title: Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study.
abstract: BACKGROUND
  With use of EGFR tyrosine-kinase inhibitor monotherapy for patients with activating EGFR mutation-positive non-small-cell lung cancer (NSCLC), median progression-free survival has been extended to about 12 months. Nevertheless, new strategies are needed to further extend progression-free survival and overall survival with acceptable toxicity and tolerability for this population. We aimed to compare the efficacy and safety of the combination of erlotinib and bevacizumab compared with erlotinib alone in patients with non-squamous NSCLC with activating EGFR mutation-positive disease.
  
  
  METHODS
  In this open-label, randomised, multicentre, phase 2 study, patients from 30 centres across Japan with stage IIIB/IV or recurrent non-squamous NSCLC with activating EGFR mutations, Eastern Cooperative Oncology Group performance status 0 or 1, and no previous chemotherapy for advanced disease received erlotinib 150 mg/day plus bevacizumab 15 mg/kg every 3 weeks or erlotinib 150 mg/day monotherapy as a first-line therapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, as determined by an independent review committee. Randomisation was done with a dynamic allocation method, and the analysis used a modified intention-to-treat approach, including all patients who received at least one dose of study treatment and had tumour assessment at least once after randomisation. This study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-111390.
  
  
  RESULTS
  Between Feb 21, 2011, and March 5, 2012, 154 patients were enrolled. 77 were randomly assigned to receive erlotinib and bevacizumab and 77 to erlotinib alone, of whom 75 patients in the erlotinib plus bevacizumab group and 77 in the erlotinib alone group were included in the efficacy analyses. Median progression-free survival was 16·0 months (95% CI 13·9-18·1) with erlotinib plus bevacizumab and 9·7 months (5·7-11·1) with erlotinib alone (hazard ratio 0·54, 95% CI 0·36-0·79; log-rank test p=0·0015). The most common grade 3 or worse adverse events were rash (19 [25%] patients in the erlotinib plus bevacizumab group vs 15 [19%] patients in the erlotinib alone group), hypertension (45 [60%] vs eight [10%]), and proteinuria (six [8%] vs none). Serious adverse events occurred at a similar frequency in both groups (18 [24%] patients in the erlotinib plus bevacizumab group and 19 [25%] patients in the erlotinib alone group).
  
  
  CONCLUSIONS
  Erlotinib plus bevacizumab combination could be a new first-line regimen in EGFR mutation-positive NSCLC. Further investigation of the regimen is warranted.
  
  
  BACKGROUND
  Chugai Pharmaceutical Co Ltd.
authors.affiliation: National Kyushu Cancer Center, Fukuoka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Seto
authors.affiliation: Kanagawa Cardiovascular and Respiratory Center, Kanagawa, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kato
authors.affiliation: The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nishio
authors.affiliation: National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: Kinki-chuo Chest Medical Center, Osaka, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Atagi
authors.affiliation: Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hosomi
authors.affiliation: National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Aichi Cancer Center, Aichi, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.affiliation: Miyagi Cancer Center, Miyagi, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Maemondo
authors.affiliation: Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakagawa
authors.affiliation: Tokyo Medical University Hospital, Tokyo, Japan.
authors.forename: Seisuke
authors.initials: S
authors.lastname: Nagase
authors.affiliation: Kyushu University Hospital, Fukuoka, Japan.
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.affiliation: National Cancer Center, Chiba, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Yamanaka
authors.affiliation: Chugai Pharmaceutical Co Ltd, Tokyo, Japan.
authors.forename: Kosei
authors.initials: K
authors.lastname: Tajima
authors.affiliation: Chugai Pharmaceutical Co Ltd, Tokyo, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Harada
authors.affiliation: Izumi Municipal Hospital, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.affiliation: Wakayama Medical University, Wakayama, Japan. Electronic address: nbyamamo@wakayama-med.ac.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D011799:Quinazolines / Q000008:administration & dosage*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors