FDA Approval Summary: Pembrolizumab for the Treatment of Tumor Mutational Burden–High Solid Tumors

Abstract

The FDA approved pembrolizumab on June 16, 2020, 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. FDA granted the approval based on a clinically important overall response rate (29%; 95% confidence interval, 21–39) and duration of response (57% of responses lasting ≥ 12 months) in the subset of patients with TMB-H solid tumors (n = 102) spanning nine different tumor types enrolled in a multicenter single-arm trial (KEYNOTE-158). The efficacy of pembrolizumab was supported by the results of whole-exome sequencing (WES) analyses of TMB in additional patients enrolled across multiple pembrolizumab clinical trials, and a scientific understanding of the effects of PD-1 inhibition. Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed in prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on TMB, and the fourth based on the presence of a biomarker rather than the primary site of origin.

A Novel Mitochondrial-Related Nuclear Gene Signature Predicts Overall Survival of Lung Adenocarcinoma Patients

“…Based on these features, it is indicated that LUAD patients with high NMGs signature may benefit more from immune checkpoint inhibitors (Lucibello et al, 2021). In concordance with a more inflamed tumor microenvironment, tumor mutation counts (also known as tumor mutation burden, TMB) level was significantly higher in the high NMGs signature than in the low group, which has already been granted as an effective biomarker for selecting patients who may respond to pembrolizumab by FDA (Marcus et al, 2021).…”

Combined Assessment of the Tumor–Stroma Ratio and Tumor Immune Cell Infiltrate for Immune Checkpoint Inhibitor Therapy Response Prediction in Colon Cancer

“…Mutational load was defined as the sum of silent and non-silent mutations per megabase (Mb). Using the recently FDA-approved cut-off of 10 mutations per megabase (mut/Mb), the tumors were categorized into a TMB-low (TMB-L, ≤10 mut/Mb) and a TMB-high (TMB-L, >10 mut/Mb) group for further analysis [ 39 ]. As a genomic classifier in the CPTAC validation cohort, we analyzed synonymous and non-synonymous single nucleotide variants (SNV).…”

Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)

“…In 2020, FDA approved PD-1 antibody pembrolizumab for the treatment of TMB-H (TMB >10 mutations/megabase) solid tumors. This approval was based on the results of the KEYNOTE-158 trial ( Marcus et al, 2021 ). Pembrolizumab achieved an overall response rate (ORR) of 29% in TMB-H patients (13%, n = 102).…”