title: Afatinib, an irreversible ErbB family blocker, with protracted temozolomide in recurrent glioblastoma: a case report.
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/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.
authors.affiliation: Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada.
authors.forename: Jad
authors.initials: J
authors.lastname: Alshami
authors.affiliation: Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Guiot
authors.affiliation: Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada.
authors.forename: Scott
authors.initials: S
authors.lastname: Owen
authors.affiliation: Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada.
authors.forename: Petr
authors.initials: P
authors.lastname: Kavan
authors.affiliation: Drug Metabolism & Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Neil
authors.initials: N
authors.lastname: Gibson
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria.
authors.forename: Flavio
authors.initials: F
authors.lastname: Solca
authors.affiliation: Boehringer Ingelheim RCV GmbH & Co. KG, Vienna, Austria.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Cseh
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.affiliation: Clinical Research Unit, Montreal Neurological Institute and Hospital, McGill University Health Center, Montreal, Canada.|Radiation Oncology, Jewish General Hospital, Montreal, Canada.
authors.forename: Thierry
authors.initials: T
authors.lastname: Muanza
mesh_terms: D000077716:Afatinib; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy* / Q000601:surgery; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005838:Genotype; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy* / Q000601:surgery; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000532:radiotherapy / Q000601:surgery; D018739:Oncogene Proteins v-erbB / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011799:Quinazolines / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018739:Oncogene Proteins v-erbB; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; C410723:epidermal growth factor receptor VIII; D000077716:Afatinib; D003606:Dacarbazine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077204:Temozolomide
keywords: afatinib; epidermal growth factor receptor; glioblastoma; next-generation sequencing; temozolomide