Merck Gains Traditional FDA Approval for Pembrolizumab

A tightened biomarker threshold now defines who qualifies for pembrolizumab in TMB-H solid tumors, and the shift carries direct consequences for companion diagnostic workflows and patient eligibility protocols. On October 16, 2026, the FDA converted Merck's accelerated approval for pembrolizumab (Keytruda) and the subcutaneous co-formulation pembrolizumab and berahyaluronidase alfa-pmph (Keytruda Qlex) to traditional approval for unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors, redefining TMB-H upward from ≥10 to ≥13 mutations/megabase (mut/Mb).

The revision is not cosmetic. Efficacy to support traditional approval was not confirmed in patients with TMB scores of 10 to <13 mut/Mb, meaning a population previously eligible under accelerated approval no longer meets the indication threshold. Regulatory affairs teams managing labeling, companion diagnostic authorizations, and patient selection criteria will need to reconcile existing SOPs against the amended prescribing information.

Efficacy data came from KEYNOTE-158 (NCT02628067), evaluated across two patient groups: Cohort M, which prospectively enrolled patients with TMB-H, non-MSI-H tumors, and Cohorts A through J, a prospectively planned retrospective analysis spanning ten tumor-type cohorts. The primary endpoints were objective response rate (ORR) and duration of response (DOR) assessed by blinded independent central review per RECIST v1.1 in 220 patients with TMB ≥13 mut/Mb. ORR reached 36% (95% CI: 30, 43), with 58% of responders sustaining response for ≥12 months.

Dosing for the monotherapy arm follows the established pembrolizumab schedule: 200 mg every three weeks or 400 mg intravenously every six weeks, capped at 24 months. Pediatric dosing is set at 2 mg/kg every three weeks, up to 200 mg. The safety profile is consistent with the known pembrolizumab monotherapy profile; prescribing information retains warnings for immune-mediated adverse reactions, infusion-related reactions, allogeneic hematopoietic stem cell transplantation complications, and embryo-fetal toxicity.

For QA and regulatory leads, the precedent is the more consequential signal: this conversion demonstrates that FDA is prepared to narrow biomarker-defined indications when confirmatory data fail to validate the full accelerated-approval population. Companion diagnostic manufacturers whose assays are calibrated or labeled against the prior ≥10 mut/Mb threshold will need to assess whether an updated authorization or labeling amendment is required under 21 CFR Part 809.

Full prescribing information for both Keytruda and Keytruda Qlex will be posted to Drugs@FDA; teams managing formulary updates and clinical protocol amendments should treat the October 16 approval date as the operative compliance reference point.

Source: FDA Drugs Resources, Approved Drugs (What's New RSS Feed) via fda.gov, October 22, 2026.