title: Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation.
abstract: OBJECTIVE
  Patients with advanced non-small cell lung cancer (NSCLC) harboring a sensitive epidermal growth factor receptor (EGFR) mutation have been shown to exhibit a marked response to EGFR-tyrosine kinase inhibitor (TKI) treatment. Pemetrexed and gefitinib were reported to have a schedule-dependent cytotoxic synergism. We evaluated the efficacy and safety of a combination regimen of gefitinib and pemetrexed as first-line chemotherapy in EGFR-mutated NSCLC patients.
  
  
  METHODS
  Systemic therapy-naïve patients with advanced non-squamous NSCLC harboring a sensitive EGFR mutation were included in this study. Pemetrexed was administered on day 1 at a dose of 500 mg/m(2), and gefitinib was sequentially administered on days 2-16. This treatment regimen was repeated every 3 weeks until disease progression.
  
  
  RESULTS
  Twenty-six patients were enrolled in this study. The median number of treatment cycles was 16 (range, 1-35). The overall response rate (ORR) was 84.6% (95% confidence interval [CI], 70.7-98.5%), and the disease control rate (DCR) was 96.2% (95% CI, 88.9-100%). Grade 3/4 hematological toxicities included neutropenia (15.4%), leukopenia (7.7%), and anemia (3.8%). No grade 4 non-hematological toxicities were observed. The main grade 3 non-hematological toxicities were infection (11.5%), increased alanine aminotransferase (11.5%) and aspartate aminotransferase (7.7%) levels, fatigue (3.8%), diarrhea (3.8%), and pneumonitis (3.8%). We observed a median progression-free survival (PFS) of 18.0 months (95% CI, 15.0-21.0 months) and a median survival time (MST) of 32.0 months (95% CI, 28.5-35.5 months). There were no treatment-related deaths.
  
  
  CONCLUSIONS
  The combination regimen used in this study showed a high ORR, long median PFS, and acceptable toxicity. A future randomized trial on pemetrexed plus gefitinib compared with gefitinib alone is warranted.
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan. Electronic address: y-naruo@sc4.so-net.ne.jp.
authors.forename: Naruo
authors.initials: N
authors.lastname: Yoshimura
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Shinzoh
authors.initials: S
authors.lastname: Kudoh
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Shigeki
authors.initials: S
authors.lastname: Mitsuoka
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yoshimoto
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Oka
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakai
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Suzumira
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Kuniomi
authors.initials: K
authors.lastname: Matusura
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Medical Education and General Practice, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tochino
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Asai
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Premier Preventive Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Clinical Oncology, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan; Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawaguchi
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Osaka City University, 1-4-3, Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Hirata
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000068437:Pemetrexed / Q000008:administration & dosage / Q000009:adverse effects; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000068437:Pemetrexed; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: Epidermal growth factor receptor; First-line treatment; Gefitinib; Non-small cell lung cancer; Pemetrexed; Phase II study