FDA Converts Keytruda TMB-High Cancer Indication to Traditional Approval

FDA granted traditional approval to Merck’s Keytruda (pembrolizumab) and Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph) for certain patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors, while raising the biomarker threshold used to determine eligibility for treatment.

The approval covers adult and pediatric patients whose tumors have a TMB of at least 13 mutations per megabase (mut/Mb), as determined by an FDA-authorized test, whose disease has progressed following prior treatment and who have no satisfactory alternative treatment options.

Keytruda had gained accelerated approval in 2020 for patients with TMB-H solid tumors defined as having at least 10 mut/Mb. FDA said the conversion to traditional approval was accompanied by a narrower indication because clinical benefit was not confirmed in patients whose tumors had TMB levels between 10 and less than 13 mut/Mb.

The decision is significant because it converts a tumor-agnostic accelerated approval to traditional approval while tightening the biomarker cutoff used to identify eligible patients.

The approval was supported by efficacy data from 220 patients enrolled in the KEYNOTE-158 trial whose tumors had TMB levels of at least 13 mut/Mb, according to FDA. Patients in Cohorts A through J received pembrolizumab 200 mg intravenously every three weeks, while those in Cohort M received 400 mg every six weeks until disease progression or unacceptable toxicity.

Across the two groups, the objective response rate was 36%, with 58% of responding patients maintaining their response for at least 12 months.

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