KEYTRUDA is a programmed death receptor-1 (PD-1)-blocking antibody indicated:...for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.

...the U.S. Food and Drug Administration (FDA) has accepted and granted priority review for a new supplemental Biologics License Application (sBLA) for KEYTRUDA, Merck’s anti-PD-1 therapy. The application seeks accelerated approval of KEYTRUDA monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors with tissue tumor mutational burden-high (TMB-H) ≥10 mutations/megabase...

...- Confirmation of high mutation burden by whole genome/exome sequencing performed in a CLIA-certified laboratory and/or the use of Foundation One next generation sequence panel or another CLIA approved targeted sequencing lab with publicly available correlations between number of mutations found in the panel and mutations per megabase and/or genome; for protocol purposes a high mutation burden will be defined as at least 180 non-synonymous coding-region mutations by whole exome/genome sequencing (well above two standard deviations of the number of median similar mutations described in pediatric CNS cancers) AND/OR a high tumor mutation burden (TMB) or intermediate TMB based on the reporting parameters of the panel; TMB parameters provided for the...

...- Any advanced solid tumor that has failed at least one line of therapy and is TMB-H (≥10 mut/Mb, F1CDx assay), excluding dMMR/MSI-H tumors....

...Consistent with high tumor mutation load TMB-H (≥10 mutations/megabases) 3....

...Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors and Other Lymphoma Version 1.1 (RECIST 1.1) per Site Assessment (Each Disease Indication Evaluated Separately)`ORR by RECIST 1.1 per Site Assessment for MSI-H or TMBH Solid Tumors (Each Cohort Evaluated Separately)`ORR by International Working Group (IWG) Response Criteria (Cheson, 2007) per BICR Assessment for rrcHL Cohort`Number of Participants with Dose-Limiting Toxicities (DLTs)`Number of Participants Experiencing Adverse Events (AEs)`Number of Participants Discontinuing Study Drug Due to AEs...

...TMB was associated with ORR (p≤0.016), PFS (p≤0.005), and OS (p≤0.029) of pembrolizumab...TMB ≥175 mutations/exome is associated with clinically meaningful improvement in the efficacy of pembrolizumab monotherapy and improved outcomes for pembrolizumab versus chemotherapy across a wide range of previously treated advanced solid tumor types.

Objective responses were observed in 30 (29%; 95% CI 21–39) of 102 patients in the tTMB-high group and 43 (6%; 5–8) of 688 in the non-tTMB-high group. tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy.

A T-cell–-inflamed GEP, PD-L1 expression, and TMB predicted response to pembrolizumab in multiple tumor types.