Use of cancer immunotherapies in the real-world in the setting of microsatellite instability

Background:In May 2017, the FDA approved for the first time a cancer therapy (pembrolizumab) for use in patients based on the presence of a genomic marker (microsatellite instability, or MSI) rather than anatomical tumor type. Real-world data on the rates and clinical impact of MSI on treatment selection and response are scant, especially outside of colorectal cancer.Methods:We performed a retrospective study of all patients treated in the Flatiron Health network (>265 oncology practices across the U.S.) between January 2011 and June 2017, and who underwent FoundationOne tumor sequencing as part of routine clinical care. Tumor type was determined by pathologist review of specimens submitted to Foundation Medicine. Data on therapy use was sourced from electronic health records (EHRs). Assessment of MSI was performed from DNA sequencing across the coding regions of >300 genes.Results:Our overall cohort included n=16,020 patients. Among patients in whom MSI status could be assessed (n=12,411), 207 patients had MSI-high tumors. The observed rate of MSI-high was 1.7% across all tumor types combined; tumor-specific rates varied significantly, from 4.9% in colorectal adenocarcinoma to 0.3% in breast and non-small cell lung cancer. The rate of MSI-high was 2.4% in patients with an unknown primary based on specimen review. A total of 1,329 patients received common checkpoint inhibitors (nivolumab, pembrolizumab, atezolizumab). Among the checkpoint-inhibitor treated patients with known MSI status (n=1,175), 14 (1.2%) had MSI-high tumors, and the majority of these patients (n=8) had colorectal cancer.Conclusions:Evidence of MSI-high is rare in real world cancer care settings. Early identification of patients with this biomarker is important in order to efficiently match them to treatment. Further evaluation of the real-world effectiveness of immune checkpoint inhibitors in the MSI-high population is still needed. Because most patients receiving these therapies today do not have high MSI, exploration of additional biomarkers for immunotherapy response is also critical.