Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: A case report

// Jad Alshami 1 , Marie-Christine Guiot 1 , Scott Owen 1 , Petr Kavan 1 , Neil Gibson 2 , Flavio Solca 3 , Agnieszka Cseh 3 , David A. Reardon 4 , Thierry Muanza 1, 5 1 Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada 2 Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany 3 Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria 4 Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA 5 Radiation Oncology, Jewish General Hospital, Montreal, Canada Correspondence to: Thierry M. Muanza, e-mail: thierry.muanza@mcgill.ca Keywords: afatinib, temozolomide, glioblastoma, next-generation sequencing, epidermal growth factor receptor Received: April 15, 2015 Accepted: September 11, 2015 Published: September 21, 2015 ABSTRACT 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/m 2 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.