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

Authors

  • Daniel T. Milton MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Gregory J. Riely MD, PhD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Christopher G. Azzoli MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Jorge E. Gomez MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Robert T. Heelan MD,

    1. Department of Radiology, Memorial Sloan- Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Mark G. Kris MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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    • Mark Kris severed as a consultant to and received honoraria from Novartis more than 3 years ago.

  • Lee M. Krug MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • William Pao MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Barbara Pizzo MD,

    1. Department of Nursing, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Naiyer A. Rizvi MD,

    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
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  • Vincent A. Miller MD

    Corresponding author
    1. Department of Medicine, Thoracic Oncology Service, Division of Solid Tumor Oncology, Memorial Sloan-Kettering Cancer Center and the Weill Medical College of Cornell University, New York, New York
    • Memorial Sloan-Kettering Cancer Center, Room 1012, Howard Building, 1275 York Ave., New York, NY 10021
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    • Fax: (212) 794-4357


  • Presented in part at the American Society of Clinical Oncology Annual Meeting, 2005; Orlando, Florida.

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 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.

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