Companion diagnostics for pembrolizumab in patients with dMMR/MSI-H tumors

Pembrolizumab is approved in the US for unresectable or metastatic mismatch repair–deficient (dMMR)/microsatellite instability–high (MSI-H) solid tumors that progressed after prior treatment and with no satisfactory alternative treatment options. As part of post-marketing commitments, pan-tumor bridging studies were conducted, using data from clinical trials that supported pembrolizumab’s initial tumor-agnostic approval, to clinically validate two companion diagnostics (CDx) for identifying patients with dMMR/MSI-H tumors eligible for pembrolizumab treatment. Pembrolizumab efficacy (objective response rate [ORR]) was evaluated by MMR/MSI status determined using CDx (Ventana MMR RxDx Panel and FoundationOne ® CDx) among participants with advanced dMMR/MSI-H tumors, and per clinical trial assay (CTA; immunohistochemistry or polymerase chain reaction), who enrolled in KEYNOTE-158 cohort K (noncolorectal cancer) or KEYNOTE-164 (colorectal cancer). ORR was estimated for participants enrolled in KEYNOTE-158 cohort K and KEYNOTE-164 using statistical methods appropriate for bridging of CTA to CDx. Agreement between CTA and CDx was evaluated by overall percent agreement (OPA), positive percent agreement (PPA), and negative percent agreement (NPA) using tumor samples from participants enrolled in KEYNOTE-158 cohorts A-K, KEYNOTE-164, and KEYNOTE-177, or commercially procured tumor samples with MMR/MSI status evaluated by both CTA and CDx. Overall, 444 participants with dMMR/MSI-H tumors per CTA were included in the efficacy analysis (KEYNOTE-158 cohort K, n = 321; KEYNOTE-164, n = 123). ORR was enriched in participants who also had dMMR/MSI-H tumors per the CDx (Ventana MMR RxDx Panel, 34.7%; FoundationOne CDx, 43.0%), while ORR was 31.8% among all participants with dMMR/MSI-H tumors per the CTA, regardless of MMR/MSI status by either of the two CDx. When the CTA and Ventana MMR RxDx Panel ( n = 934) were compared, OPA was 90.9%, PPA was 72.0%, and NPA was 98.5%. When the CTA and FoundationOne CDx ( n = 1174) were compared, OPA was 94.5%, PPA was 69.8%, and NPA was 99.3%. When Ventana MMR RxDx Panel and FoundationOne CDx ( n = 662) were compared, OPA was 95.9%, PPA was 79.8%, and NPA was 98.3%. Ventana MMR RxDx Panel and FoundationOne CDx demonstrated high agreement with each other and, when compared with the CTA, both were able to identify participants with dMMR/MSI-H tumors likely to respond to pembrolizumab. ClinicalTrials.gov, NCT02628067, NCT02460198, NCT02563002.