title: A phase II, randomized, multicenter study to assess the efficacy, safety, and tolerability of zibotentan (ZD4054) in combination with pemetrexed in patients with advanced non-small cell lung cancer.
abstract: OBJECTIVE
  This study evaluated overall survival (OS) of patients with advanced non-squamous NSCLC following treatment with the specific endothelin A receptor antagonist, zibotentan in combination with pemetrexed compared with pemetrexed monotherapy.
  
  
  METHODS
  In this double-blinded, placebo-controlled study, patients with advanced NSCLC with non-squamous histology who had failed first-line platinum-based chemotherapy were randomized to receive either once-daily zibotentan 10 mg in combination with 3-weekly pemetrexed 500 mg/m(2) or placebo plus 3-weekly pemetrexed 500 mg/m(2). OS was calculated as the interval from date of randomization to date of death from any cause. Safety and tolerability were evaluated by recording the incidence of adverse events (AE) according to Common Toxicity Criteria for AE (CTCAE).
  
  
  RESULTS
  Sixty-six patients were randomized and completed the study (zibotentan plus pemetrexed, n = 30; placebo plus pemetrexed, n = 36). At the data cutoff, a total of 44 deaths had occurred, 20 and 24 in the zibotentan and placebo groups, respectively. No significant difference in OS was observed between the zibotentan and placebo treatment groups (HR, 1.13; 80% CI 0.77, 1.67; P = 0.69). The majority of AE were of CTCAE grade 1 or 2, and the most commonly reported AE in both treatment groups was anemia (23 and 25% of patients in the zibotentan and placebo groups, respectively).
  
  
  CONCLUSIONS
  There was no survival signal in patients with NSCLC following treatment with zibotentan in combination with pemetrexed. No new issues related to safety for either zibotentan or pemetrexed were identified.
authors.affiliation: Service de Pneumologie, Hôpital Saint Antoine, 184 Rue du Faubourg, Saint-Antoine, 75571 Paris Cedex 12, France. christos.chouaid@sat.aphp.fr
authors.forename: Christos
authors.initials: C
authors.lastname: Chouaid
authors.forename: Faith
authors.initials: F
authors.lastname: Nathan
authors.forename: Kristine
authors.initials: K
authors.lastname: Pemberton
authors.forename: Thomas
authors.initials: T
authors.lastname: Morris
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D004311:Double-Blind Method; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D009362:Neoplasm Metastasis; D000068437:Pemetrexed; D011759:Pyrrolidines / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D005971:Glutamates; D011759:Pyrrolidines; C511404:ZD4054; D000068437:Pemetrexed; D006147:Guanine