SWI/SNF complex alterations as a biomarker of immunotherapy efficacy in pancreatic cancer.

Background Immune checkpoint inhibitors (ICIs), which have transformed the care of multiple malignancies, fail to demonstrate efficacy in pancreatic cancer. Recently, genomic biomarkers have been associated with response to ICIs: microsatellite instability high (MSI-H) and tumor mutation burden (TMB) ≥10 mutations/Mb. Some investigations suggest that alterations in Switch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling genes may predispose to improved outcomes with immunotherapy. The current study examined a possible role for SWI/SNF complex abnormalities in pancreatic cancer responsiveness to ICIs. Methods We interrogated a database of 6,831 cancer patients that had undergone next generation sequencing (NGS) in order to evaluate those with advanced pancreatic cancer, SWI/SNF alterations, and outcomes depending on immunotherapy treatment. Results Of 6,831 cancer patients, nine had metastatic pancreatic adenocarcinoma harboring SWI/SNF chromatin remodeling gene alterations and had received ICIs: seven had an ARID1A alteration (77%); two, ARID1B (22%); three, SMARCA4 (33%); one, SMARCB1 (11%); and one, PBRM1 (11%). Three patients possessed more than one SWI/SNF complex alteration. Only three tumors were microsatellite unstable. Eight of 9 patients (89%) achieved an objective response, including a complete remission, with the two longest responses ongoing at 33+ and 36+ months. Median progression-free and overall survival was 9 and 15 months, respectively. Responses occurred even in the presence of microsatellite stability, low TMB and/or low PD-L1 expression. Conclusion A small subset of patients with pancreatic cancer have genomic alterations in the SWI/SNF chromatin remodeling components and these patients appear to be responsive to ICIs, suggesting the need for prospective trials. Trial registration ClinicalTrials.gov NCT02478931FUNDING. Joan and Irwin Jacobs Fund and by National Cancer Institute at the National Institutes of Health [Grant No. NIH P30 CA023100 (RK) and LRP KYGF9753 (GPB), as well as the Gershenson Family, the Duarte Family, and anonymous patient donors (GPB).