title: Phase II study of pemetrexed and cisplatin plus cetuximab followed by pemetrexed and cetuximab maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer.
abstract: OBJECTIVE
  The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC).
  
  
  METHODS
  In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety.
  
  
  RESULTS
  Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up.
  
  
  CONCLUSIONS
  Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature.
authors.affiliation: University Medical Center Mannheim of Heidelberg University, Mannheim, Germany. Electronic address: gerald.schmid-bindert@medma.uni-heidelberg.de.
authors.forename: Gerald
authors.initials: G
authors.lastname: Schmid-Bindert
authors.affiliation: La Maddalena Clinic for Cancer, University of Palermo, Palermo, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gebbia
authors.affiliation: Medizinische Universitaetsklinik und Poliklinik, Tuebingen, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Mayer
authors.affiliation: Hospital del Mar, Barcelona, Spain.
authors.forename: Edurne
authors.initials: E
authors.lastname: Arriola
authors.affiliation: Hospital Universitari Arnau de Vilanova, Lleida, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Márquez-Medina
authors.affiliation: Athens School of Medicine, Athens, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Syrigos
authors.affiliation: Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, The Netherlands.
authors.forename: Bonne
authors.initials: B
authors.lastname: Biesma
authors.affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany.
authors.forename: Monika Iris
authors.initials: MI
authors.lastname: Leschinger
authors.affiliation: Eli Lilly and Company, Copenhagen, Denmark.
authors.forename: Bente
authors.initials: B
authors.lastname: Frimodt-Moller
authors.affiliation: Eli Lilly France, Suresnes, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Ripoche
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: Scott P
authors.initials: SP
authors.lastname: Myrand
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: Tuan S
authors.initials: TS
authors.lastname: Nguyen
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Hozak
authors.affiliation: Eli Lilly and Company, Indianapolis, USA.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Zimmermann
authors.affiliation: Eli Lilly Oncology, Houten, The Netherlands.
authors.forename: Carla
authors.initials: C
authors.lastname: Visseren-Grul
authors.affiliation: Krankenhaus Martha-Maria Halle-Doelau, Halle, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schuette
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D060828:Induction Chemotherapy; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed; D057170:Translational Research, Biomedical; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D000068818:Cetuximab; D002945:Cisplatin
keywords: Cetuximab; Cisplatin; Epidermal growth factor receptor; Folate receptor-alpha; NSCLC; Pemetrexed; Thymidylate synthase; Thyroid transcription factor