Analytical accuracy and clinical performance of the OncoMate MSI Dx Analysis System in a subset of KEYNOTE-775 endometrial carcinoma classified as MSS (not MSI-H) by the companion diagnostic

Background: Advanced endometrial carcinoma (EC) presents a major clinical challenge, with poor prognosis and few treatment options. Pembrolizumab (KEYTRUDA ® ) in combination with lenvatinib (LENVIMA ® ) has been approved by the FDA for the treatment of adult patients with advanced EC that is mismatch repair proficient (pMMR) or not microsatellite instability high (MSI-H). The OncoMate ® MSI Dx Analysis System is a PCR-based assay for MSI determination in FFPE tumor tissue with custom software for automated analysis. Here, we present analytical accuracy and clinical performance data that supported FDA approval of the OncoMate ® MSI Dx assay as a companion diagnostic (CDx) to identify patients with advanced EC who may benefit from treatment with pembrolizumab plus lenvatinib. Design: Analytical accuracy was assessed retrospectively in 255 EC samples from the KEYNOTE-775 clinical trial by comparing OncoMate ® MSI Dx assay results with a commercially available immunohistochemistry (IHC) panel. Clinical performance was evaluated in a bridging study (n=489) linking MSI status with outcomes from KEYNOTE-775. The efficacy of pembrolizumab plus lenvatinib versus treatment of physician's choice (TPC) was estimated for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), and duration of response (DOR) for the CDx-defined microsatellite stable (MSS; equivalent to not MSI-H) subpopulation. Results: Analytical accuracy was high: agreement between MSS vs pMMR results was 99.0% (95% CI, 96.5-99.7%), agreement between MSI-H vs dMMR results was 91.7% (95% CI, 80.4-96.7%), and overall agreement was 97.6% (95% CI, 95.0-98.9%). In the clinical cohort, patients with MSS tumors identified by the OncoMate ® MSI Dx assay demonstrated significant benefit from pembrolizumab plus lenvatinib versus TPC, with improvements in PFS, OS, ORR, and DOR consistent with published trial results. Conclusion: The OncoMate ® MSI Dx assay was accurate compared with an established IHC orthogonal method and provided complementary information to IHC about tumor MMR status for some patients. The assay, which directly assesses DNA MMR function via microsatellites, retrospectively identified EC patients who would benefit from combination treatment with pembrolizumab plus lenvatinib compared with TPC. Specifically, pembrolizumab plus lenvatinib efficacy in a subset of KEYNOTE-775 participants with CDx-defined MSS (not MSI-H) tumors was comparable to the efficacy observed in all IHC-defined pMMR participants randomized in the original trial. These results support use of the OncoMate ® MSI Dx assay for this indication and validate that PCR- and IHC-based methods identify comparable patient populations who benefit from pembrolizumab plus lenvatinib.