The US Food and Drug Administration (FDA) has raised the tumor mutational burden (TMB) threshold for pembrolizumab (Keytruda) and pembrolizumab/berahyaluronidase alfa-pmph (Keytruda Qlex) from 10 to 13 mutations per megabase (mut/Mb), narrowing eligibility for patients with previously treated advanced solid tumors.
The decision converts the previous accelerated approval to traditional approval for adults and pediatric patients with unresectable or metastatic TMB-high (TMB-H) solid tumors that have progressed following prior treatment and for whom no satisfactory alternative treatment options exist. TMB status must be determined using an FDA-authorized test.
The FDA revised the threshold because efficacy supporting traditional approval was not confirmed in patients with TMB levels of 10 to less than 13 mut/Mb.
The decision was supported by KEYNOTE-158, a multicohort, nonrandomized phase 2 trial evaluating pembrolizumab in previously treated unresectable or metastatic solid tumors. Cohort M prospectively enrolled patients with TMB-H tumors that were not microsatellite instability-high (MSI-H), while cohorts A through J contributed a prospectively planned retrospective analysis of patients with TMB-H tumors across 10 tumor-specific cohorts.
The efficacy population included 220 patients with TMB levels of at least 13 mut/Mb who received at least 1 dose of pembrolizumab, including 145 patients in cohort M and 75 in cohorts A through J. There was no randomized comparator.
The primary efficacy measures were objective response rate and duration of response, assessed by blinded independent central review using modified RECIST version 1.1 criteria.
Across both groups, the objective response rate was 36%, and 58% of responders maintained their response for at least 12 months.
Patients in cohorts A through J received intravenous pembrolizumab 200 mg every 3 weeks, while cohort M received 400 mg every 6 weeks until disease progression or unacceptable toxicity.
The FDA reported that the safety profile remained consistent with that previously established for pembrolizumab monotherapy. Prescribing information includes warnings for immune-mediated adverse reactions, infusion-related reactions, complications following allogeneic hematopoietic stem cell transplantation, and embryo-fetal toxicity.
For the updated indication, the recommended intravenous dose is 200 mg every 3 weeks or 400 mg every 6 weeks in adults, and 2 mg/kg every 3 weeks in pediatric patients, up to 200 mg per dose. Treatment continues until disease progression, unacceptable toxicity, or a maximum of 24 months for adult and pediatric patients.
Dosing for the subcutaneous pembrolizumab/berahyaluronidase alfa-pmph formulation is provided separately in its prescribing information.
Source: FDA