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Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M

Abstract

Here we studied cell-free plasma DNA (cfDNA) collected from subjects with advanced lung cancer whose tumors had developed resistance to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) AZD9291. We first performed next-generation sequencing of cfDNA from seven subjects and detected an acquired EGFR C797S mutation in one; expression of this mutant EGFR construct in a cell line rendered it resistant to AZD9291. We then performed droplet digital PCR on serial cfDNA specimens collected from 15 AZD9291-treated subjects. All were positive for the T790M mutation before treatment, but upon developing AZD9291 resistance three molecular subtypes emerged: six cases acquired the C797S mutation, five cases maintained the T790M mutation but did not acquire the C797S mutation and four cases lost the T790M mutation despite the presence of the underlying EGFR activating mutation. Our findings provide insight into the diversity of mechanisms through which tumors acquire resistance to AZD9291 and highlight the need for therapies that are able to overcome resistance mediated by the EGFR C797S mutation.

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Figure 1: Acquired resistance to AZD9291 mediated by acquired EGFR C797S mutation.
Figure 2: NGS of baseline and progression cfDNA demonstrates several different genomic presentations of acquired EGFR C797S.

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Acknowledgements

This study was supported in part by the National Cancer Institute of the National Institutes of Health (R01CA135257 (P.A.J.), R01CA114465 (P.A.J.) and P01CA154303 (P.A.J.)), AstraZeneca, the Conquer Cancer Foundation of ASCO (G.R.O.), the Stading-Younger Cancer Research Foundation (G.R.O.), and the Department of Medical Oncology at Dana-Farber Cancer Institute. We would like to thank the numerous lung cancer patients and clinical investigators that contributed to this scientific effort.

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Contributions

K.S.T., P.A.J. and G.R.O. designed the study. E.F., B.C.C., S.E.M., M.C., P.A.J. and G.R.O. enrolled patients and provided specimens. C.P.P., D.S., B.D., Z.L., A.M., A.V., Y.K., D.E. and J.C.B. performed and/or designed experiments. K.S.T. and G.R.O. drafted the manuscript. All authors reviewed the final manuscript.

Corresponding author

Correspondence to Geoffrey R Oxnard.

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Competing interests

K.S.T., D.S., B.D., Z.L., A.M., M.C. and J.C.B. are employees of AstraZeneca. E.F. has received consulting fees from Boehringer-Ingelheim, GlaxoSmithKline, Eli Lilly, Pfizer, and Roche. B.C.C. has received consulting fees from Boehringer-Ingelheim, GlaxoSmithKline, and Novartis and has received research grants from AstraZeneca, Bayer, Boehringer-Ingelheim, and Novartis. P.A.J. has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Clovis, Chugai, and Genentech; is co-inventor on a patent held by the Dana-Farber Cancer Institute for the use of EGFR genotyping; and receives a share of post-market licensing revenue distributed by Dana-Farber Cancer Institute. G.R.O. has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Clovis, Genentech, Novartis, and Sysmex. All other authors have no disclosures.

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Thress, K., Paweletz, C., Felip, E. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M. Nat Med 21, 560–562 (2015). https://doi.org/10.1038/nm.3854

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