Molecular Characteristics Predict Clinical Outcomes: Prospective Trial Correlating Response to the EGFR Tyrosine Kinase Inhibitor Gefitinib with the Presence of Sensitizing Mutations in the Tyrosine Binding Domain of the EGFR Gene

• Published in: Clinical cancer research Vol. 17; no. 10; pp. 3500 - 3506
• Main Authors: Rizvi, Naiyer A., Rusch, Valerie, Pao, William, Chaft, Jamie E., Ladanyi, Marc, Miller, Vincent A., Krug, Lee M., Azzoli, Christopher G., Bains, Manjit, Downey, Robert, Flores, Raja, Park, Bernard, Singh, Bhuvanesh, Zakowski, Maureen, Heelan, Robert T., Shen, Ronglai, Kris, Mark G.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2011
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - diagnosis; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - mortality; Catalytic Domain - genetics; Drug Resistance, Neoplasm - genetics; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - chemistry; ErbB Receptors - genetics; Female; Gefitinib; Genes, erbB-1 - genetics; Genes, erbB-1 - physiology; Humans; Lung Neoplasms - diagnosis; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - mortality; Male; Medical sciences; Middle Aged; Mutation - physiology; Pharmacology. Drug treatments; Prognosis; Protein Binding - genetics; Protein Kinase Inhibitors - therapeutic use; Quinazolines - therapeutic use; Survival Analysis; Treatment Outcome; Tyrosine - metabolism; Antineoplastic agent; Human; Tyrosine; Anti-EGFR; Prognosis; Enzyme; Tyrosine kinase inhibitor; Quinazoline derivatives; Transferases; Characteristic; Enzyme inhibitor; Binding site; Epidermal growth factor receptor; Prospective; Gene; Aminoacid; Clinical trial; Genetics; Mutation; Predictive factor; Gefitinib; Protein-tyrosine kinase
• ISSN: 1078-0432; 1557-3265; 1557-3265; 1078-0432
• DOI: 10.1158/1078-0432.CCR-10-2102

Purpose: To determine if tumor regression following treatment with gefitinib correlates with the presence of sensitizing mutations in epidermal growth factor receptor (EGFR). Patients and Methods: Patients with resectable stage I and II non–small cell lung cancer (NSCLC) enriched for the likelihood of EGFR mutation (≤15 pack-year cigarette smoking history and/or a component of bronchioloalveolar carcinoma) received preoperative gefitinib for 21 days. Tumor specimens were analyzed for EGFR and KRAS mutations and EGFR protein expression and amplification. Patients with 25% or more reduction in tumor size measured bidimensionally at 3 weeks and/or patients with an EGFR mutation received adjuvant gefitinib for 2 years postoperatively. Results: Fifty patients with stage I/II NSCLC were treated. After 21 days of preoperative gefitinib a response of 25% or more was observed in 21 of 50 (42%) patients. Seventeen of 21 patients with a response had an EGFR mutation and 4 of 21 patients with a response did not (P = 0.0001). Twenty-five of 50 patients were eligible to receive adjuvant gefitinib. With a median follow-up of 44.1 months, 2-year disease free survival for EGFR mutant patients and for those who received adjuvant gefitinib was not statistically different than those who were EGFR wild-type and those who did not receive adjuvant gefitinib. The median disease free and overall survivals have not been reached. Conclusions: The presence of sensitizing EGFR mutations correlates with radiographic response. A short course of preoperative treatment serves a platform for evaluating activity of new agents and assures sufficient tumor availability for correlative analyses. Clin Cancer Res; 17(10); 3500–6. ©2011 AACR.