FDA-approved TMB cutoff for pembrolizumab in solid tumors

Answer

The approved TMB-high cutoff is ≥10 mutations per megabase (mut/Mb). FDA's June 16, 2020 accelerated approval covers adult and pediatric patients with unresectable or metastatic solid tumors that progressed after prior treatment and have no satisfactory alternative treatment options, with TMB determined by an FDA-approved test. FoundationOne CDx received the corresponding companion-diagnostic approval c177ad13; eba4c0bb.

Summary

The regulatory threshold and its clinical predictive performance are different questions. The verified regulatory sources agree on the cutoff; the colorectal-cancer review qualifies prediction without changing the approved number c177ad13; 200b33eb; eba4c0bb.

Evidence

• FDA approval announcement and companion-diagnostic record: direct regulatory evidence for ≥10 mut/Mb, the stated indication restrictions and FoundationOne CDx. This identifies a labeled cutoff, not an assay-independent biological boundary c177ad13.

• Marcus et al. 2021, FDA approval summary: corroborates the threshold and reports KEYNOTE-158's TMB-high subset: n=102, overall response rate 29% (95% CI 21–39). An observed cohort response rate does not imply that every patient meeting the cutoff responds eba4c0bb.

• Narrative review, 2023: in microsatellite-stable metastatic colorectal cancer, TMB-high patients without POLE/POLD1 mutations may not significantly benefit from checkpoint inhibitors; pathogenic POLE/POLD1-associated tumors constitute a subgroup with favorable responses. This is a qualified review conclusion, not proof that response is impossible outside that subgroup 200b33eb.

• Subbiah et al. 2024, tissue-agnostic therapy review: independently lists tumor mutational burden ≥10 mutations per megabase among FDA tissue-agnostic immunotherapy approvals. This corroborates the threshold but is a review of the approval, not an additional clinical response cohort or independent calibration of that cutoff 11dcbafd.

Methodology

All four supplied verified records are cited. The FDA source determines the regulatory answer; the approval summary supplies its trial context, and the review supplies the tumor-specific caveat. No figures are pooled. This revision adds the newly verified tissue-agnostic review while retaining the earlier report's approval-summary context and colorectal-cancer limitation. Source checking reopened the FDA announcement and FoundationOne CDx PMA record and read Europe PMC abstracts for all three papers. Full text of the reviews was not read.

Limitations

The colorectal-cancer caveat rests on one review in this corpus; the additional approval summary does not independently establish its POLE/POLD1-specific conclusion. Other tumor-specific predictive limitations and calibration across sequencing assays are not established here. Meeting the biomarker cutoff alone does not establish eligibility outside the labeled clinical context 200b33eb; eba4c0bb; c177ad13.