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Targeting Acquired and Intrinsic Resistance Mechanisms in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer

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Abstract

Over the past 2 decades, rapid advances in molecular profiling and the development of targeted therapies have dramatically improved the clinical course of advanced non-small-cell lung cancer (NSCLC). Mutations in the epidermal growth factor receptor (EGFR) gene are found in about a third of patients with advanced NSCLC, and the approval of first-generation EGFR targeted kinase inhibitors significantly improved survival when compared with platinum-based doublet chemotherapy (PBC), the previous standard of care. Inevitably, selective pressure from first-generation EGFR inhibitors led to acquired resistance mechanisms, such as the T790M mutation. The advent of third-generation EGFR inhibitors (e.g., osimertinib) successfully overcame the T790M resistance mechanism, and osimertinib subsequently became the first-line therapy for EGFR mutant NSCLC. Currently, research in EGFR mutant NSCLC is primarily focused on targeting resistance mechanisms to osimertinib. Over the past several years, many important acquired and intrinsic mechanisms of resistance to osimertinib have been identified. Acquired resistance mechanisms include C797X, mesenchymal epithelial transition factor (MET) amplification, HER2/HER3 amplification, phosphoinositide 3-kinase (PI3K) pathway mutations, RAS/mitogen-activated protein kinase (MAPK) pathway mutations, cell–cycle gene alterations, oncogenic fusions, and histologic transformations. An important intrinsic resistance mechanism to osimertinib is the EGFR exon 20 insertion mutation, which is sensitive to the newly Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor mobocertinib and the EGFR/MET bispecific antibody amivantamab. This review article aims to (1) summarize the advances in the treatment of EGFR mutant NSCLC, (2) delineate known resistance mechanisms to the current first-line therapy, osimertinib, and (3) describe the development of targeted drugs that aim to overcome these resistance mechanisms.

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Acknowledgments

The authors would like to thank Isabelle Blanchard for assistance with figure illustrations and manuscript preparation.

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M.P. Shah declares that he has no conflicts of interest that might be relevant to the contents of this article. J.W. Neal declares the following: consulting or advisory role for AstraZeneca, Genentech/Roche, Exelixis, Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, Calithera Biosciences, Amgen, Iovance Biotherapeutics, Blueprint Pharmaceuticals, Regeneron Pharmaceuticals, Natera, Sanofi/Regeneron, D2G Oncology, Surface Oncology, Turning Point Therapeutics; research funding from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Nektar Therapeutics, Takeda Pharmaceuticals, Adaptimmune, GSK, Janssen, and AbbVie.

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MPS and JWN outlined the manuscript. MPS conducted literature review and composed the manuscript. MPS and JWN revised the manuscript.

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Shah, M.P., Neal, J.W. Targeting Acquired and Intrinsic Resistance Mechanisms in Epidermal Growth Factor Receptor Mutant Non-Small-Cell Lung Cancer. Drugs 82, 649–662 (2022). https://doi.org/10.1007/s40265-022-01698-z

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