title: Intercalated chemotherapy and erlotinib for advanced NSCLC: high proportion of complete remissions and prolonged progression-free survival among patients with EGFR activating mutations.
abstract: BACKGROUND
  Pharmaco-dynamic separation of cytotoxic and targeted drugs might avoid their mutual antagonistic effect in the treatment of advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Eligible patients were treatment-naive with stage IIIB or IV NSCLC. In addition, inclusion was limited to never-smokers or light smokers or, after 2010, to patients with activating epidermal growth-factor receptor (EGFR) mutations. Treatment started with 3-weekly cycles of gemcitabine and cisplatin on days 1, 2 and 4 and erlotinib on days 5 to 15. After 4 to 6 cycles, patients continued with erlotinib maintenance.
  
  
  RESULTS
  Fifty-three patients were recruited into the trial: 24 prior to 2010 (of whom 9 were later found to be positive for EGFR mutations), and 29 EGFR mutation-positive patients recruited later. Unfavourable prognostic factors included stage IV disease (51 patients - 96%), performance status 2-3 (11 patients - 21%) and brain metastases (15 patients -28%). Grade 4 toxicity included 2 cases of neutropenia and 4 thrombo-embolic events. The 15 EGFR negative patients had 33% objective response rate, median progression-free survival (PFS) 6.0 months and median survival 7.6 months. Among 38 EGFR positive patients, complete response (CR) or partial response (PR) were seen in 16 (42.1%) and 17 (44.7%) cases, respectively. PET-CT scanning was performed in 30 patients and confirmed CR and PR in 16 (53.3%) and 9 (30.0%) cases, respectively. Median PFS for EGFR mutated patients was 21.2 months and median survival was 32.5 months.
  
  
  CONCLUSIONS
  While patients with EGFR negative tumors do not benefit from addition of erlotinib, the intercalated schedule appears most promising for those with EGFR activating mutations.
authors.affiliation: Institute of Oncology Ljubljana, Ljubljana, Slovenia ; Faculty of Medicine, University of Maribor, Maribor, Slovenia.
authors.forename: Matjaz
authors.initials: M
authors.lastname: Zwitter
authors.affiliation: Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Karmen
authors.initials: K
authors.lastname: Stanic
authors.affiliation: Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Mirjana
authors.initials: M
authors.lastname: Rajer
authors.affiliation: University Hospital for Pulmonary Diseases Golnik, Golnik, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Kern
authors.affiliation: Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Vrankar
authors.affiliation: Department of Pulmonary Medicine, University Clinical Centre Maribor, Maribor, Slovenia.
authors.forename: Natalija
authors.initials: N
authors.lastname: Edelbaher
authors.affiliation: Institute of Oncology Ljubljana, Ljubljana, Slovenia.
authors.forename: Viljem
authors.initials: V
authors.lastname: Kovac
keywords: EGFR activating mutations; Non-small cell lung cancer; cisplatin; erlotinib; gemcitabine; intercalated therapy; metabolic response