Mutation burden and tumor neoantigens in RCC patients (pts) treated with nivolumab.

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514 Background: Durable benefit with CTLA4 or PD1 blockade associates with high somatic mutation burden in melanoma and lung cancer (Snyder, NEJM 2014; Rizvi, Science 2015). The same studies suggest that tumor neoantigens arising from somatic mutations may be mediating this association. For RCC, a disease with a comparatively low mutation burden but good response to PD1 directed therapy, such associations are unknown. To examine these concepts, we used whole exome (WES) and transcriptome (RNAseq) sequencing of RCC samples from pts treated with nivolumab (Nivo). Methods: WES and RNASeq were performed on frozen pre-treatment tumor/normal tissue for 7 pts treated with Nivo and 1 pt treated with ipilimumab/Nivo (Ipi/Nivo) x 4 followed by Nivo. Efficacy was assessed by RECIST. Neoantigen prediction and HLA typing were performed in silico using NetMHC3.2 and ATHLATES, respectively. Expression of predicted neoantigens and putative pathways of resistance/response were investigated using DESeq-normalized reads. Results: Two of 7 Nivo-monotherapy pts achieved durable clinical benefit (DCB, PR > 12 months); 1 pt had a non-durable PR (5 months). For 2 Nivo/DCB pts, the burden of non-synonymous somatic mutations was 113 and 224 compared to a median of 95 in those with no DCB (range 53-124). The ratio of predicted neoantigens/total mutations was higher for pts with DCB/Objective response (all ≥ 0.5) compared to those with progressive disease (all < 0.5). The Ipi/Nivo pt experienced > 95% tumor regression ongoing 2+ years, but harbored the lowest mutation count (29) and lowest neoantigen/mutation ratio ( < 0.2) in the cohort. Across all pts, 80% of predicted neoantigens were expressed. Further, RNASeq findings differed distinctly for DCB vs. non-DCB pts in various genes of interest, including mediators of antigen presentation to T-cells (HLA-A, -B, -C; B2M) and composition of other immune regulators (CSF1R, LGALS1), but not for PDL1. Conclusions: In RCC, somatic mutations, particularly those causing tumor neoantigens, and the counterbalance between molecular immune compartments may be determinants of treatment benefit from Nivo and warrant future study. Their impact might be distinctly different in pts treated with combination immunotherapy.

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