in this cohort. In-addition, we characterized the T-Cell clone type by adaptive immunoSEQ TCR sequencing on the matched tumor/benign adjacent tissue samples. Clinical outcome data was correlated with high throughput sequencing results to delineate the characteristics of responders and non-responders. Results: Integrative NGS profiling and analysis of ccRCC tumors revealed 1) the characteristic copy number alteration including frequent loss at 3p, 8p21.3 and 9p21.3 as well as gain at 5q, and 12p12.1. 2) a low mutational burden 3) tumors with PBRM1 mutation were relatively enriched in the “No Clinical Benefit Category”. 4) CD8 immunohistochemistry showed significant enrichment of CD8+ cells ( pval-0.05) in the clinical benefit group compared to patients with no-clinical benefit. The clinical benefit group tended to have higher number of TCR clones. Conclusions: Integrative genomic sequencing analysis of ccRCC tumors in Nivolumab treated patients revealed CD8 expression as a putative biomarker. Greater T-cell clonotypes & clonal expansion correlated with clinical benefit. PBRM1 mutant status did not select for clinical benefit. A model combining CD8 expression with T-cell characteristics was developed.