The Food and Drug Administration (FDA) has granted accelerated approval to Keytruda® (pembrolizumab; Merck) as monotherapy 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. Continued approval for this indication may be contingent upon verification of benefit in a confirmatory trial.

The accelerated approval was based on data from a prospectively-planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors with TMB-H who were enrolled in the open-label phase 2 KEYNOTE-158 trial. Patients received pembrolizumab 200mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression. 

The main efficacy outcome measures were overall response rate (ORR) and duration of response (DoR) in patients who had received at least 1 dose of pembrolizumab as assessed by blinded independent central review according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Among the 102 patients who had tumors identified as TMB-H, the ORR was 29% (95% CI, 21-39); 4% of patients achieved a complete response while 25% had a partial response. Findings showed that the median DoR had not been reached after a follow-up of 11.1 months. Among the 30 responders, 57% had response durations ≥12 months and 50% had response durations ≥24 months. Moreover, among 32 patients with TMB ≥10 mut/Mb and <13 mut/Mb, the ORR was found to be 13% (95% CI, 4-29), with 2 complete responses and 2 partial responses.

The safety profile of pembrolizumab in patients with TMB-H was found to be similar to that seen in other pembrolizumab trials involving solid tumors. The most common adverse reactions (≥20%) included fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. 

The safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.

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“It’s great to see the use of innovative biomarkers and immunotherapy come together with this approval and encouraging that we now have an option for patients with TMB-H tumors across cancer types, including rare cancers,” said Roy S. Herbst, MD, PhD, ensign professor of medicine (medical oncology) and professor of pharmacology, Yale School of Medicine; chief of medical oncology, Yale Cancer Center and Smilow Cancer Hospital; and associate cancer center director for translational research, Yale Cancer Center.

Additionally, the FDA approved the FoundationOne® CDx (Foundation Medicine) test as the companion diagnostic for Keytruda to identify patients with solid tumors that are TMB-H (≥10 mutations/ megabase).

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