Investigational New Drugs

, Volume 32, Issue 1, pp 123–134 | Cite as

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

  • Wilfried E. E. EberhardtEmail author
  • 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


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.


Non-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.


  1. 1.
    National Comprehensive Cancer Network (2011) Nccn clinical practice guidelines in oncology: non-small cell lung cancer, Version 2.2012Google Scholar
  2. 2.
    Ramalingam S, Ab S (2006) Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection. Oncologist 11:655–665CrossRefPubMedGoogle Scholar
  3. 3.
    Behera M, Tk O, Chen Z, Sa K, Fr K, Cp B, Ss R (2012) Single agent maintenance therapy for advanced stage non-small cell lung cancer: a meta-analysis. Lung Cancer 77:331–338PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Ma B, Pj H (2004) The tor pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348CrossRefGoogle Scholar
  5. 5.
    Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O’reilly T, Natt F, Hall J, Ha L, Thomas G (2005) The Mtor inhibitor Rad001 sensitizes tumor cells to Dna-damaged induced apoptosis through inhibition Of P21 translation. Cell 120:747–759CrossRefPubMedGoogle Scholar
  6. 6.
    Boulay A, Zumstein-Mecker S, Stephan C, Beuvink I, Zilbermann F, Haller R, Tobler S, Heusser C, O’reilly T, Stolz B, Marti A, Thomas G, Ha L (2004) Antitumor efficacy of intermittent treatment schedules with the rapamycin derivative Rad001 correlates with prolonged inactivation of ribosomal protein S6 kinase 1 in peripheral blood mononuclear cells. Cancer Res 64:252–261CrossRefPubMedGoogle Scholar
  7. 7.
    Mabuchi S, Da A, Dc C, Klein-Szanto A, Litwin S, Mk H, Hensley H, Tc H, Jr T (2007) Rad001 (Everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res 67:2408–2413CrossRefPubMedGoogle Scholar
  8. 8.
    La Monica S, Galetti M, Rr A, Cavazzoni A, Ardizzoni A, Tiseo M, Capelletti M, Goldoni M, Tagliaferri S, Mutti A, Fumarola C, Bonelli M, Generali D, Pg P (2009) Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines. Biochem Pharmacol 78:460–468CrossRefPubMedGoogle Scholar
  9. 9.
    Nakachi I, Naoki K, Soejima K, Kawada I, Watanabe H, Yasuda H, Nakayama S, Yoda S, Satomi R, Ikemura S, Terai H, Sato T, Ishizaka A (2010) The combination of multiple receptor tyrosine kinase inhibitor and mammalian target of rapamycin inhibitor overcomes erlotinib resistance in lung cancer cell lines through C-Met inhibition. Mol Cancer Res 8:1142–1151CrossRefPubMedGoogle Scholar
  10. 10.
    Cx X, Li Y, Yue P, Tk O, Ss R, Fr K, Sy S (2011) The combination of Rad001 and Nvp-Bez235 exerts synergistic anticancer activity against non-small cell lung cancer in vitro and in vivo. PLoS One 6, E20899CrossRefGoogle Scholar
  11. 11.
    Afinitor (Everolimus) Tablets For Oral Administration [Prescribing Information] (2012) East Hanover, Nj, Usa: Novartis Pharmaceuticals CorporationGoogle Scholar
  12. 12.
    Afinitor Summary Of Product Characteristics (2012) West Sussex, United Kingdom: Novartis Europharm LimitedGoogle Scholar
  13. 13.
    Votubia Summary Of Product Characteristics (2012) West Sussex, United Kingdom: Novartis Europharm LimitedGoogle Scholar
  14. 14.
    Baselga J, Campone M, Piccart M, Ha B, Hs R, Sahmoud T, Noguchi S, Gnant M, Ki P, Lebrun F, Jt B, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Gn H (2012) Everolimus in postmenopausal hormone receptor-positive advanced breast cancer. N Engl J Med 366:520–529CrossRefPubMedGoogle Scholar
  15. 15.
    Ss R, Rd H, Saba N, Tk O, Kauh J, Dm S, Sy S, Strychor S, Tighiouart M, Egorin Mj FH, Fr K (2010) Phase 1 and pharmacokinetic study of Everolimus, a mammalian target of rapamycin inhibitor, in combination with docetaxel for recurrent/refractory nonsmall cell lung cancer. Cancer 116:3903–3909CrossRefGoogle Scholar
  16. 16.
    O’reilly T, Pm M, Wartmann M, Lassota P, Brandt R, Ha L (2011) Evaluation of the Mtor inhibitor, Everolimus, in combination with cytotoxic antitumor agents using human tumor models in vitro and in vivo. Anticancer Drugs 22:58–78CrossRefPubMedGoogle Scholar
  17. 17.
    Sandler A, Gray R, Mc P, Brahmer J, Schiller J, Dowlati A, Lilenbaum R, Johnson D (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542–2550CrossRefPubMedGoogle Scholar
  18. 18.
    Goldstraw P, Crowley J, Chansky K, Dj G, Pa G, Rami-Porta R, Pe P, Rusch V, Sobin L (2007) The IASLC lung cancer staging project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol 2:706–714CrossRefPubMedGoogle Scholar
  19. 19.
    Mg K, Pj H, Mr S, Feyer P, Clark-Snow R, Jm K, Gr M, Lw C, Mj C, Rj G, Sm G (2006) American Society of Clinical Oncology guideline for antiemetics in oncology: update 2006. J Clin Oncol 24:2932–2947CrossRefGoogle Scholar
  20. 20.
    Herrstedt J, Ms A, Roila F, Vv K (2005) ESMO minimum clinical recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (Nv). Ann Oncol 16(Suppl 1):I77–I79CrossRefPubMedGoogle Scholar
  21. 21.
    Therasse P, Sg A, Ea E, Wanders J, Rs K, Rubinstein L, Verweij J, Van Glabbeke M, At VO, Mc C, Sg G (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216CrossRefPubMedGoogle Scholar
  22. 22.
    Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, Martinelli E, Cajal S, Jones S, Vidal L, Shand N, Macarulla T, Fj R, Dimitrijevic S, Zoellner U, Tang P, Stumm M, Ha L, Lebwohl D, Baselga J (2008) Dose- and schedule-dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 26:1603–1610CrossRefPubMedGoogle Scholar
  23. 23.
    O’donnell A, Faivre S, Ha B, Iii RD, Papadimitrakopoulou V, Shand N, Ha L, Hazell K, Zoellner U, Jm K, Brock C, Jones S, Raymond E, Judson I (2008) Phase I pharmacokinetic and pharmacodynamic study of the oral mammalian target of rapamycin inhibitor everolimus in patients with advanced solid tumors. J Clin Oncol 26:1588–1595CrossRefPubMedGoogle Scholar
  24. 24.
    Xu B, Wu Y, Shen L, Ye D, Jappe A, Cherfi A, Wang H, Yuan R (2011) Two dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors. J Hematol Oncol 4:3PubMedCentralCrossRefPubMedGoogle Scholar
  25. 25.
    Okamoto I, Doi T, Ohtsu A, Miyazaki M, Tsuya A, Kurei K, Kobayashi K, Nakagawa K (2010) Phase I clinical and pharmacokinetic study of Rad001 (Everolimus) administered daily to Japanese patients with advanced solid tumors. Jpn J Clin Oncol 40:17–23PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Dt M, Gj R, Cg A, Je G, Rt H, Mg K, Lm K, Pao W, Pizzo B, Na R, Va M (2007) Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer. Cancer 110:599–605CrossRefGoogle Scholar
  27. 27.
    Vansteenkiste J, Solomon B, Boyer M, Wolf J, Miller N, Sl D, Pylvaenaeinen I, Petrovic K, Dimitrijevic S, Anrys B, Laack E (2011) Everolimus in combination with pemetrexed in patients with advanced non-small cell lung cancer previously treated with chemotherapy: a phase I study using a novel, adaptive Bayesian dose-escalation model. J Thorac Oncol 6:2120–2129CrossRefPubMedGoogle Scholar
  28. 28.
    Al H, Ej S, Vk W, Sun J, Cj R, Am L, Fong L, Dr B, Je R (2011) A phase 1 study of everolimus and sorafenib for metastatic clear cell renal cell carcinoma. Cancer 117:4194–4200CrossRefGoogle Scholar
  29. 29.
    Ke B, Wp P, Younis I, He U, Ma M, Gc B, Sy Z, Jp G, Jj L, Truax R, Kl M, La H, Mm O’n, Broadwater G, Hi H, Jc B (2011) A Phase I study of bevacizumab (B) in combination with everolimus (E) and erlotinib (E) in advanced cancer (Bee). Cancer Chemother Pharmacol 67:465–474CrossRefGoogle Scholar
  30. 30.
    Jc Y, Shah M, Ito T, Cl B, Em W, Van Cutsem E, Tj H, Okusaka T, Capdevila J, Eg DV, Tomassetti P, Me P, Hoosen S, Haas T, Lincy J, Lebwohl D, Oberg K (2011) Everolimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 364:514–523CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Wilfried E. E. Eberhardt
    • 1
    • 10
    Email author
  • Paul Mitchell
    • 2
  • Joan H. Schiller
    • 3
  • Michael P. Brown
    • 4
  • Michael Thomas
    • 5
  • Glenn Mills
    • 6
  • Valentine Jehl
    • 8
  • Shweta R. Urva
    • 7
  • Jeffrey J. De Leo
    • 7
  • Sven Gogov
    • 8
  • Vassiliki Papadimitrakopoulou
    • 9
  1. 1.Department of Medical Oncology, West German Cancer CentreUniversitätsklinikum EssenEssenGermany
  2. 2.Ludwig Oncology UnitAustin HospitalMelbourneAustralia
  3. 3.University of Texas Southwestern Medical CenterDallasUSA
  4. 4.Cancer Clinical Trials UnitRoyal Adelaide HospitalAdelaideAustralia
  5. 5.Internistische Onkologie der Thoraxtumoren, Translational Lung Research Center Heidelberg (TLRC-H), German Center for Lung ResearchThoraxklinik am Universitätsklinikum HeidelbergHeidelbergGermany
  6. 6.Louisiana State University Health Sciences Center/Feist-Weiller Cancer CenterShreveportUSA
  7. 7.Novartis Pharmaceuticals CorporationFlorham ParkUSA
  8. 8.Novartis Pharmaceuticals CorporationBaselSwitzerland
  9. 9.The University of Texas MD Anderson Cancer CenterHoustonUSA
  10. 10.Department of Medical Oncology, West German Cancer Centre, University Hospital EssenUniversity Duisburg-EssenEssenGermany

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