Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: A case report
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Jad Alshami1, Marie-Christine Guiot1, Scott Owen1, Petr Kavan1, Neil Gibson2, Flavio Solca3, Agnieszka Cseh3, David A. Reardon4, Thierry Muanza1,5
1Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada
2Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
3Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria
4Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
5Radiation Oncology, Jewish General Hospital, Montreal, Canada
Thierry M. Muanza, e-mail: [email protected]
Keywords: afatinib, temozolomide, glioblastoma, next-generation sequencing, epidermal growth factor receptor
Received: April 15, 2015 Accepted: September 11, 2015 Published: September 21, 2015
There are few effective treatments for recurrent glioblastoma multiforme (GBM). We present a patient with recurrent GBM who achieved a prolonged response to treatment with afatinib, an irreversible ErbB family blocker, plus temozolomide. A 58-year-old female patient was diagnosed with multifocal primary GBM. After surgical resection, first-line therapy comprised radiotherapy and temozolomide. Following disease progression after 3 temozolomide cycles, the patient entered a phase I/II clinical trial of afatinib (20–40 mg daily for 28 days) plus temozolomide (50 mg/m2 every 21/28 days). Next-generation sequencing analysis of the brain tumor specimen was performed. At the last assessment, 63 treatment cycles had been completed and the patient had survived for ~5 years since recurrence. Significant disease regression was observed after 5 cycles and was maintained during long-term follow-up. Adverse events were consistent with the known tolerability profile of afatinib and were managed by treatment interruption/dose reduction. The patient had several epidermal growth factor receptor (EGFR) aberrations, including gene amplification and EGFRvIII positivity. Three somatic mutations were identified, including an unprecedented extracellular-domain substitution (D247Y). The patient has survived ~6-fold longer than normally expected in patients with recurrent GBM. The complex EGFR genotype may underlie sustained response to afatinib plus temozolomide.
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