Keytruda is now approved for adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) mutations/megabase] solid tumors.- Merck inc.

Merck Inc., announced that the FDA has approved Keytruda, Merck’s anti-PD-1 therapy, as monotherapy for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [ greater than 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.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of Keytruda in pediatric patients with TMB-H central nervous system cancers have not been established.

“For the second time, Keytruda monotherapy is now approved based on a biomarker rather than the location in the body where the tumor originated,” said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. “TMB-H, defined as 10 mutations per megabase or more, can help identify patients most likely to benefit from Keytruda. We’re pleased that our collaborative efforts to advance biomarker research have resulted in our ability to provide a new treatment option that addresses a high unmet medical need for these patients with cancer.”

Data Supporting the Approval : The accelerated approval was based on data from a prospectively-planned retrospective analysis of 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors with TMB-H, who were enrolled in KEYNOTE-158 (NCT02628067), a multicenter, non-randomized, open-label trial evaluating Keytruda (200 mg every three weeks). The trial excluded patients who previously received an anti-PD-1 or other immune-modulating monoclonal antibody, or who had an autoimmune disease, or a medical condition that required immunosuppression. TMB status was assessed using the FoundationOne CDx assay and pre-specified cutpoints of greater than 10 and greater than 13 mut/Mb, and testing was blinded with respect to clinical outcomes. Tumor response was assessed every nine weeks for the first 12 months and every 12 weeks thereafter.

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) in the patients who received at least one dose of Keytruda as assessed by blinded independent central review (BICR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

In KEYNOTE-158,: 1,050 patients were included in the efficacy analysis population. TMB was analyzed in the subset of 790 patients with sufficient tissue for testing based on protocol-specified testing requirements. Of the 790 patients, 102 (13%) had tumors identified as TMB-H, defined as TMB greater than 10 mut/Mb. The study population characteristics of these 102 patients were: median age of 61 years (range, 27 to 80); 34% age 65 or older; 34% male; 81% White; and 41% Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 and 58% ECOG PS of 1. Fifty-six percent of patients had at least two prior lines of therapy.

In the 102 patients whose tumors were TMB-H, Keytruda demonstrated an ORR of 29% (95% CI, 21-39), with a complete response rate of 4% and a partial response rate of 25%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months). Among the 30 responding patients, 57% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. In a pre-specified analysis of patients with TMB greater than 13 mut/Mb (n=70), Keytruda demonstrated an ORR of 37% (95% CI, 26-50), with a complete response rate of 3% and a partial response rate of 34%. After a median follow-up time of 11.1 months, the median DOR had not been reached (range, 2.2+ to 34.8+ months).

Among the 26 responding patients, 58% had ongoing responses of 12 months or longer, and 50% had ongoing responses of 24 months or longer. In an exploratory analysis in 32 patients whose cancer had TMB greater than 10 mut/Mb and less than 13 mut/Mb, the ORR was 13% (95% CI, 4-29), including two complete responses and two partial responses. The median duration of exposure to Keytruda was 4.9 months (range, 0.03 to 35.2 months). The most common adverse reactions for Keytruda (reported in ?20% of patients) were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain and abdominal pain.