title: Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001.
abstract: OBJECTIVE
  Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations.
  
  
  METHODS
  In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest.
  
  
  RESULTS
  Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths.
  
  
  CONCLUSIONS
  Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.
authors.affiliation: *Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan; †Department of Hematology/Oncology, Vanderbilt Vanderbilt University Medical Center, Nashville, TN; ‡Department of Respiratory Medicine, NHO Shikoku Cancer Center, Matsuyama, Japan; §Department of Respiratory Medicine, NHO Iwakuni Clinical Center, Iwakuni, Japan; ‖Department of Medical Oncology, NHO Yamaguchi-Ube Medical Center, Ube, Japan; ¶Department of Respiratory Internal Medicine, Japanese Red Cross Kobe Hospital, Kobe, Japan; #Division of Clinical Oncology, Sumitomo Besshi Hospital, Niihama, Japan; **Department of Clinical Research, NHO Yamaguchi-Ube Medical Center, Ube, Japan; ††Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan; ‡‡Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan; and §§Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.
authors.forename: Eiki
authors.initials: E
authors.lastname: Ichihara
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Hotta
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Nogami
authors.forename: Shoichi
authors.initials: S
authors.lastname: Kuyama
authors.forename: Daizo
authors.initials: D
authors.lastname: Kishino
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujii
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kozuki
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tabata
authors.forename: Daijiro
authors.initials: D
authors.lastname: Harada
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chikamori
authors.forename: Keisuke
authors.initials: K
authors.lastname: Aoe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueoka
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hosokawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Bessho
authors.forename: Akiko
authors.initials: A
authors.lastname: Hisamoto-Sato
authors.forename: Toshio
authors.initials: T
authors.lastname: Kubo
authors.forename: Isao
authors.initials: I
authors.lastname: Oze
authors.forename: Nagio
authors.initials: N
authors.lastname: Takigawa
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Kiura
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D011799:Quinazolines; D000068258:Bevacizumab; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib