Skip to main content

Advertisement

SpringerLink
Log in

A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM)

  • Clinical Study - Patient Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Twenty-two patients with recurrent glioblastoma (GBM) were prospectively treated with everolimus and gefitinib, designed to test the combined inhibition of mammalian target of rapamycin (mTOR) and epidermal growth factor receptor (EGFR) as part of a larger clinical trial. The primary endpoint was radiographic response rate. Secondary endpoints included progression-free survival and correlation of molecular profiles with treatment response. 36% of patients had stable disease and 14% a partial response; however, responses were not durable and only one patient was progression-free at six months. Radiographic changes were not well characterized by conventional response criteria, and implied differential effects of therapy within the tumor and/or antiangiogenic effects. EGFR and PTEN status did not clearly predict response to treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. doi:10.1056/NEJMoa043330

    Article  PubMed  CAS  Google Scholar 

  2. Salomon DS, Brandt R, Ciardiello F, Normanno N (1995) Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183–232. doi:10.1016/1040-8428(94)00144-I

    Article  PubMed  CAS  Google Scholar 

  3. Chakravarti A, Chakladar A, Delaney MA, Latham DE, Loeffler JS (2002) The epidermal growth factor receptor pathway mediates resistance to sequential administration of radiation and chemotherapy in primary human glioblastoma cells in a RAS-dependent manner. Cancer Res 62:4307–4315

    PubMed  CAS  Google Scholar 

  4. Shinojima N, Tada K, Shiraishi S et al (2003) Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res 63:6962–6970

    PubMed  CAS  Google Scholar 

  5. Li B, Yuan M, Kim IA, Chang CM, Bernhard EJ, Shu HK (2004) Mutant epidermal growth factor receptor displays increased signaling through the phosphatidylinositol-3 kinase/AKT pathway and promotes radioresistance in cells of astrocytic origin. Oncogene 23:4594–4602. doi:10.1038/sj.onc.1207602

    Article  PubMed  CAS  Google Scholar 

  6. Rich JN, Reardon DA, Peery T et al (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142. doi:10.1200/JCO.2004.08.110

    Article  PubMed  CAS  Google Scholar 

  7. Prados MD, Lamborn KR, Chang S et al (2006) Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma. Neuro-oncology 8:67–78. doi:10.1215/S1522851705000451

    Article  PubMed  CAS  Google Scholar 

  8. Halatsch ME, Schmidt U, Behnke-Mursch J, Unterberg A, Wirtz CR (2006) Epidermal growth factor receptor inhibition for the treatment of glioblastoma multiforme and other malignant brain tumours. Cancer Treat Rev 32:74–89. doi:10.1016/j.ctrv.2006.01.003

    Article  PubMed  CAS  Google Scholar 

  9. Mellinghoff IK, Wang MY, Vivanco I et al (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024. doi:10.1056/NEJMoa051918

    Article  PubMed  CAS  Google Scholar 

  10. Haas-Kogan DA, Prados MD, Tihan T et al (2005) Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 97:880–887

    Article  PubMed  CAS  Google Scholar 

  11. Bent MVD, Brandes A, Rampling R et al (2007) Randomized phase II trial of erlotinib (E) versus temozolomide (TMZ) or BCNU in recurrent glioblastoma multiforme (GBM): EORTC 26034. Paper presented at the Abstracts for the Twelfth Annual Meeting of the Society for Neuro-Oncology, 1 October 2007

  12. Prados M, DeBoer R, Chang S et al (2007) Phase II study of Tarceva plus Temodar during and following radiotherapy in patients newly diagnosed with glioblastoma or gliosarcoma. Paper presented at the Abstracts for the Twelfth Annual Meeting of the Society for Neuro-Oncology, 1 October 2007

  13. Hudson CC, Liu M, Chiang GG et al (2002) Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014. doi:10.1128/MCB.22.20.7004-7014.2002

    Article  PubMed  CAS  Google Scholar 

  14. Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ (2002) Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J 16:771–780. doi:10.1096/fj.01-0658com

    Article  PubMed  CAS  Google Scholar 

  15. Galanis E, Buckner JC, Maurer MJ et al (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 23:5294–5304. doi:10.1200/JCO.2005.23.622

    Article  PubMed  CAS  Google Scholar 

  16. Chang SM, Wen P, Cloughesy T et al (2005) Phase II study of CCI-779 in patients with recurrent glioblastoma multiforme. Invest New Drugs 23:357–361. doi:10.1007/s10637-005-1444-0

    Article  PubMed  CAS  Google Scholar 

  17. Goudar RK, Shi Q, Hjelmeland MD et al (2005) Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition. Mol Cancer Ther 4:101–112

    PubMed  CAS  Google Scholar 

  18. Reardon DA, Quinn JA, Vredenburgh JJ et al (2006) Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 12:860–868. doi:10.1158/1078-0432.CCR-05-2215

    Article  PubMed  CAS  Google Scholar 

  19. Doherty L, Gigas DC, Kesari S et al (2006) Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas. Neurology 67:156–158. doi:10.1212/01.wnl.0000223844.77636.29

    Article  PubMed  CAS  Google Scholar 

  20. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205–216. doi:10.1093/jnci/92.3.205

    Article  PubMed  CAS  Google Scholar 

  21. Choe G, Horvath S, Cloughesy TF et al (2003) Analysis of the phosphatidylinositol 3′-kinase signaling pathway in glioblastoma patients in vivo. Cancer Res 63:2742–2746

    PubMed  CAS  Google Scholar 

  22. Shaffer DR, Abrey LE, Beekman K et al (2006) A phase I/II trial of RAD 001 with gefitinib in patients with castrate metastatic prostate cancer and glioblastoma multiforme. J Clin Oncol 24:638s

    Google Scholar 

  23. Hu X, Pandolfi PP, Li Y, Koutcher JA, Rosenblum M, Holland EC (2005) mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7:356–368. doi:10.1593/neo.04595

    Article  PubMed  CAS  Google Scholar 

  24. Shih AH, Dai C, Hu X, Rosenblum MK, Koutcher JA, Holland EC (2004) Dose-dependent effects of platelet-derived growth factor-B on glial tumorigenesis. Cancer Res 64:4783–4789. doi:10.1158/0008-5472.CAN-03-3831

    Article  PubMed  CAS  Google Scholar 

  25. Cloughesy TF, Yoshimoto K, Nghiemphu P et al (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5(1):e8

    Article  PubMed  CAS  Google Scholar 

  26. O’Reilly KE, Rojo F, She QB et al (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508. doi:10.1158/0008-5472.CAN-05-2925

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuro-Oncology Branch, National Cancer Institute, 9030 Old Georgetown Road, Bethesda, MD, 20892, USA

    Teri N. Kreisl

  2. Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Andrew B. Lassman & Lauren E. Abrey

  3. David Geffen School of Medicine, University of California Los Angeles, 405 Hilgard Avenue, Los Angeles, CA, 90095 (DG), USA

    Paul S. Mischel

  4. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Neal Rosen, Howard I. Scher & David Shaffer

  5. Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Julie Teruya-Feldstein

  6. Department of Radiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Eric Lis

Authors
  1. Teri N. Kreisl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew B. Lassman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul S. Mischel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Neal Rosen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Howard I. Scher
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julie Teruya-Feldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. David Shaffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eric Lis
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Lauren E. Abrey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lauren E. Abrey.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kreisl, T.N., Lassman, A.B., Mischel, P.S. et al. A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). J Neurooncol 92, 99–105 (2009). https://doi.org/10.1007/s11060-008-9741-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-008-9741-z

Keywords

Search

Navigation