title: Activity of the EGFR-HER2 dual inhibitor afatinib in EGFR-mutant lung cancer patients with acquired resistance to reversible EGFR tyrosine kinase inhibitors.
abstract: BACKGROUND
  The purpose of this study was to evaluate the efficacy of afatinib in EGFR-mutant metastatic NSCLC patients with acquired resistance to erlotinib or gefitinib.
  
  
  METHODS
  We retrospectively analyzed the outcome of patients with EGFR-mutant advanced NSCLC treated with afatinib after failure of chemotherapy and EGFR TKIs.
  
  
  RESULTS
  A total of 96 individuals were included in the study. According to EGFR status, most patients (n = 63; 65.6%) harbored a deletion in exon 19, and de novo T790M mutation was detected in 2 cases (T790M and exon 19). Twenty-four (25%) patients underwent repeated biopsy immediately before starting afatinib and secondary T790M was detected in 8 (33%) samples. Among the 86 patients evaluable for efficacy, response rate was 11.6%, with a median progression free-survival (PFS) and overall survival (OS) of 3.9 and 7.3 months, respectively. No significant difference in PFS and OS was observed according to type of last therapy received before afatinib, type of EGFR mutation or adherence to Jackman criteria, and patients benefiting from afatinib therapy had longer PFS and OS (P < .001). Outcome results for repeated biopsy patients were similar to the whole population, with no evidence of response in T790M-positive patients. All patients were evaluable for toxicity, and 81% experienced an AE of any grade, with grade 3 to 4 AEs, mainly diarrhea and skin toxicity, occurring in 19 (20%) patients.
  
  
  CONCLUSIONS
  Our results showed that afatinib has only modest efficacy in a real life population of EGFR mutant NSCLC patients with acquired resistance to erlotinib or gefitinib.
authors.affiliation: Department of MedicalOncology, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Landi
authors.affiliation: Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Tiseo
authors.affiliation: Division of Medical Oncology, Ospedale Santa Maria della Misericordia, Perugia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Chiari
authors.affiliation: High Specialization Hospitals, Oncological Pulmonary First Unit, Rome, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Ricciardi
authors.affiliation: Fondazione Ricerca Traslazionale, FoRT, Rome, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rossi
authors.affiliation: Division Of Medical Oncology, Istituto Tumori "Giovanni Paolo II", IRCCS, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Galetta
authors.affiliation: Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria, San Luigi Gonzaga, Turin, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
authors.affiliation: Division of Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.affiliation: Department of MedicalOncology, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Armida
authors.initials: A
authors.lastname: D'Incecco
authors.affiliation: Department of MedicalOncology, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Minuti
authors.affiliation: Department of MedicalOncology, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Carmelo
authors.initials: C
authors.lastname: Tibaldi
authors.affiliation: Department of MedicalOncology, Istituto Toscano Tumori, Livorno, Italy.
authors.forename: Jessica
authors.initials: J
authors.lastname: Salvini
authors.affiliation: Medical Oncology Unit, University Hospital of Parma, Parma, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: Division of Medical Oncology, Fondazione IRCSS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Eva Regina
authors.initials: ER
authors.lastname: Haspinger
authors.affiliation: Division of Medical Oncology, Ospedale San Gerardo, Monza, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortinovis
authors.affiliation: Division of Medical Oncology, Azienda Ospedaliera Universitaria Integrate, Verona, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Santo
authors.affiliation: Medical Oncology Service, Cannizzaro Hospital, Catania, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Banna
authors.affiliation: Division Of Medical Oncology, Istituto Tumori "Giovanni Paolo II", IRCCS, Bari, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Catino
authors.affiliation: Department of Oncology, University of Turin, Azienda Ospedaliero-Universitaria, San Luigi Gonzaga, Turin, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: GiajLevra
authors.affiliation: Division of Medical Oncology, Ospedale Santa Maria della Misericordia, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
authors.affiliation: Division of Thoracic Oncology, Istituto Europeo di Oncologia, Milano, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: de Marinis
authors.affiliation: Department of MedicalOncology, Istituto Toscano Tumori, Livorno, Italy. Electronic address: f.cappuzzo@gmail.com.
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003967:Diarrhea / Q000209:etiology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Acquired resistance; Afatinib; Erlotinib; Gefitinib; NSCLC