title: Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer.
abstract: Metastatic EGFR-mutant lung cancers are sensitive to the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells, including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. Four of four xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but four of four AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Meador
authors.affiliation: Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Hailing
authors.initials: H
authors.lastname: Jin
authors.affiliation: Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Nebhan
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Valentina
authors.initials: V
authors.lastname: Pirazzoli
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Huy
authors.initials: H
authors.lastname: Vuong
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Hutchinson
authors.affiliation: Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Peilin
authors.initials: P
authors.lastname: Jia
authors.affiliation: Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Rosana
authors.initials: R
authors.lastname: Eisenberg
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut. Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut. Department of Medicine, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Katerina
authors.initials: K
authors.lastname: Politi
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Zhongming
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: AstraZeneca Oncology Innovative Medicines, Alderley Park, Macclesfield, Cheshire, United Kingdom.
authors.forename: Darren A E
authors.initials: DA
authors.lastname: Cross
authors.affiliation: Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee. Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee. william.pao@vanderbilt.edu.
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000178:Acrylamides / Q000494:pharmacology / Q000627:therapeutic use; D000077716:Afatinib; D000368:Aged; D000814:Aniline Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000077716:Afatinib; D000814:Aniline Compounds; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D011799:Quinazolines; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines