Prevalence of microsatellite instability and association with pembrolizumab (p) usage in a real-world clinico-genomic database

Background:In May 2017, the FDA approved for the first time a cancer therapy (P) for use in patients based on the presence of a genomic marker (microsatellite instability-high, or MSI-H) instead of tissue of origin. The real-world prevalence of MSI-H and the impact of the FDA approval on P treatment patterns is not well characterized.Methods:We performed a retrospective study of patients in the Flatiron Health (FH) network ( > 265 oncology practices across the U.S) from Jan 2011 to Sept 2017, who received FoundationOne tumor sequencing as part of routine clinical care. Tumor type was determined by pathologist review of specimens sent to Foundation Medicine. Treatment data was curated from FH's electronic health record-derived database. MSI was assessed using DNA sequencing across 395 genes. Fisher’s exact test was used for statistical comparisons of P use after FDA approval in MSI-H v. non-MSI-H patients and P use in MSI-H patients pre- and post- FDA approval.Results:Among patients with known MSI status (n = 14,944), 251 (1.7%) had MSI-H tumors. Tumor-specific rates of MSI-H varied by histology: 14.2% in endometrial cancer, 5.5% in colorectal cancer (CRC), 5.2% in other gastrointestinal (GI) cancers, and < 0.5% in breast and non-small cell lung cancer. Among the 34 MSI-H patients treated with P, CRC was the most common tumor type (35.3%), followed by stomach cancer (17.6%), and > 10 others. Among immune checkpoint inhibitor (ICPI)-naive patients with tumor types in which P was not indicated prior to the MSI-H approval, usage post-approval was higher in MSI-H patients (5.2%) than non-MSI-H patients (0.6%) (OR = 9.8; 95% CI 4.6-19.2; p < 0.001). Among MSI-H patients, we found no evidence that rates of first exposure to P differed 4 months pre- v. post-approval (13.4 v. 18.1% ; p = 0.5).Conclusions:Evidence of MSI-H is rare outside of endometrial, CRC, and GI cancers. Among tumor types in which P was approved only for MSI-H patients, usage was higher in MSI-H v. non-MSI-H patients post-approval. Longer follow up will determine the extent and trajectory of adoption, and additional clinical outcome data will characterize the effectiveness of ICPI agents among MSI-H patients treated in routine practice.