Aurélien Marabelle, MD at Gustave Roussy discusses the FDA Approval of Second Biomarker-Based Indication for Pembrolizumab (KEYTRUDA)
The FDA issued accelerated clearance, regardless of tumor type, for the second biomarker-based indication for Merck’s Keytruda (pembrolizumab) anti-PD-1 therapy. The therapy is now indicated for adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) (≥10 mutations / megabase) solid tumors (determined by an FDA-approved test) that progressed after previous treatment and for which there are no appropriate alternative therapies.
Pembrolizumab enhances the body’s immune system’s ability to help recognize and kill tumor cells by blocking the interaction between the programmed cell death protein 1 ( PD-1) and its ligands, PD-L1 and PD-L2. This stimulates T lymphocytes which can affect tumor as well as healthy cells. Due to the high number of mutations present in tumors with TMB-H, they are easier to recognise for the immune system, and thus may be more likely to respond to some immunotherapies.
The accelerated approval is focused on tumor response rate and response durability, as demonstrated in a prospectively expected retrospective review of 10 patient cohorts enrolled in the KEYNOTE-158 study. In patients with many previously treated unresectable or metastatic solid tumors with TMB-H, the non-randomized, multicenter, open-label trail assessed the effects of 200 mg of pembrolizumab every 3 weeks.
Pembrolizumab demonstrated an objective response rate of 29 percent (95 percent CI, 21-39), a total response rate of 4 percent and a partial response rate of 25 percent in 102 patients whose tumors were TMB-H. Researchers found that “57 percent of the 30 responding patients had ongoing responses of 12 months or longer, and 50 percent had continuous responses of 24 months or longer.”
FoundationOne CDx, a diagnostic companion to pembrolizumab, was also approved today by the FDA as the only approved diagnostic companion for measuring TMB. A robust genomic profiling assay (GPA) helps to classify patients who fulfill the criteria for pembrolizumab therapy and are available for prescription use only. The diagnosis explicitly describes TMB, a measure of the number of somatic mutations per coding area within the genome of a tumor. The KEYNOTE-158 trial included a FoundationOne CDx-based clinical trial assay to assess TMB status for the tumor tissue.
Continued approval for the indication of pembrolizumab may be subject to confirmatory results from the trial, including verification evidence and a summary of clinical benefits. Furthermore, “the protection and efficacy of Keytruda has not been proven in pediatric patients with TMB-H central nervous system cancer.”
Potentially serious or fatal immune-mediated adverse reactions, such as pneumonitis, colitis and hepatitis, can occur when pembrolizumab is used, among other conditions. There can also be serious or life-threatening reactions to the infusion. Fatigue, musculoskeletal discomfort, reduced appetite, among others, were the most common side effects identified by KEYNOTE-158 trial participants.