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A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients

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Abstract

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29–75) and median KPS was 90 (70–100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2–47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

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Author contributions

Statistical Analysis was performed by (YY, DL and AR), Drafting/revising the manuscript-all authors. Study concept or design-JJR, AR, YY, MG. Analysis or interpretation of data-JJR, YY, DL, MG. Statistical Analysis was performed by (YY, DL and AR)

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Authors and Affiliations

  1. Department of Neurology, Northwestern University, 710 North Lake Shore Drive, Abbott Hall, Room 1123, Chicago, IL, 60611, USA

    J. J. Raizer & S. Grimm

  2. James Cancer Hospital, Ohio State University, Columbus, OH, USA

    P. Giglio & V. K. Puduvalli

  3. Departments of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA

    J. Hu, S. Phuphanich & J. Rudnick

  4. Austin Brain Tumor Center, Austin, USA

    M. Groves & C. Conrad

  5. Department of Neurology, NorthShore University Health System, Evanston, USA

    R. Merrell & N. Vick

  6. Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, USA

    M. Loghin, W. K. Yung, I. W. Tremont-Lukats & J. De Groot

  7. Department of Neurology, Rush University Medical Center, Chicago, USA

    N. Paleologos

  8. Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, USA

    Y. Yuan & D. Liu

  9. Department of Preventive Medicine, Northwestern University, Chicago, USA

    A. Rademaker

  10. Dell Medical School, The University of Texas, Austin, USA

    B. Vaillant

  11. Department of Neurology, University of Washington, Seattle, USA

    M. Chamberlain

  12. Department of Pathology, Princess Margaret Cancer Centre, Toronto, Canada

    K. Aldape

  13. Neuro-Oncology Branch, NIH, Bethesda, USA

    M. R. Gilbert

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  1. J. J. Raizer
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  2. P. Giglio
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  3. J. Hu
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  9. M. Loghin
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Brain Tumor Trials Collaborative

Corresponding author

Correspondence to J. J. Raizer.

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Conflict of interest

JJR-Research Support: Genentech, Novartis, Plexxikon, Celldex, Diffusion, Stemline; Advisory Board: Stemline, Novocure, Midatech, AbbVie, Proximagen; Speakers Bureau: Genentech. MG-Research Support: GSK. Speakers Bureau: Foundation Medicine; Advisory Board: Incyte, Genentech, Foundation Medicine. VKP-Advisory board and honoraria: Nektar therapeutics, Orbus Pharma, Celgene, Genentech, Foundation Medicine; Speaker: Depuy Synthes. AY-Consultant: Merck, Actelion, DNAtrix; Honoraria: Merck, Actalion; Research Fund, None. JR-Advisory Board: Novocure. SG-Advisory Board: AbbVie and Novocure, JD-Advisory Board: Genentech, Novartis, Celldex, Foundation Medicine, Celldex, Deciphera Pharmaceuticals. Research Support: Sanofi-Aventis, AstraZeneca, EMD-Serono, Eli Lilly, Novartis, Deciphera Pharmaceuticals. PG, JH, RM, CC, SP, ML, NP, YY, DL, AR, BV, MC, NV, IWT-L, KA, MRG—none.

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Trial was supported by Genentech and “Head for the Cure Foundation”.

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Raizer, J.J., Giglio, P., Hu, J. et al. A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients. J Neurooncol 126, 185–192 (2016). https://doi.org/10.1007/s11060-015-1958-z

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