title: Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study.
abstract: OBJECTIVE
  Ipilimumab, which is an anti-cytotoxic T-cell lymphocyte-4 monoclonal antibody, showed a survival benefit in melanoma with adverse events (AEs) managed by protocol-defined guidelines. A phase II study in lung cancer assessed the activity of ipilimumab plus paclitaxel and carboplatin.
  
  
  METHODS
  Patients (N = 204) with chemotherapy-naive non-small-cell lung cancer (NSCLC) were randomly assigned 1:1:1 to receive paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) with either placebo (control) or ipilimumab in one of the following two regimens: concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimumab plus paclitaxel and carboplatin).Treatment was administered intravenously every 3 weeks for ≤ 18 weeks (induction). Eligible patients continued ipilimumab or placebo every 12 weeks as maintenance therapy. Response was assessed by using immune-related response criteria and modified WHO criteria. The primary end point was immune-related progression-free survival (irPFS). Other end points were progression-free survival (PFS), best overall response rate (BORR), immune-related BORR (irBORR), overall survival (OS), and safety.
  
  
  RESULTS
  The study met its primary end point of improved irPFS for phased ipilimumab versus the control (hazard ratio [HR], 0.72; P = .05), but not for concurrent ipilimumab (HR, 0.81; P = .13). Phased ipilimumab also improved PFS according to modified WHO criteria (HR, 0.69; P = .02). Phased ipilimumab, concurrent ipilimumab, and control treatments were associated with a median irPFS of 5.7, 5.5, and 4.6 months, respectively, a median PFS of 5.1, 4.1, and 4.2 months, respectively, an irBORR of 32%, 21% and 18%, respectively, a BORR of 32%, 21% and 14%, respectively, and a median OS of 12.2, 9.7, and 8.3 months. Overall rates of grade 3 and 4 immune-related AEs were 15%, 20%, and 6% for phased ipilimumab, concurrent ipilimumab, and the control, respectively. Two patients (concurrent, one patient; control, one patient) died from treatment-related toxicity.
  
  
  CONCLUSIONS
  Phased ipilimumab plus paclitaxel and carboplatin improved irPFS and PFS, which supports additional investigation of ipilimumab in NSCLC.
authors.affiliation: Yale Cancer Center and Smilow Cancer Hospital, New Haven, CT, USA. thomas.lynch@yale.edu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.forename: Alexander
authors.initials: A
authors.lastname: Luft
authors.forename: Piotr
authors.initials: P
authors.lastname: Serwatowski
authors.forename: Fabrice
authors.initials: F
authors.lastname: Barlesi
authors.forename: Raju
authors.initials: R
authors.lastname: Chacko
authors.forename: Martin
authors.initials: M
authors.lastname: Sebastian
authors.forename: Joel
authors.initials: J
authors.lastname: Neal
authors.forename: Haolan
authors.initials: H
authors.lastname: Lu
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Cuillerot
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage*; D010919:Placebos; D016016:Proportional Hazards Models; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D010919:Placebos; D016190:Carboplatin; D017239:Paclitaxel