Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer

Wilfried E E Eberhardt, Paul Mitchell, Joan H. Schiller, Michael P. Brown, Michael Thomas, Glenn Mills, Valentine Jehl, Shweta R. Urva, Jeffrey J. De Leo, Sven Gogov, Vassiliki Papadimitrakopoulou

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Introduction: One standard of care for advanced non-small cell lung cancer (NSCLC) is paclitaxel plus carboplatin±bevacizumab. This two-step phase I study evaluated the feasibility of adding everolimus to paclitaxel plus carboplatin±bevacizumab for advanced NSCLC. Methods: Adults with advanced NSCLC naive to systemic therapy were enrolled. A Bayesian dose-escalation model was used to identify feasible daily or weekly everolimus doses given with paclitaxel (200 mg/m2 q21 days) and carboplatin (AUC 6 mg/mL/min q21 days) (step 1) and paclitaxel (200 mg/m2 q21 days), carboplatin (AUC 6 mg/mL/min q21 days), and bevacizumab (15 mg/kg q21 days) (step 2). Primary endpoint was end-of-cycle 1 dose-limiting toxicity (DLT) rate. Secondary endpoints included safety; relative dose intensities of paclitaxel, carboplatin, and bevacizumab; pharmacokinetics; and tumor response. Results Fifty-two patients were enrolled and received everolimus 5 mg/day plus carboplatin and paclitaxel (step 1 daily; n=13); everolimus 30 mg/week plus carboplatin and paclitaxel (step 1 weekly; n=13); everolimus 5 mg/day plus carboplatin, paclitaxel, and bevacizumab (step 2 daily; n=13); or everolimus 30 mg/week plus carboplatin, paclitaxel, and bevacizumab (step 2 weekly; n=13). End-of-cycle1 DLT rate was 16.7% (step 1 daily), 30.8% (step 1 weekly), 30.0% (step 2 daily), and 16.7% (step 2 weekly). Cycle 1 DLTs were grade 3 neutropenia, anal abscess, diarrhea, and thrombocytopenia and grade 4 myalgia, cellulitis, neutropenia, febrile neutropenia, pulmonary embolism, and thrombocytopenia. The most common adverse events were neutropenia, fatigue, anemia, and thrombocytopenia. One patient (step 2 daily) experienced complete response, 10 patients partial response. Conclusions: The feasible everolimus doses given with carboplatin and paclitaxel±bevacizumab were 5 mg/day and 30 mg/week. Neither schedule was very well tolerated in this unselected NSCLC population.

Original languageEnglish (US)
Pages (from-to)123-134
Number of pages12
JournalInvestigational New Drugs
Volume32
Issue number1
DOIs
StatePublished - Feb 2014

Keywords

  • Dose-limiting toxicity
  • Everolimus
  • Non-small cell lung cancer

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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    Eberhardt, W. E. E., Mitchell, P., Schiller, J. H., Brown, M. P., Thomas, M., Mills, G., Jehl, V., Urva, S. R., De Leo, J. J., Gogov, S., & Papadimitrakopoulou, V. (2014). Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non-small cell lung cancer. Investigational New Drugs, 32(1), 123-134. https://doi.org/10.1007/s10637-013-9958-3