Predictive Biomarkers and Personalized Medicine Acquired Resistance to EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Lung Cancer : Distinct Natural History of Patients with Tumors Harboring the T 790 M Mutation

Purpose: Patients with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI) after a median of 10 to 16 months. In half of these cases, a second EGFR mutation, T790M, underlies acquired resistance. We undertook this study to examine the clinical course of patients harboring the T790M mutation following progression on TKI. Experimental Design: EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective rebiopsy protocol in which postprogression tumor specimens were collected for molecular analysis. Postprogression survival and characteristics of disease progression were compared in patients with and without T790M. Results: We identified T790M in the initial rebiopsy specimens from 58 of 93 patients (62%, 95% CI: 52–72). T790Mwasmore common in biopsies of lung/pleura tissue and lymph nodes than inmore distant sites (P 1⁄4 0.014). Median postprogression survival was 16 months (interquartile range 1⁄4 9–29 months); patients with T790M had a significantly longer postprogression survival (P 1⁄4 0.036). Patients without T790Mmore often progressed in a previously uninvolved organ system (P1⁄4 0.014) and exhibited a poorer performance status at time of progression (P 1⁄4 0.007). Conclusions: Among patients with acquired resistance to EGFR TKIs, the presence of T790M defines a clinical subset with a relatively favorable prognosis and more indolent progression. Knowledge of T790M status is therefore important both for the clinical care of these patients and for the optimal design and interpretation of clinical trials in this setting. Clin Cancer Res; 17(6); 1616–22. 2010 AACR.

[1]  C. Sima,et al.  Phase II Trial of Dasatinib for Patients with Acquired Resistance to Treatment with the Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Erlotinib or Gefitinib , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[2]  M. Ladanyi,et al.  Rebiopsy of Lung Cancer Patients with Acquired Resistance to EGFR Inhibitors and Enhanced Detection of the T790M Mutation Using a Locked Nucleic Acid-Based Assay , 2011, Clinical Cancer Research.

[3]  L. Tanoue.  Gefitinib or Chemotherapy for Non–Small-Cell Lung Cancer with Mutated EGFR , 2011 .

[4]  Susan Quinn,et al.  Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  A. Iafrate,et al.  SNaPshot multigene assay to detect mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). , 2010 .

[6]  P. Jänne,et al.  Randomized phase II trial of erlotinib (E) alone or in combination with carboplatin/paclitaxel (CP) in never or light former smokers with advanced lung adenocarcinoma: CALGB 30406. , 2010 .

[7]  A. Lash,et al.  Initial results of LC-MAP: An institutional program to routinely profile tumor specimens for the presence of mutations in targetable pathways in all patients with lung adenocarcinoma. , 2010 .

[8]  M. Taron,et al.  Outcome to erlotinib in non-small cell lung cancer (NSCLC) patients (p) according to the presence of the EGFR T790M mutation and BRCA1 mRNA expression levels in pretreatment biopsies. , 2010 .

[9]  M. Ladanyi,et al.  Assessment of EGFR mutation status in lung adenocarcinoma by immunohistochemistry using antibodies specific to the two major forms of mutant EGFR. , 2010, The Journal of molecular diagnostics : JMD.

[10]  W. Pao,et al.  High dose weekly erlotinib achieves therapeutic concentrations in CSF and is effective in leptomeningeal metastases from epidermal growth factor receptor mutant lung cancer , 2010, Journal of Neuro-Oncology.

[11]  S. Toyooka,et al.  Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. , 2010, The Lancet. Oncology.

[12]  N. Girard,et al.  Analysis of Genetic Variants in Never-Smokers with Lung Cancer Facilitated by an Internet-Based Blood Collection Protocol: A Preliminary Report , 2010, Clinical Cancer Research.

[13]  M. Kris,et al.  Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[14]  L. Tanoue,et al.  Detection of Mutations in EGFR in Circulating Lung-Cancer Cells , 2010 .

[15]  L. Tanoue,et al.  Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma , 2010 .

[16]  Lin Huan,et al.  Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer , 2010 .

[17]  M. Ladanyi,et al.  Core needle lung biopsy specimens: adequacy for EGFR and KRAS mutational analysis. , 2010, AJR. American journal of roentgenology.

[18]  John R. Engen,et al.  Novel mutant-selective EGFR kinase inhibitors against EGFR T790M , 2009, Nature.

[19]  William Pao,et al.  Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. , 2009, The Journal of clinical investigation.

[20]  Gregory J Riely,et al.  Impact of Epidermal Growth Factor Receptor and KRAS Mutations on Clinical Outcomes in Previously Untreated Non–Small Cell Lung Cancer Patients: Results of an Online Tumor Registry of Clinical Trials , 2009, Clinical Cancer Research.

[21]  M. Ladanyi,et al.  Rebiopsy of patients (pts) with acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  T. Mok,et al.  Biomarker analyses from a phase III, randomized, open-label, first-line study of gefitinib (G) versus carboplatin/paclitaxel (C/P) in clinically selected patients (pts) with advanced non-small cell lung cancer (NSCLC) in Asia (IPASS). , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  I. Wistuba,et al.  Phase II randomized study of biomarker-directed treatment for non-small cell lung cancer (NSCLC): The BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) clinical trial program. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  P. Jänne,et al.  Noninvasive Detection of EGFR T790M in Gefitinib or Erlotinib Resistant Non–Small Cell Lung Cancer , 2009, Clinical Cancer Research.

[25]  Alona Muzikansky,et al.  First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[26]  P. Jänne,et al.  Mechanisms of Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small Cell Lung Cancer , 2008, Clinical Cancer Research.

[27]  U. McDermott,et al.  The T790M “gatekeeper” mutation in EGFR mediates resistance to low concentrations of an irreversible EGFR inhibitor , 2008, Molecular Cancer Therapeutics.

[28]  M. Meyerson,et al.  The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP , 2008, Proceedings of the National Academy of Sciences.

[29]  V. Seshan,et al.  Prognostic and Therapeutic Implications of EGFR and KRAS Mutations in Resected Lung Adenocarcinoma , 2008, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[30]  N. Hanna,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2008 .

[31]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[32]  William Pao,et al.  Prospective Assessment of Discontinuation and Reinitiation of Erlotinib or Gefitinib in Patients with Acquired Resistance to Erlotinib or Gefitinib Followed by the Addition of Everolimus , 2007, Clinical Cancer Research.

[33]  Robert Gray,et al.  Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. , 2006, The New England journal of medicine.

[34]  P. Wen,et al.  Response and resistance in a non-small-cell lung cancer patient with an epidermal growth factor receptor mutation and leptomeningeal metastases treated with high-dose gefitinib. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[35]  Nobuyoshi Shimizu,et al.  Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. , 2006, Cancer research.

[36]  M. Ladanyi,et al.  Clinical Course of Patients with Non–Small Cell Lung Cancer and Epidermal Growth Factor Receptor Exon 19 and Exon 21 Mutations Treated with Gefitinib or Erlotinib , 2006, Clinical Cancer Research.

[37]  M. Ladanyi,et al.  Rapid polymerase chain reaction-based detection of epidermal growth factor receptor gene mutations in lung adenocarcinomas. , 2005, The Journal of molecular diagnostics : JMD.

[38]  Patricia L. Harris,et al.  Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[39]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[40]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.