The Priority Review

Approvals

FDA grants traditional approval for pembrolizumab in TMB-H tumors; 36% had an objective response

The FDA granted traditional approval to pembrolizumab for TMB-H solid tumors; the objective response rate was 36% (95% CI: 30, 43) in 220 patients in KEYNOTE-158. The approval defines TMB-H as 13 or more mut/Mb, up from the 10 mut/Mb used in the accelerated approval.

By The Priority Review desk

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The FDA granted traditional approval to pembrolizumab (Keytruda, Merck) and to pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex, Merck) for adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors, defined as 13 or more mutations/megabase (mut/Mb). In KEYNOTE-158, the objective response rate across 220 patients with TMB of 13 mut/Mb or more was 36% (95% CI: 30, 43), the FDA said. The approval converts an accelerated approval that set the TMB-H cutoff at 10 mut/Mb and amends the indication to the 13 mut/Mb definition.

Why it matters

Previously, pembrolizumab received accelerated approval for adult and pediatric patients with unresectable or metastatic TMB-H solid tumors, with TMB-H defined as 10 or more mut/Mb, the FDA said. The new approval converts that accelerated approval to traditional approval and defines TMB-H as 13 or more mut/Mb. The FDA said efficacy to support traditional approval was not confirmed in patients with TMB of 10 to <13 mut/Mb. On its Accelerated Approval Program page, the FDA says it grants traditional approval for a drug when the confirmatory trial shows that the drug provides a clinical benefit.

Approval and efficacy figures

The FDA gave October 16, 2026 as the date of the approval. The FDA listed objective response rate (ORR) and duration of response (DOR) as the major efficacy outcome measures, assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of five target lesions per organ.

  • Patients with TMB of 13 mut/Mb or more who received at least one dose of pembrolizumab: 220
  • ORR across both groups: 36% (95% CI: 30, 43)
  • Patients with a DOR of 12 months or more: 58%

Approval for patients

The indication covers adult and pediatric patients with unresectable or metastatic TMB-H solid tumors, as determined by an FDA-authorized test. The FDA said the tumors must have progressed following prior treatment and the patients must have no satisfactory alternative treatment options. The agency defines TMB-H for this indication as 13 or more mut/Mb.

Efficacy and cohorts

The FDA said efficacy was evaluated in two groups of patients in KEYNOTE-158 (NCT02628067).

  • Cohort M prospectively enrolled patients with tumors that were TMB-H and not microsatellite instability-high (MSI-H). Cohort M contributed 145 of the 220 patients.
  • Cohorts A through J consisted of a prospectively planned retrospective analysis of patients with TMB-H tumors identified within 10 cohorts (A through J) of patients with various previously treated unresectable or metastatic solid tumors. Cohorts A through J contributed 75 of the 220 patients.

Patients in Cohorts A-J received pembrolizumab 200 mg every three weeks. Patients in Cohort M received pembrolizumab 400 mg intravenously every six weeks. Patients stayed on treatment until unacceptable toxicity or documented disease progression.

The FDA said the safety profile of pembrolizumab monotherapy for the updated indication was consistent with the known safety profile of pembrolizumab monotherapy. The prescribing information includes warnings and precautions for immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.

The recommended dose of pembrolizumab monotherapy for the updated indication is 200 mg every three weeks or 400 mg every six weeks until disease progression, unacceptable toxicity, or up to 24 months. For pediatric patients the recommended dose is 2 mg/kg every three weeks (up to a maximum of 200 mg) until disease progression, unacceptable toxicity, or up to 24 months. For dosage and administration information for pembrolizumab and berahyaluronidase alfa-pmph, the FDA refers readers to its prescribing information.

Full prescribing information

The FDA said the full prescribing information for Keytruda and Keytruda QLEX will be posted on Drugs@FDA. The agency said this review used the Assessment Aid, a voluntary submission in which the applicant sets out its data to help the FDA's assessment.

Sources