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



Saran, Frank, Welsh, Liam, James, Allan, McBain, Catherine, Gattamaneni, Rao, Jefferies, Sarah, Harris, Fiona, Pemberton, Karine, Schaible, Jennifer, Bender, Shaun
et al (show 2 more authors) (2021) Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial. JOURNAL OF NEURO-ONCOLOGY, 155 (3). pp. 307-317.

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Abstract

<h4>Background</h4>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.<h4>Methods</h4>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 O<sup>6</sup>-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.<h4>Results</h4>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.<h4>Conclusions</h4>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.<h4>Trial registration</h4>NCT00977431 (first posted September 15, 2009).

Item Type: Article
Uncontrolled Keywords: Glioblastoma, Afatinib, Dose-escalation, Temozolomide, Radiotherapy
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 07 Mar 2023 15:49
Last Modified: 07 Mar 2023 15:49
DOI: 10.1007/s11060-021-03877-6
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3168827