Feasibility of adding everolimus to carboplatin and paclitaxel, with or without bevacizumab, for treatment-naive, advanced non–small cell lung cancer
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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-cycle 1 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.
KeywordsNon-small cell lung cancer Everolimus Dose-limiting toxicity
This study was supported by Novartis Pharmaceuticals Corporation. Editorial assistance in the preparation of this manuscript was provided by Melanie Leiby, PhD, of ApotheCom (Yardley, PA, USA) and was funded by Novartis Pharmaceuticals Corporation.
Conflict of interest
Jeffrey De Leo, Sven Gogov, Valentine Jehl, and Shweta Urva are employees of Novartis Pharmaceuticals. Sven Gogov and Shweta Urva hold stock in Novartis Pharmaceuticals.
Wilfried Eberhardt has received support for travel to meetings for the study or other purpose and provision of writing assistance, medicines, equipment, or administrative support from Novartis Pharmaceuticals; served as a consultant for Novartis Pharmaceuticals; received payment for lectures including service on speakers bureaus from Novartis Pharmaceuticals; and payment for development of educational presentations from Novartis Pharmaceuticals.
Joan Schiller has received consulting fees or honorarium from Novartis Pharmaceuticals.
Michael P. Brown has received grant funding from Novartis and served as an advisory board member for Novartis.
Michael Thomas has received grants, consulting fees or honorarium, support for travel to meetings, and fees for participation in other review activities from Novartis Pharmaceuticals.
Glenn Mills and Vassiliki Papadimitrakopoulou have grant funding from Novartis Pharmaceuticals.
Paul Mitchell declares no conflict of interest.
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