title: Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial.
abstract: LUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC).
  
  
  
  Patients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m2on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2-21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint.
  
  
  
  Based on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70-0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85-1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis.
  
  
  
  Although recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.
authors.affiliation: Melvin and Bren Simon Cancer Center, Indiana University School of Medicine, Indiana University, Indianapolis, IN, USA. Electronic address: nhanna@iupui.edu.
authors.forename: Nasser H
authors.initials: NH
authors.lastname: Hanna
authors.affiliation: Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany; Institute of Clinical Pharmacology, Georg-August-University Göttingen, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: Department of Oncology, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sullivan
authors.affiliation: Instituto Nacional del Cáncer, Santiago, Chile.
authors.forename: Osvaldo Rudy
authors.initials: OR
authors.lastname: Aren
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Myung-Ju
authors.initials: MJ
authors.lastname: Ahn
authors.affiliation: Internal Medicine, National Kidney and Transplant Institute, Quezon City, Philippines.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Tiangco
authors.affiliation: Boehringer Ingelheim (Canada) Ltd, Burlington, ON, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Voccia
authors.affiliation: Pneumology Clinic, Asklepios Fachkliniken, Gauting, Germany.
authors.forename: Joachim von
authors.initials: JV
authors.lastname: Pawel
authors.affiliation: Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kovcin
authors.affiliation: Jewish General Hospital, Montréal, Québec, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Agulnik
authors.affiliation: Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Gaschler-Markefski
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.
authors.forename: José
authors.initials: J
authors.lastname: Barrueco
authors.affiliation: Boehringer Ingelheim Pharmaceuticals GmbH & Co. KG, Biberach, Germany.
authors.forename: Patricia
authors.initials: P
authors.lastname: Sikken
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Schloss
authors.affiliation: Yonsei Cancer Center, Yonsei University Health System, Seoul, South Korea.
authors.forename: Joo-Hang
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D000068437:Pemetrexed / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010919:Placebos; D016896:Treatment Outcome
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D010919:Placebos; D000068437:Pemetrexed; C530716:nintedanib
keywords: Angiogenesis inhibitor; Nintedanib; Non-small cell lung cancer; Phase III; Second-line