Tumor Mutational Burden as a Predictor of Immunotherapy Response: Is More Always Better?

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
John H StricklerMustafa Khasraw

Abstract

Immune checkpoint inhibitors, including antibodies that block programmed cell death protein-1 (PD-1) and PD-L1, have transformed the management of many cancers. However, the majority of patients have primary or acquired resistance to these immunotherapies. There is a significant unmet need for predictive biomarkers that can reliably identify patients who derive a clinically meaningful response from PD-1/PD-L1 blockade. High tumor mutational burden (TMB-H) has shown promise as a biomarker in lung cancer, but the broad applicability of TMB-H as a biomarker of response across all solid tumors is unclear. The FDA has approved the PD-1 inhibitor, pembrolizumab, as a therapy for all solid tumors with TMB equal to or greater than 10 mutations/megabase as measured by the FoundationOne CDx assay. This approval was based on an exploratory analysis of the KEYNOTE-158 study, which was a single-arm, phase II multi-cohort study of pembrolizumab for select, previously treated advanced solid tumors. Here, we elucidate the caveats of using TMB as a biomarker with a universal threshold across all solid tumors. While we recognize the importance of this and other FDA pan-cancer approvals, several questions about TMB as a predictive biomarker remai...Continue Reading

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Citations

Mar 9, 2021·Expert Review of Anticancer Therapy·Aaron C TanMustafa Khasraw
Mar 26, 2021·Frontiers in Oncology·Alhadi AlmangushAntti A Mäkitie
May 13, 2021·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Kelvin K-W Chan, Ian F Tannock
Jul 3, 2021·International Journal of Molecular Sciences·Sara BravacciniPaola Ulivi
Jul 14, 2021·Seminars in Cancer Biology·Vaidehi JobanputraOlivier Elemento
Aug 7, 2021·Journal for Immunotherapy of Cancer·Ahmet HaziniLen Seymour
Sep 18, 2021·Expert Opinion on Pharmacotherapy·Jane E Rogers, Arvind Dasari

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