title: Successful treatment with afatinib after gefitinib- and erlotinib-induced hepatotoxicity.
abstract: Clinical trials of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib have shown that some patients receiving these agents develop severe hepatotoxicity that necessitates treatment cessation. Both drugs undergo extensive hepatic metabolism mediated predominantly by cytochrome P450 family enzymes. Afatinib is a second-generation, irreversible EGFR-TKI that competes with ATP for binding to EGFR and the related proteins HER2 and HER4 and whose major circulating metabolites are covalent drug-protein adducts. We here describe a patient with EGFR mutation-positive lung adenocarcinoma who developed severe hepatotoxicity during treatment first with gefitinib and then with erlotinib, but who was subsequently able to continue treatment with afatinib for at least 44 weeks with no evidence of hepatotoxicity or disease progression. As far as we are aware, this is the first report of successful treatment with afatinib after the development of high-grade hepatotoxicity during both gefitinib and erlotinib therapy.
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan. hayashi_h@dotd.med.kindai.ac.jp.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Respiratory Medicine, National Hospital Organization, Osaka Minami Medical Center, 2-1 Kido-higashimachi, Kawachi, Osaka, Nagano, 586-8521, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Kudo
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000209:etiology; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use
chemical_list: D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib
keywords: Afatinib; Epidermal growth factor receptor (EGFR); Hepatotoxicity; Non–small cell lung cancer (NSCLC); Tyrosine kinase inhibitor (TKI)