e21064 Background: Merkel cell carcinoma (MCC) is an immunogenic neuroendocrine malignancy with promising responses to immune checkpoint blockade (ICB). Although ICB is standard of care in advanced MCC patients, approximately 50% of patients are resistant to ICB. Thus, it is crucial to identify biomarkers predictive of response. Methods: To understand the genomic landscape of MCC, we performed exome capture sequencing on 27 tumor and matched normal samples from 25 patients with MCC treated at Memorial Sloan Kettering. Herein, we report the analysis of 16 paired samples from 14 patients. Nonsynonymous, high-confidence somatic mutations were identified and tumor reads aligned to the Merkel cell polyoma virus (MCPyV) were quantified. Results: Tumor and matched normal samples were sequenced to a median target coverage depth of 53x and 79x reads, respectively. One sample was not analyzed due to inadequate coverage. The MCPyV genome was detected in 12 of 13 patients (92%). The median somatic mutation burden among analyzed samples was 19 nonsynonymous variants per exome (range: 8 - 120). No recurrent driver mutations were identified in any sample. Four samples lacked potential driver mutations and, among the remaining 11 samples, 36 putatively oncogenic mutations were detected in 33 genes (variant allele frequency: 0.08 – 1), including genes involved in the cell cycle checkpoint ( TP53, RB1), DNA damage repair ( ERCC4, FANCA, FANCD2), PI3K-AKT-mTOR ( PIK3CA, PIK3CG), and Notch ( NOTCH1, NOTCH2) pathways. One sample with undetected MCPyV DNA demonstrated loss of heterozygosity of both TP53 and RB1. Four samples contained strand coordinated clusters of mutations in more than 20 distinct gene regions, suggesting an APOBEC-high mutagenesis signature. Conclusions: The MCPyV genome was detected in most tumors analyzed and tumor mutation burden was low in such tumors, consistent with published literature. Analysis of an additional 11 sample pairs is ongoing, along with personalized neoantigen binding predictions on all samples. Immunohistochemistry (IHC) for PDL1 and CD8 expression is in progress. Associations between the aforementioned and response to ICB will be reported.
In-field and abscopal response after short-course radiation therapy in patients with metastatic Merkel cell carcinoma progressing on PD-1 checkpoint blockade: a case series