title: Anti-angiogenic-specific adverse events in patients with non-small cell lung cancer treated with nintedanib and docetaxel.
abstract: OBJECTIVE
  LUME-Lung 1 was a randomized, placebo-controlled, Phase III trial investigating nintedanib+docetaxel versus placebo+docetaxel in patients with advanced NSCLC progressing after first-line chemotherapy. Progression-free survival was significantly improved with nintedanib+docetaxel in the overall population and overall survival was significantly improved in the pre-specified analysis of patients with adenocarcinoma. We evaluated the frequency of characteristic adverse events (AEs) commonly seen with existing anti-angiogenic agents.
  
  
  METHODS
  The incidence and intensity of AEs were evaluated in all patients who received at least one dose of study medication (N=1307) and for the two main histologies: adenocarcinoma (n=653) and squamous cell carcinoma (SCC; n=553). AEs of special interest were analyzed by category, preferred term, and worst CTCAE grade and included perforation, hypertension, bleeding, thromboembolic events, and skin disorders.
  
  
  CONCLUSIONS
  The incidence of patients with all-grade gastrointestinal (GI) perforations was low and balanced between arms (0.5% in both) and across histologies; the incidence of non-GI perforations was 1.2% with nintedanib+docetaxel versus 0.2% with placebo+docetaxel. The incidence of some events was higher with nintedanib+docetaxel versus placebo+docetaxel; hypertension (3.5% vs 0.9%), rash (11.0% vs 8.1%), and cutaneous adverse reactions (13.0% vs 10.7%). Rash and cutaneous adverse reactions were predominantly Grade 1-2 with both treatments. The incidence of all-grade bleeding was also slightly higher in nintedanib+docetaxel-treated patients (14.1% vs 11.6%) driven by between-treatment differences in the SCC subpopulation; most events were Grade 1-2. The proportion of patients with a thromboembolic event was low and comparable between arms for all grades (5.1% vs 4.6%) and Grade ≥3 (2.1% vs 3.1%). Safety evaluation of the LUME-Lung 1 study showed that the frequency of AEs commonly associated with other anti-angiogenic agents was lower with nintedanib+docetaxel. Survival benefits from addition of nintedanib to docetaxel in patients with adenocarcinoma after first-line therapy can be achieved alongside a manageable safety profile.
authors.affiliation: Department of Thoracic Oncology, Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany. Electronic address: Dr.martin.reck@web.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Reck
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Mellemgaard
authors.affiliation: Pneumology Clinic, Asklepios Fachkliniken, Gauting, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: von Pawel
authors.affiliation: Lung Cancer Unit, Meir Medical Center, Kfar Saba, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Gottfried
authors.affiliation: Clinical Facility, Dnepropetrovsk Medical Academy, Clinical Hospital #4, Dnepropetrovsk, Ukraine.
authors.forename: Igor
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: Division of Thoracic Oncology, Jilin Province Cancer Hospital, Changchun, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Pulmonary Department-Oncology Unit, General Hospital of Thessaloniki, Thessaloniki, Greece.
authors.forename: Kostas
authors.initials: K
authors.lastname: Zarogoulidis
authors.affiliation: Department of Thoracic Surgery, Leningrad Regional Clinical Hospital, St. Petersburg, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Luft
authors.affiliation: Department of Medical Oncology, Centre René Gauducheau, Nantes, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.
authors.forename: José
authors.initials: J
authors.lastname: Barrueco
authors.affiliation: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA.
authors.forename: Hesham
authors.initials: H
authors.lastname: Aboshady
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Hocke
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Kaiser
authors.affiliation: Department of Medical Oncology, Centre René Gauducheau, Nantes, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy; D020533:Angiogenesis Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects; D008175:Lung Neoplasms / Q000188:drug therapy*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D043823:Taxoids; D000077143:Docetaxel; C530716:nintedanib
keywords: Angiogenesis inhibitors; Drug-related side effects and adverse reactions; Non-small cell lung cancer