FDA Grants Traditional Approval to Pembrolizumab in TMB-High Solid Tumors

The FDA has granted traditional approval to pembrolizumab (Keytruda) or pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) for adult and pediatric patients with unresectable or metastatic tumor mutational burden–high (TMB-H) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.¹ The approval, granted on October 16, 2026, requires that TMB-H status be determined by an FDA-authorized test.

The action converts the previous accelerated approval to traditional approval and amends the indication to define TMB-H as ≥13 mutations/megabase (mut/Mb). Under the accelerated approval, TMB-H was defined as ≥10 mut/Mb. The FDA stated that efficacy to support traditional approval was not confirmed in patients with a TMB of 10 to <13 mut/Mb.

Study Design

Efficacy was evaluated in 2 groups of patients in KEYNOTE-158 (NCT02628067). Cohort M prospectively enrolled patients with TMB-H tumors that were not microsatellite instability–high (MSI-H). Cohorts A through J comprised a prospectively planned retrospective analysis of patients with TMB-H tumors identified within 10 cohorts of patients with various previously treated unresectable or metastatic solid tumors.

Patients in cohorts A through J received pembrolizumab 200 mg every 3 weeks, and patients in cohort M received pembrolizumab 400 mg intravenously every 6 weeks, each until unacceptable toxicity or documented disease progression.

Efficacy Results

The major efficacy outcome measures were objective response rate (ORR) and duration of response (DOR) in 220 patients with tumors with a TMB of ≥13 mut/Mb who received at least 1 dose of pembrolizumab: 145 in cohort M and 75 in cohorts A through J. Responses were assessed by blinded independent central review per RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Across both groups, the ORR was 36% (95% CI, 30-43), and 58% of patients had a DOR of at least 12 months.

Safety Profile

The safety profile of pembrolizumab monotherapy for the updated indication was consistent with the known safety profile of the agent. 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.

Dosing and Administration

For the updated indication, the recommended dose of pembrolizumab monotherapy is 200 mg every 3 weeks or 400 mg every 6 weeks in adults, continued until disease progression, unacceptable toxicity, or up to 24 months. Pediatric patients should receive 2 mg/kg every 3 weeks, up to a maximum of 200 mg, using the same treatment duration limits. Dosing and administration information for pembrolizumab and berahyaluronidase alfa-pmph is available in its prescribing information.

The FDA review used the Assessment Aid, a voluntary submission from the applicant intended to facilitate the agency’s assessment.

Prior Regulatory History

The FDA granted accelerated approval to pembrolizumab on June 16, 2020, for adult and pediatric patients with unresectable or metastatic TMB-H solid tumors, defined as ≥10 mut/Mb, that had progressed following prior treatment and had no satisfactory alternative treatment options.² That approval was based on KEYNOTE-158 data in 102 patients with TMB-H tumors, in whom the ORR was 29% (95% CI, 21-39) and 57% of responses lasted at least 12 months. The FoundationOne CDx assay was identified as the companion diagnostic.

The subcutaneous formulation, pembrolizumab and berahyaluronidase alfa-pmph, was approved on September 19, 2025, for adult and pediatric patients 12 years and older across the solid tumor indications approved for intravenous pembrolizumab.³

REFERENCES

1. FDA grants traditional approval for pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph for unresectable or metastatic TMB-H solid tumors with updated indication. News release. FDA. October 16, 2026. Accessed October 22, 2026. https://tinyurl.com/mr287hdp

2. FDA approves pembrolizumab for adults and children with TMB-H solid tumors. News release. FDA. June 16, 2020. Accessed October 22, 2026. https://tinyurl.com/uwx4px28

2. FDA approves pembrolizumab and berahyaluronidase alfa-pmph for subcutaneous injection. News release. FDA. September 19, 2025. Accessed October 22, 2026. https://tinyurl.com/yhduvdba