title: Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial.
abstract: BACKGROUND
  Afatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy.
  
  
  METHODS
  Patients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m(2)/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes.
  
  
  RESULTS
  Two hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent.
  
  
  CONCLUSIONS
  Afatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy.
  
  
  BACKGROUND
  NCT01085136 (clinicaltrials.gov).
authors.affiliation: West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen German Cancer Research Center, German Cancer Consortium (DKTK), Heidelberg, Germany martin.schuler@uk-essen.de.
authors.forename: M
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Department of Medical Research, National Taiwan University and National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: J C-H
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul.
authors.forename: K
authors.initials: K
authors.lastname: Park
authors.affiliation: Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: J-H
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Oncologie Médicale, Institut de Cancérologie de l'Ouest, Nantes, France.
authors.forename: J
authors.initials: J
authors.lastname: Bennouna
authors.affiliation: Taipei Cancer Center, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
authors.forename: Y-M
authors.initials: YM
authors.lastname: Chen
authors.affiliation: Services de Pneumologie, CHI Créteil, Créteil, France.
authors.forename: C
authors.initials: C
authors.lastname: Chouaid
authors.affiliation: 1st Oncological Pulmonary Unit, San Camillo, High Specialization Hospital, Rome Thoracic Oncology Division, European Institute of Oncology, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: De Marinis
authors.affiliation: Department of Medical Oncology, Jiangsu Province Cancer Hospital, Nanjing, China.
authors.forename: J-F
authors.initials: JF
authors.lastname: Feng
authors.affiliation: IRCCS AOU San Martino IST, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Grossi
authors.affiliation: Lung Cancer, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: D-W
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Pulmonary Oncology, Affiliated Hospital of Academy of Military Medical Science, Beijing.
authors.forename: X
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Department of Pulmonology, Koranyi National Institute for Pulmonology, Budapest, Hungary.
authors.forename: J
authors.initials: J
authors.lastname: Strausz
authors.affiliation: Abdominal Department, Kharkiv Regional Clinical Oncology Center, Kharkiv, Ukraine.
authors.forename: Y
authors.initials: Y
authors.lastname: Vinnyk
authors.affiliation: Department of Medicine A, University Hospital, Münster, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Wiewrodt
authors.affiliation: Department of Oncology, Tongji University Medical School Cancer Institute, Shanghai, China.
authors.forename: C
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Biostatistics, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: Clinical Development Medical Affairs-Oncology, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, USA.
authors.forename: V K
authors.initials: VK
authors.lastname: Chand
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif, France.
authors.forename: D
authors.initials: D
authors.lastname: Planchard
mesh_terms: D000077716:Afatinib; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D018450:Disease Progression; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000009:adverse effects / Q000627:therapeutic use*; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017239:Paclitaxel; D000077156:Gefitinib
keywords: NSCLC; afatinib; paclitaxel; squamous cell