FDA Approves Pembrolizumab for Adults and Children With Tumor Mutational Burden–High Solid Tumors

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On June 16, the U.S. Food and Drug Administration (FDA) granted accelerated approval to pembrolizumab (Keytruda) 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 FDA also approved the FoundationOneCDx assay as a companion diagnostic for pembrolizumab.


Efficacy was investigated in a prospectively planned retrospective analysis of 10 cohorts of patients with various previously treated unresectable or metastatic TMB-H solid tumors enrolled in the multicenter, nonrandomized, open-label KEYNOTE-158 trial. Patients received pembrolizumab at 200 mg intravenously every 3 weeks until unacceptable toxicity or documented disease progression.

The main efficacy outcome measures were overall response rate and duration of response in patients who had received at least one dose of pembrolizumab as assessed by blinded independent central review according to Response Evaluation Criteria in Solid Tumors version 1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.


A total of 102 patients (13%) had tumors identified as TMB-H; the overall response rate for these patients was 29% (95% confidence interval = 21%–39%), with a 4% complete response rate and 25% partial response rate. The median duration of response was not reached, with 57% of patients having response durations ≥ 12 months and 50% of patients having response durations ≥ 24 months.

Adverse reactions occurring in patients with TMB‑H tumors enrolled in KEYNOTE-158 were similar to those occurring in patients with other solid tumors who received pembrolizumab as a single agent. The most common adverse reactions to pembrolizumab are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain. Pembrolizumab is associated with immune-mediated side effects including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and skin adverse reactions.

The prescribing information for pembrolizumab includes a “Limitation of Use” stating that the safety and effectiveness of pembrolizumab in pediatric patients with TMB-H central nervous system cancers have not been established.

The recommended pembrolizumab dosage regimen for adult patients with TMB-H solid tumors is 200 mg every 3 weeks or 400 mg every 6 weeks; for pediatric patients, the recommended regimen is 2 mg/kg (up to a maximum of 200 mg) every 3 weeks.