A Pilot Study of Preoperative Gefitinib for Early-Stage Lung Cancer to Assess Intratumor Drug Concentration and Pathways Mediating Primary Resistance

Abstract

Targeted agents such as tyrosine kinase inhibitors have been extensively studied in preclinical systems and in advanced-stage patients. Little is known about levels of kinase inhibitors found in tumors as opposed to plasma. Similarly, effects of inhibitors on tumor signaling pathways in patient-based materials are unclear. To explore these questions, we conducted a trial of a brief course of preoperative gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, in early-stage non-small cell lung cancer. Patient with early-stage non-small cell lung cancer received 4 weeks of gefitinib 250 mg daily before surgical resection. Pre- and posttreatment computerized tomography scans and positron emission tomography scans were used to assess clinical response. Gefitinib and surgical toxicity were evaluated. Tumor tissue was evaluated for gefitinib levels and was compared with plasma gefitinib levels. Activated signaling molecules including EGFR, STAT3, ERK, and AKT were examined in surgically resected tumor tissue. Twenty-three patients participated in the study, and all had surgical resection of tumors. No toxicities unrelated to known effects of gefitinib or surgery were encountered. Twenty-two patients had stable disease, and one had progression in tumor size. There was no correlation with positron emission tomography response and computerized tomography response. Tumor levels of gefitinib were approximately 40-fold higher than plasma levels, indicating potential tumor concentration of gefitinib. Tyrosine phosphorylated STAT3 was abundant in the surgically resected tumor tissue, indicating potential role in primary resistance in vivo. This study confirms previous preclinical observations that tumor tissues concentrate gefitinib. Persistent STAT3 may be leading to primary resistance to EGFR inhibitors in vivo.