Objective:

The article examines the objective, findings, and clinical context described in FDA raises TMB threshold for pembrolizumab.

Approach:

• Regulatory decision: The FDA raised the TMB-high threshold from 10 to 13 mutations per megabase (mut/Mb) for pembrolizumab and pembrolizumab/berahyaluronidase alfa-pmph in the specified indication.
• Supporting evidence: The decision was supported by KEYNOTE-158, a multicohort, nonrandomized phase 2 trial. Efficacy was assessed in 220 patients with TMB levels of at least 13 mut/Mb using objective response rate and duration of response, reviewed by blinded independent central r…

Key Findings:

• The indication covers adults and pediatric patients with unresectable or metastatic TMB-H solid tumors that progressed after prior treatment, when no satisfactory alternative treatment options exist; TMB must be determined using an FDA-authorized test.
• Across the 220-patient efficacy population, the objective response rate was 36%; 58% of responders maintained response for at least 12 months.
• The FDA stated that efficacy supporting traditional approval was not confirmed in patients with TMB levels from 10 to less than 13 mut/Mb.
• The FDA reported that the safety profile remained consistent with that previously established for pembrolizumab monotherapy.

Interpretation:

The FDA converted the prior accelerated approval to traditional approval while narrowing eligibility to patients with TMB levels of at least 13 mut/Mb.

Limitations:

• KEYNOTE-158 had no randomized comparator.
• The efficacy population combined patients from prospectively enrolled cohort M and a prospectively planned retrospective analysis of cohorts A through J.

Conclusion:

The updated indication includes intravenous dosing of 200 mg every 3 weeks or 400 mg every 6 weeks for adults, and 2 mg/kg every 3 weeks for pediatric patients, up to 200 mg per dose. Treatment continues until progression, unacceptable toxicity, or a maximum of 24 months. Subcutaneous dosing is specified separately in its prescribing information.

Sources:

• FDA