Elsevier

Journal of Thoracic Oncology

Volume 15, Issue 9, September 2020, Pages 1409-1424
Journal of Thoracic Oncology

Review Article
The Promises and Challenges of Tumor Mutation Burden as an Immunotherapy Biomarker: A Perspective from the International Association for the Study of Lung Cancer Pathology Committee

https://doi.org/10.1016/j.jtho.2020.05.019Get rights and content
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Abstract

Immune checkpoint inhibitor (ICI) therapies have revolutionized the management of patients with NSCLC and have led to unprecedented improvements in response rates and survival in a subset of patients with this fatal disease. However, the available therapies work only for a minority of patients, are associated with substantial societal cost, and may lead to considerable immune-related adverse events. Therefore, patient selection must be optimized through the use of relevant biomarkers. Programmed death-ligand 1 protein expression by immunohistochemistry is widely used today for the selection of programmed cell death protein 1 inhibitor therapy in patients with NSCLC; however, this approach lacks robust sensitivity and specificity for predicting response. Tumor mutation burden (TMB), or the number of somatic mutations derived from next-generation sequencing techniques, has been widely explored as an alternative or complementary biomarker for response to ICIs. In theory, a higher TMB increases the probability of tumor neoantigen production and therefore, the likelihood of immune recognition and tumor cell killing. Although TMB alone is a simplistic surrogate of this complex interplay, it is a quantitative variable that can be relatively readily measured using currently available sequencing techniques. A large number of clinical trials and retrospective analyses, employing both tumor and blood-based sequencing tools, have evaluated the performance of TMB as a predictive biomarker, and in many cases reveal a correlation between high TMB and ICI response rates and progression-free survival. Many challenges remain before the implementation of TMB as a biomarker in clinical practice. These include the following: (1) identification of therapies whose response is best informed by TMB status; (2) robust definition of a predictive TMB cut point; (3) acceptable sequencing panel size and design; and (4) the need for robust technical and informatic rigor to generate precise and accurate TMB measurements across different laboratories. Finally, effective prediction of response to ICI therapy will likely require integration of TMB with a host of other potential biomarkers, including tumor genomic driver alterations, tumor-immune milieu, and other features of the host immune system. This perspective piece will review the current clinical evidence for TMB as a biomarker and address the technical sequencing considerations and ongoing challenges in the use of TMB in routine practice.

Keywords

TMB
NSCLC
Immunotherapy
Biomarker
PD-L1

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Disclosure: Dr. Beasley reports receiving other assistance from Loxo Oncology outside of the submitted work. Dr. Botling reports receiving grants and personal fees from AstraZeneca, Merck Sharp & Dohme, Roche Holdings AG, Pfizer, Boehringer Ingelheim, Novartis, Illumina, and Bristol Myers Squibb outside of the submitted work. Dr. Bubendorf reports receiving personal fees from Bristol Myers Squibb; and grants and personal fees from Merck Sharp & Dohme and Roche Holdings AG during the conduct of the study. Dr. Hwang reports receiving grants from AstraZeneca; grants and personal fees from Merck, Novartis, and Takeda; and personal fees from Roche, Bayer, and Pfizer outside of the submitted work. Dr. Longshore reports receiving grants from Agilent Technologies; grants and personal fees from Roche Diagnostics, AstraZeneca, and Biodesix; and personal fees from Bristol Myers Squibb, Genentech, Merck, Pfizer, AbbVie, Bayer, Loxo Oncology, and Spectrum pharmaceuticals outside of the submitted work. Dr. Lopez-Rios reports receiving grants and personal fees from Thermo Fisher and Bristol Myers Squibb during the conduct of the study; and personal fees from Thermo Fisher, Bristol Myers Squibb, Pfizer, Merck Sharp & Dohme, Roche Holdings AG, Eli Lilly, AstraZeneca, and Bayer outside of the submitted work. Dr. Mino-Kenudson reports receiving grants from Novartis; and personal fees from H3 Biomedicine, and AstraZeneca outside of the submitted work. Dr. Nicholson reports receiving grants and personal fees from Pfizer and personal fees from Merck, Boehringer Ingelheim, Novartis, AstraZeneca, Bristol Myers Squibb, Roche Holdings AG, AbbVie, and Oncologica outside of the submitted work. Dr. Peters reports receiving personal fees from AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bistrol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp & Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar S.A., Pfizer, Regeneron, Sanofi, Seattle Genetics, and Takeda; nonfinancial support from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Meyers Squibb, Clovis, F. Hoffmann La Roche, Illumina, Merck Sharp & Dohme, Merck Serono, Novartis, Pfizer, and Sanofi; and personal fees from Bioinvent outside of the submitted work. Dr. Wistuba reports receiving grants and personal fees from Genentech/Roche, Bayer, Bristol Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Merck, and Guardant Health; and personal fees from GlaxoSmithKline and Merck Sharp & Dohme; grants from Oncoplex, DepArray, Adaptive, Adaptimmune, EMD Serono, Takeda, Amgen, Johnson & Johnson, Karus, Iovance, 4D, Oncocyte, Novartis, and Akoya outside of the submitted work; Dr. Tsao reports receiving grants and personal fees from Merck, Bayer, and AstraZeneca; and personal fees from Bristol-Meyers Squibb, Hoffmann La Roche, Takeda, and Amgen outside of the submitted work. The remaining authors declare no conflict of interest.