Background Pembrolizumab is approved in the United States for unresectable or metastatic microsatellite instability-high (MSI-H)/mismatch repair–deficient (dMMR) solid tumors that progress after treatment. As part of a post-marketing commitment, we conducted a pan-tumor bridging study to determine MSI/MMR status for the purpose of developing 2 companion diagnostic assays. This bridging study was designed to evaluate clinical outcomes with second-line pembrolizumab and concordance with local enrollment assays. Concordance between the 2 companion diagnostic assays was also assessed.

Methods Patients with MSI-H/dMMR tumors, determined per local clinical trial assay (IHC, PCR, or NGS), who enrolled in the KEYNOTE-164 study (advanced colorectal cancer) or cohort K of the KEYNOTE-158 study (advanced non-colorectal cancer) were reevaluated for pembrolizumab efficacy (objective response rate [ORR] per RECIST v1.1) according to MSI/MMR status determined by companion diagnostic assays (Roche Tissue Diagnostics MMR RxDx Panel [RTD; IHC using MLH1, MSH2, MSH6, PMS2] and FoundationOne^®CDx [NGS]). Agreement between the clinical trial assay and companion diagnostic assays was evaluated by overall percent agreement (OPA), positive percent agreement (PPA), and negative percent agreement (NPA) using the efficacy population; a supplemental population (KEYNOTE 158 cohorts A-J, KEYNOTE-177, and commercially procured tumor bank) was also used to assess NPA.

Results 444 patients with MSI-H/dMMR tumors per the clinical trial assay were analyzed for efficacy (n = 123, KEYNOTE-164; n = 321, KEYNOTE-158 cohort K). ORR is reported in table 1; responses were enriched in patients with MSI-H/dMMR tumors (RTD assay: 34.7%; FoundationOne CDx: 43.0%; clinical trial assay: 31.8%). When the clinical trial assay and RTD assay (n = 934) were compared, OPA was 90.9%, PPA was 72.0%, and NPA was 98.5%. When the clinical trial assay and FoundationOne CDx assay (n = 1174) were compared, OPA was 94.5%, PPA was 69.8%, and NPA was 99.3%. When the RTD and FoundationOne CDx assays (n = 662) were compared, OPA was 95.9%, PPA was 87.0%, and NPA was 97.1%.

Conclusions Although the RTD and FoundationOne CDx assays measure different analytes, they are comparable for the selection of patients with MSI-H/dMMR tumors likely to respond to pembrolizumab. Despite both companion diagnostic assays having lower concordance to the clinical trial assay, they demonstrated high concordance with each other and were able to better identify responders to pembrolizumab than the clinical trial assay.

Acknowledgements Medical writing and/or editorial assistance was provided by Holly C. Cappelli, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Ethics Approval The study protocol and all amendments were approved by the relevant institutional review board or ethics committee at each study site.

Consent All patients provided written informed consent to participate in the clinical trial.