Non-small cell lung (NSCLC) cancer is responsible for approximately 85% of the 221,130 lung cancer cases in the US in 2011. Chemotherapy and chemotherapy with targeted monoclonal antibodies for patients with NSCLC remain modestly effective. Therefore, more effective targeted agents are needed for systemic therapy of different NSCLCs as well as the biomarkers associated with treatment benefit. The association between somatic mutations in the epidermal growth factor receptor (EGFR) and the clinical efficacy of the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib, was discovered in 2004. Subsequent clinical studies done in Japan, China, East Asia, and Europe showed NSCLC patients with EGFR mutations treated with gefitinib or erlotinib have a 2-3 fold greater response and progression-free survival with less toxicity than those treated with platinum-based systemic chemotherapy. Further information is needed about patients with NSCLC and EGFR mutations treated with the different EGFR inhibitors in the US, Europe, and around the world. In addition, defining the mechanisms of resistance, identifying means of overcoming resistance to EGFR inhibitors, and improvements in the inhibitors are needed.
The aims of the study are to prospectively validate the frequency and type of acquired resistance mutations and genomic changes arising in subjects with advanced NSCLC and somatic sensitizing mutations of EGFR treated with EGFR inhibitors. Studies of EGFR mutations in NSCLC patients treated with EGFR inhibitors around the world will define the relationship between EGFR mutations, response to treatment, progression-free survival, and survival in subjects with NSCLC treated with erlotinib and gefitinib in subjects with European ethnic background and those from East Asia. The experiments on different therapeutic approaches in lung cancer cell lines and models of acquired resistance to EGFR inhibitors will be done by studying tumors and tumor cell lines harvested or established from patients with clinical resistance to EGFR tyrosine kinase inhibitors. This will facilitate the development of more effective EGFR inhibitors either alone, or with other tyrosine kinase inhibitors and additional targeted agents.
Patients with lung cancer need more effective targeted agents and more biomarkers associated with their treatment benefit rather than less efficacious empiric combination chemotherapy. The treatment of lung cancer patients with genetic changes or mutations in their epidermal growth factor receptor (EGFR) has changed from empiric chemotherapy to treatment with agents that target the EGFR, gefitinib and erlotinib. The studies in this grant will identify why these agents quit working in some patients and help develop therapies which will work longer or find new drugs that work better than these older agents.
|Hu, Yuebi; Alden, Ryan S; Odegaard, Justin I et al. (2017) Discrimination of Germline EGFR T790M Mutations in Plasma Cell-Free DNA Allows Study of Prevalence Across 31,414 Cancer Patients. Clin Cancer Res 23:7351-7359|
|Kosaka, Takayuki; Tanizaki, Junko; Paranal, Raymond M et al. (2017) Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors. Cancer Res 77:2712-2721|
|Saxon, Jamie A; Sholl, Lynette M; Jänne, Pasi A (2017) EGFR L858M/L861Q cis Mutations Confer Selective Sensitivity to Afatinib. J Thorac Oncol 12:884-889|
|Nishino, Mizuki; Dahlberg, Suzanne E; Fulton, Linnea E et al. (2016) Volumetric Tumor Response and Progression in EGFR-mutant NSCLC Patients Treated with Erlotinib or Gefitinib. Acad Radiol 23:329-36|
|Lin, Jessica J; Cardarella, Stephanie; Lydon, Christine A et al. (2016) Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol 11:556-65|
|Lampson, Benjamin L; Nishino, Mizuki; Dahlberg, Suzanne E et al. (2016) Activity of erlotinib when dosed below the maximum tolerated dose for EGFR-mutant lung cancer: Implications for targeted therapy development. Cancer :|
|Sacher, Adrian G; Paweletz, Cloud; Dahlberg, Suzanne E et al. (2016) Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer. JAMA Oncol 2:1014-22|
|Sacher, Adrian G; Dahlberg, Suzanne E; Heng, Jennifer et al. (2016) Association Between Younger Age and Targetable Genomic Alterations and Prognosis in Non-Small-Cell Lung Cancer. JAMA Oncol 2:313-20|
|Nishino, Mizuki; Cardarella, Stephanie; Dahlberg, Suzanne E et al. (2015) Interstitial lung abnormalities in treatment-naïve advanced non-small-cell lung cancer patients are associated with shorter survival. Eur J Radiol 84:998-1004|
|Ercan, Dalia; Choi, Hwan Geun; Yun, Cai-Hong et al. (2015) EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors. Clin Cancer Res 21:3913-23|
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