Investigating the efficacy and use of immunotherapy in treatment of microsatellite instability low (MSI-L) solid tumors.

845 Background: The development of immune checkpoint inhibitors has changed the treatment approach for microsatellite instability-high (MSI-H) tumors. Pembrolizumab was FDA-approved in 2017 for the treatment of MSI-H solid tumors. This approval does not include microsatellite stable (MSS) tumors, which make up the vast majority of colorectal cancers. Clinical trials to date have not demonstrated significant benefit from immunotherapy for MSS tumors. However, clinically used cut-offs to define MSI-H solid tumors do not completely capture the biologic heterogeneity of MSI tumors. Microsatellite instability-low (MSI-L) tumors include tumors with instability at a single site in contrast to multiple sites seen in MSI-H. In clinical practice MSS and MSI-L are grouped under the broader MSS definition. However, it remains unknown how impactful immunotherapy would be within this biologic spectrum of MSI-L tumors. Methods: We conducted a retrospective chart review of solid cancer patients with tumor sequencing data available at the OHSU Knight Diagnostic Laboratory between June 2019 and July 2024. We identified tumors with microsatellite instability between 3-5% abnormal sites to define MSI-L tumors. Total microsatellite sites assessed=207. Tumors with instability at >5% of sites were excluded as these were categorized as MSI-H. A diverse group of cancer types were analyzed including primary brain, gastro-esophageal, pancreatic, breast, prostate, colorectal, lung, biliary, salivary, ovarian, urothelial, squamous, GIST, thyroid, sarcoma, melanoma, and neuroendocrine. Our primary aim was to evaluate for any documented response or disease stability following immunotherapy treatment in MSI-L tumors. Results: Among 570 patients identified as having either high tumor mutational burden (TMB >10) or MSS tumors during this period, 61 had tumor specimens that fit the category of MSI-L. A total of 9 out of 61 patients were treated with immunotherapy. The immunotherapy regimens used included pembrolizumab, nivolumab, and durvalumab to treat a variety of cancer types including esophageal adenocarcinoma, sarcoma, glioblastoma, ovarian serous carcinoma, pancreatic adenocarcinoma, lung adenocarcinoma, urothelial carcinoma, squamous cell carcinoma, and liver cholangiocarcinoma. 2/9 patients (22.2%) had a documented response to immunotherapy and 3/9 patients had documented stability (30%). 8/9 patients had low TMB (