title: A phase I-II study of combined blockade of the ErbB receptor network with trastuzumab and gefitinib in patients with HER2 (ErbB2)-overexpressing metastatic breast cancer.
abstract: OBJECTIVE
  To determine the safety, and efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in combination with trastuzumab in patients with metastatic HER2-positive metastatic breast cancer.
  
  
  METHODS
  Patients with HER2-overexpressing breast cancer were treated with trastuzumab 2 mg/kg/week and gefitinib 250 to 500 mg/day. The primary end point of the study was to increase the proportion progression-free from 50% to 65% at 6 months in chemotherapy-naive patients and from 50% to 70% at 3 months in patients previously treated with chemotherapy in the metastatic setting.
  
  
  RESULTS
  In the phase I study, all patients treated with gefitinib 500 mg/day developed grade 3 diarrhea. The phase II study was conducted using trastuzumab and gefitinib 250 mg/day. One patient achieved a complete response, 2 had a partial response, and 6 had stable disease for an overall response rate of 9% and a clinical benefit rate of 28% (9 of 32). Median time to progression (TTP) was 3 months (95% confidence interval, 2.3-4.1) in patients with no prior systemic therapy in the metastatic setting (n = 23). In patients treated with prior systemic therapy (n = 9), the median TTP of 5.3 months (95% confidence interval, 2.8-8.1). Overall median survival was 27 months. TTP was similar in EGFR-positive compared with EGFR-negative patients.
  
  
  CONCLUSIONS
  Gefitinib 250 mg/day was the maximal dose that can be safely administered with weekly trastuzumab. Interim analysis of the efficacy suggested that the combination was unlikely to result in clinical benefit compared with trastuzumab alone. These results do not support the use of this combination in patients with HER2-positive breast cancer.
authors.affiliation: Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, 2200 Pierce Avenue, Nashville, TN 37232, USA. carlos.arteaga@vanderbilt.edu
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Anne
authors.initials: A
authors.lastname: O'Neill
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Michael
authors.initials: M
authors.lastname: Pins
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Sparano
authors.forename: George W
authors.initials: GW
authors.lastname: Sledge
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Davidson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D005260:Female; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011485:Protein Binding; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000077156:Gefitinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab