title: Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial.
abstract: BACKGROUND
  The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC).
  
  
  METHODS
  Patients from 211 centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m(2) by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2-21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov, number NCT00805194.
  
  
  RESULTS
  Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8-11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months [95% CI 2·9-3·9] vs 2·7 months [2·6-2·8]; hazard ratio [HR] 0·79 [95% CI 0·68-0·92], p=0·0019). After a median follow-up of 31·7 months (IQR 27·8-36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months [95% CI 8·5-12·6] vs 7·9 months [6·7-9·1]; HR 0·75 [95% CI 0·60-0·92], p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months [95% CI 10·6-15·1] vs 10·3 months [95% CI 8·6-12·2]; HR 0·83 [95% CI 0·70-0·99], p=0·0359), but not in the total study population (median 10·1 months [95% CI 8·8-11·2] vs 9·1 months [8·4-10·4]; HR 0·94, 95% CI 0·83-1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), reversible increases in alanine aminotransferase (51 [7·8%] vs six [0·9%]), and reversible increases in aspartate aminotransferase (22 [3·4%] vs three [0·5%]). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three).
  
  
  CONCLUSIONS
  Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Grosshansdorf, Germany; German Centre for Lung Research, Grosshansdorf, Germany. Electronic address: mreck@lungenclinic.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Corporate Division Medicine, TA Oncology, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Mellemgaard
authors.affiliation: Department of Medical Oncology, Centre ICO René Gauducheau, Nantes, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.affiliation: Department of Thoracic Oncology, St Petersburg State Medical University, St Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.affiliation: The Maria Sklodowska-Curie Institute of Oncology, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Krzakowski
authors.affiliation: Pneumology Clinic, Asklepios Fachkliniken Munchen-Gauting, Gauting, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.affiliation: Lung Cancer Unit, Meir Medical Centre, Kfar Saba, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
authors.affiliation: Clinical Facility, Dnepropetrovsk Medical Academy, Dnepropetrovsk Municipal Clinical Hospital no 4, Dnepropetrovsk, Ukraine.
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Medical Affairs, Boehringer Ingelheim Pharma, Ingelheim, Germany.
authors.forename: Claudia-Nanette
authors.initials: CN
authors.lastname: Gann
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT, USA.
authors.forename: José
authors.initials: J
authors.lastname: Barrueco
authors.affiliation: Medical Data Services and Biostatistics, Boehringer Ingelheim Pharma, Biberach an der Riss, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Gaschler-Markefski
authors.affiliation: Department of Oncology, University of Turin, AUO San Luigi, Orbassano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Novello
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001208:Asia; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012307:Risk Factors; D013019:South Africa; D043823:Taxoids / Q000008:administration & dosage; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel; C530716:nintedanib