Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall‐cell lung cancer

• Published in: Cancer Vol. 110; no. 3; pp. 599 - 605
• Main Authors: Milton, Daniel T., Riely, Gregory J., Azzoli, Christopher G., Gomez, Jorge E., Heelan, Robert T., Kris, Mark G., Krug, Lee M., Pao, William, Pizzo, Barbara, Rizvi, Naiyer A., Miller, Vincent A.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.08.2007; Wiley-Liss
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - pathology; Aged; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Dose-Response Relationship, Drug; EGFR; Everolimus; Female; gefitinib; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - pathology; Male; Medical sciences; Middle Aged; mTOR; NSCLC; Pneumology; Quinazolines - administration & dosage; RAD001; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; Survival Rate; Tumors; Tumors of the respiratory system and mediastinum; United States - epidemiology; United States; Antineoplastic agent; Quinazoline derivatives; Lung cancer; non-small cell lung carcinoma; Epidermal growth factor receptor; EGFR; Cancerology; mTOR; Bronchus disease; Advanced stage; Protein synthesis inhibitor; Gefitinib; Protein-tyrosine kinase; Everolimus; Human; Protein kinase mTOR; Lung disease; NSCLC; Respiratory disease; Enzyme; Transferases; Enzyme inhibitor; Lactone; Malignant tumor; Macrolide; Phase I trial; RAD001
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.22816

BACKGROUND. Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall‐cell lung cancer (NSCLC). METHODS. Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3‐patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily. RESULTS. Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose‐limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the tmax, Cmax, and AUC0‐8h of either agent. Two partial radiographic responses were identified among the 8 response‐evaluable patients. CONCLUSIONS. For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way. Cancer 2007. © 2007 American Cancer Society. A phase 1 study was performed to determine a safe dose of everolimus (RAD001) combined with gefitinib in patients with advanced nonsmall‐cell lung cancer. Treatment‐related toxicity was acceptable and encouraging activity leads the authors to recommend the combination of everolimus 5 mg and gefitinib 250 mg, each administered daily, for further study.