Abstract 4278: A composite neoantigen score is more strongly associated with therapeutic response than tumor mutational burden in a cohort of late-stage anti-PD-1-treated melanoma patients

Checkpoint inhibitor therapy has demonstrated meaningful, if varied antitumor activity, with patient response influenced by a variety of biological factors, including complex interactions between the tumor and immune system. Thus, it is of increasing interest to identify composite biomarkers integrating multiple biological features to better predict immunotherapy response. In this study we use a comprehensive tumor immungenomics profiling platform to examine the effectiveness of our composite neoantigen score for stratifying patient response to checkpoint blockade therapy compared to tumor mutational burden and other biomarkers.Pre-treatment tumor/normal samples from 55 unresectable, stage III/IV melanoma patients who underwent anti-PD-1 therapy were characterized to assess factors influencing response. RECIST criteria were used to evaluate tumor response to therapy, with a median follow-up of 18 months. For each patient, a single paired FFPE tumor and normal blood sample was collected and profiled using Personalis' ImmunoID NeXT platform; an augmented exome/transcriptome platform and analysis pipeline, which produces comprehensive tumor mutation information, gene expression quantification, neoantigen characterization, HLA typing and LOH, TCR repertoire profiling and tumor microenvironment profiling. These data were then analyzed together with clinical outcome, and a composite neoantigen score computed for each patient along with other biomarkers such as tumor mutational burden (TMB).In this cohort, an elevated pretreatment composite neoantigen score combining neoantigen predictions adjusted based on resistance mechanisms that affect neoantigen presentation on the MHC complex was more strongly predictive of response to PD-1 blockade than TMB alone. This was true for both response and non-response via RECIST criteria and progression free survival. We also found that the composite neoantigen score was a stronger predictor of patient response when compared to neoantigen burden alone. Additionally, we observed increased response to anti-PD-1 therapy in patients with elevated pretreatment TCR clonality. Combining the composite neoantigen score and TCR clonality data revealed a significant association with non-response to therapy. Patients with high composite neoantigen score and TCR clonality that failed to achieve complete response revealed potential resistance mechanisms to anti-PD-1 therapy. Specifically, we identified patients with high expression of IDO1 o