FDA Grants Full Approval to Pembrolizumab for Patients With Tumor Mutational Burden-High Solid Tumors

Clinical Summary: 

• Regulatory Update: The FDA granted traditional approval to pembrolizumab and pembrolizumab plus berahyaluronidase alfa for adult and pediatric patients with previously treated, unresectable or metastatic tumor mutational burden (TMB)-high solid tumors with no satisfactory alternative treatment options. The approval increases the TMB threshold from at least 10 to at least 13 mutations per megabase. 
• Key Outcomes: This conversion was based on results from the KEYNOTE-158 trial, which demonstrated an objective response rate of 36% among patients with TMB of at least 13 mutations per megabase, with 58% of responders maintaining their response for at least 12 months. Efficacy supporting traditional approval was not confirmed in patients with TMB between 10 and less than 13 mutations per megabase. 
• Clinical Relevance: This approval maintains pembrolizumab as a treatment option across eligible patients with solid tumor types while narrowing the biomarker-defined population. The revised threshold underscores the importance of accurate TMB testing when determining patient eligibility.

The US Food and Drug Administration (FDA) has approved pembrolizumab (Keytruda; Merck) and pembrolizumab plus berahyaluronidase alfa (Keytruda Qlex; Merck) for adult and pediatric patients with previously untreated, unresectable or metastatic tumor mutational burden (TMB)-high solid tumors, while revising the biomarker threshold used to determine treatment eligibility. 

The October 16, 2026, decision converts the previous accelerated approval of pembrolizumab to traditional approval and increases the TMB threshold to from at least 10 mutations per megabase to at least 13 mutations per megabase, as determined by an FDA-authorized test. 

The revised indication applies to patients whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options. The FDA determined that the available efficacy evidence did not support traditional approval for patients with TMB between 10 and less than 13 mutations per megabase,

This approval was supported by findings from the KEYNOTE-158 trial, which evaluated pembrolizumab in 220 patients with previously treated unresectable or metastatic solid tumors. 

The efficacy analysis included 2 patient populations. Cohort M prospectively enrolled 145 patients with TMB-high tumors that were not microsatellite instability-high (MSI-H), while Cohorts A through J included 75 patients with TMB-high disease identified across a prospectively planned retrospective analysis across multiple solid tumor cohorts. 

Patients in Cohorts A through J received 200 mg of pembrolizumab every 3 weeks, while patients in Cohort M received 400 mg of pembrolizumab intravenously every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity. The primary end points were objective response rate (ORR) and duration of response, as assessed via blinded independent central review according to modified RECIST v1.1.

At analysis, the ORR was 36%. Among patients who achieved a response, 58% maintained their response for at least 12 months.

These findings supported the conversion to traditional approval for patients meeting the updated TMB threshold. However, efficacy was not confirmed in patients with TMB between 10 and less than 13 mutations per megabase, resulting in a narrower biomarker-defined indication.

The safety profile of pembrolizumab monotherapy in this population was consistent with previously established findings. 

The recommended adult dose of pembrolizumab monotherapy is 200 mg administered intravenously every 3 weeks or 400 mg intravenously every 6 weeks until disease progression, unacceptable toxicity, or for a maximum treatment duration of 24 months.

 For pediatric patients, the recommended dose is 2 mg/kg administered intravenously every 3 weeks, up to a maximum dose of 200 mg, until disease progression, unacceptable toxicity, or a maximum of 24 months.

Dosing and administration of pembrolizumab plus berahyaluronidase alfa should follow the product-specific prescribing information.

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.

Source: 

US Food and Drug Administration. FDA grants traditional approval for pembrolizumab or pembrolizumab and berahyaluronidase alfa-pmph for unresectable or metastatic TMB-H solid tumors with updated indication. Accessed on: October 22, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pembrolizumab-or-pembrolizumab-and-berahyaluronidase-alfa-pmph