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

✍ Scribed by Daniel T. Milton; Gregory J. Riely; Christopher G. Azzoli; Jorge E. Gomez; Robert T. Heelan; Mark G. Kris; Lee M. Krug; William Pao; Barbara Pizzo; Naiyer A. Rizvi; Vincent A. Miller

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 123 KB
• Volume: 110
• Category: Article
• ISSN: 0008-543X
• DOI: 10.1002/cncr.22816

✦ Synopsis

Abstract

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. Cancer 2007. © 2007 American Cancer Society.