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.
Neighborhood vulnerability was associated with poorer survival among women with epithelial ovarian cancer, with a stronger association among Black women.
