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

Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG, Krug LM, Pao W, Pizzo B, Rizvi NA, Miller VA
Cancer. 2007 110 (3): 599-605

PMID: 17577220 · 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 t(max), C(max), and AUC(0-8h) 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.

(c) 2007 American Cancer Society.

MeSH Terms (17)

Adenocarcinoma Aged Antineoplastic Combined Chemotherapy Protocols Carcinoma, Non-Small-Cell Lung Carcinoma, Squamous Cell Dose-Response Relationship, Drug Everolimus Female Gefitinib Humans Lung Neoplasms Male Middle Aged Quinazolines Sirolimus Survival Rate United States

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