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. 2024 Sep 14;8(1):204.
doi: 10.1038/s41698-024-00679-7.

Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab

Douglas I Lin  1 , Julia C F Quintanilha  2 , Natalie Danziger  2 , Lixin Lang  3 , Diane Levitan  3 , Cynthia Hayne  4 , Matthew C Hiemenz  2 , David L Smith  2 , Lee A Albacker  2 , Jeffrey Leibowitz  2 , Douglas A Mata  2 , Brennan Decker  2 , Sotirios Lakis  5 , Nimesh R Patel  2 , Ryon P Graf  2 , Julia A Elvin  2 , Jeffrey S Ross  2 , Varun Pattani  2 , Richard S P Huang  2 , Amy K Wehn  3
Affiliations

Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab

Douglas I Lin et al. NPJ Precis Oncol. .

Abstract

Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis. Across solid tumor types, F1CDx demonstrated a high analytical concordance with both PCR (n = 264) and IHC (n = 279) with an overall percent agreement (OPA) of 97.7% and 97.8%, respectively. As part of a retrospective bridging clinical study from KEYNOTE-158 Cohort K and KEYNOTE-164, patients with MSI-H tumors as determined by F1CDx demonstrated an objective response rate (ORR) of 43.0% to pembrolizumab. In real-world cancer patients from a deidentified clinicogenomic database, F1CDx was at least equivalent in assessing clinical outcome following immunotherapy compared with MMR IHC. Demonstrated analytical and clinical performance of F1CDx led to the pan-tumor FDA approval in 2022 of F1CDx to identify MSI-H solid tumor patients for treatment with pembrolizumab. F1CDx is an accurate, reliable, and FDA-approved method for the identification of MSI-H tumors for treatment with pembrolizumab.

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Conflict of interest statement

The authors declare the following competing interests: D.I.L., J.C.F.Q., N.D., M.C.H., D.L.S., L.A.A., J.L., D.A.M., B.D., S.L., N.R.P., R.P.G., J.A.E., J.S.R., V.P., and R.S.P.H. are employed by Foundation Medicine, Inc., a wholly-owned subsidiary of Roche, and are stockholders of Roche. L.L., D.L., and A.K.W. are full-time employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, and hold stock and/or restricted stock units in Merck & Co., Inc., Rahway, NJ, USA.

Figures

Fig. 1
Fig. 1. Representative MMR IHC stains for MSS and MSI-H tumors as determined by F1CDx FB-MSI.
A–E High-grade EMCA (A) in a 73-year-old woman showing intact MSH2 (B), MSH6 (C), MLH1 (D), PMS2 (E) expression by IHC. This tumor was MSS by F1CDx. F–J Endometrioid EMCA (F) in an 80-year-old woman showing intact MSH2 (G), MSH6 (H), and loss of MLH1 (I) and PMS2 (J) expression by IHC with internal positive controls (lymphocytes and stromal cells). This tumor was MSI-H by F1CDx. Scale bar = 0.1 mm.
Fig. 2
Fig. 2. Clinical validity of F1CDx FB-MSI in real world samples.
A mCRC patients (n = 246): Time To Next Treatment (TTNT) and Time To Treatment Discontinuation (TTD) of patients treated with immunotherapy. B EMCA patients (n = 105): Time to Next Treatment and Time to Treatment Discontinuation of patients treated with immunotherapy.
Fig. 3
Fig. 3. Proposed algorithm for determining eligibility for immunotherapy in advanced, metastatic or recurrent solid tumors via the validated NGS-based F1CDx assay to detect MSI-H status.
NGS, next-generation sequencing; CGP, comprehensive genomic profiling; dMMR, mismatch repair-deficient; pMMR, mismatch repair-proficient; MSI-H, microsatellite instability-high; MSS, microsatellite stable; TMB, tumor mutational burden; TMB-H, high TMB.
See this image and copyright information in PMC

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