title: Prospective assessment of continuation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed.
abstract: BACKGROUND
  Patients with epidermal growth factor receptor (EGFR) mutation positive non-small-cell lung cancer exhibited marked response to gefitinib or erlotinib. In most cases, however, the patients showed disease progression after EGFR-tyrosine kinase inhibitor (TKI) treatment. We evaluated the efficacy and safety of pemetrexed in combination with EGFR-TKI in patients with disease progression.
  
  
  METHODS
  Patients with EGFR-mutant stage IIIB or IV non-small-cell lung cancer that progressed during gefitinib or erlotinib therapy were administered pemetrexed with the continuation of EGFR-TKI treatment. Pemetrexed was administered on day 1 at a dose of 500 mg/m, and EGFR-TKI was sequentially administered on days 2 to 16. This treatment was repeated every 3 weeks until disease progression. The primary endpoint was disease control rate.
  
  
  RESULTS
  Twenty-seven patients were enrolled in this study. The median number of treatment cycles was six. Overall response rate was 25.9% (95% confidence interval, 9.4%-42.4%) and disease control rate was 77.8% (95% confidence interval, 62.1%-93.5%). Grade 3/4 hematological toxicities were neutropenia (22.2%), leukopenia (14.8%), and anemia (7.4%). Grade 4 nonhematological toxicities were not observed. Major grade 3 nonhematological toxicities were anorexia (14.8%), infection (14.8%), and fatigue (11.1%). The median progression-free survival was 7.0 months, and median survival time was 11.4 months. No treatment-related deaths occurred.
  
  
  CONCLUSIONS
  Pemetrexed in combination with erlotinib or gefitinib after disease progression shows favorable response and acceptable toxicity.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, Abeno-ku, Osaka, Japan. y-naruo@sc4.so-net.ne.jp
authors.forename: Naruo
authors.initials: N
authors.lastname: Yoshimura
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Okishio
authors.forename: Shigeki
authors.initials: S
authors.lastname: Mitsuoka
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kimura
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Masaji
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirashima
authors.forename: Haruko
authors.initials: H
authors.lastname: Daga
authors.forename: Koji
authors.initials: K
authors.lastname: Takeda
authors.forename: Kazuto
authors.initials: K
authors.lastname: Hirata
authors.forename: Shinzoh
authors.initials: S
authors.lastname: Kudoh
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000139:chemically induced; D000855:Anorexia / Q000139:chemically induced; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D016001:Confidence Intervals; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D000077156:Gefitinib; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D007239:Infections / Q000139:chemically induced; D053208:Kaplan-Meier Estimate; D007970:Leukopenia / Q000139:chemically induced; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D000068437:Pemetrexed; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage
chemical_list: D005971:Glutamates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068437:Pemetrexed; D006147:Guanine; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D000077156:Gefitinib