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    Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial

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    Authors
    Saran, F.
    Welsh, L.
    James, A.
    McBain, Catherine A
    Gattamaneni, Rao
    Jefferies, S.
    Harris, F.
    Pemberton, K.
    Schaible, J.
    Bender, S.
    Cseh, A.
    Brada, M.
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    Affiliation
    The Royal Marsden NHS Foundation Trust, London, UK.
    Issue Date
    2021
    
    Metadata
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    Abstract
    Background: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. Methods: This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. Results: Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. Conclusions: This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection.
    Citation
    Saran F, Welsh L, James A, McBain C, Gattamaneni R, Jefferies S, et al. Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial Vol. 155, Journal of Neuro-Oncology. Springer Science and Business Media LLC; 2021. p. 307–17.
    Journal
    Journal of Neuro-oncology
    URI
    http://hdl.handle.net/10541/624943
    DOI
    10.1007/s11060-021-03877-6
    PubMed ID
    34787778
    Type
    Article
    ae974a485f413a2113503eed53cd6c53
    10.1007/s11060-021-03877-6
    Scopus Count
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