title: A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1).
abstract: BACKGROUND
  This trial was designed to evaluate the activity and safety of ganetespib in combination with docetaxel in advanced non-small cell lung cancer (NSCLC) and to identify patient populations most likely to benefit from the combination.
  
  
  METHODS
  Patients with one prior systemic therapy for advanced disease were eligible. Docetaxel (75 mg/m(2) on day 1) was administered alone or with ganetespib (150 mg/m(2) on days 1 and 15) every 3 weeks. The primary end points were progression-free survival (PFS) in two subgroups of the adenocarcinoma population: patients with elevated lactate dehydrogenase (eLDH) and mutated KRAS (mKRAS).
  
  
  RESULTS
  Of 385 patients enrolled, 381 were treated. Early in the trial, increased hemoptysis and lack of efficacy were observed in nonadenocarcinoma patients (n = 71); therefore, only patients with adenocarcinoma histology were subsequently enrolled. Neutropenia was the most common grade ≥3 adverse event: 41% in the combination arm versus 42% in docetaxel alone. There was no improvement in PFS for the combination arm in the eLDH (N = 114, adjusted hazard ratio (HR) = 0.77, P = 0.1134) or mKRAS (N = 89, adjusted HR = 1.11, P = 0.3384) subgroups. In the intent-to-treat adenocarcinoma population, there was a trend in favor of the combination, with PFS (N = 253, adjusted HR = 0.82, P = 0.0784) and overall survival (OS) (adjusted HR = 0.84, P = 0.1139). Exploratory analyses showed significant benefit of the ganetespib combination in the prespecified subgroup of adenocarcinoma patients diagnosed with advanced disease >6 months before study entry (N = 177): PFS (adjusted HR = 0.74, P = 0.0417); OS (adjusted HR = 0.69, P = 0.0191).
  
  
  CONCLUSIONS
  Advanced lung adenocarcinoma patients treated with ganetespib in combination with docetaxel had an acceptable safety profile. While the study's primary end points were not met, significant prolongation of PFS and OS was observed in patients >6 months from diagnosis of advanced disease, a subgroup chosen as the target population for the phase III study.
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA ssramal@emory.edu.
authors.forename: S
authors.initials: S
authors.lastname: Ramalingam
authors.affiliation: Division of Medical Oncology, University of Ottawa, Ottawa, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Goss
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology, Badalona, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Department of Surgery, University Medical Center Mannheim, Mannheim, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schmid-Bindert
authors.affiliation: Institute for Pulmonary Diseases of Vojvodina, Faculty of Medicine, University of Novi Sad, Novi Sad.
authors.forename: B
authors.initials: B
authors.lastname: Zaric
authors.affiliation: Clinic for Oncology, Medical Center Bezanijska Kosa, Belgrade, Serbia.
authors.forename: Z
authors.initials: Z
authors.lastname: Andric
authors.affiliation: Department of Oncology, Multiple-Discipline Clinical Hospital #4, Dnipropetrovsk, Ukraine.
authors.forename: I
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: Surgical Department of Tumor Diagnostics, Russian Academy of Medical Science, Moscow, Russia.
authors.forename: D
authors.initials: D
authors.lastname: Komov
authors.affiliation: Oncology Clinic, University of Sarajevo Clinics Center, Sarajevo, Bosnia.
authors.forename: T
authors.initials: T
authors.lastname: Ceric
authors.affiliation: Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, USA.
authors.forename: F
authors.initials: F
authors.lastname: Khuri
authors.affiliation: Department for Respiratory Diseases Jordanovac, University of Zagreb, Zagreb, Croatia.
authors.forename: M
authors.initials: M
authors.lastname: Samarzija
authors.affiliation: Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Felip
authors.affiliation: Department of Medical Oncology, Oncological Institute Ion Chiricuta, Cluj-Napoca, Romania.
authors.forename: T
authors.initials: T
authors.lastname: Ciuleanu
authors.affiliation: Department of Medical Oncology, McGill University Health Centre, Montreal, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Hirsh
authors.affiliation: Third Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Wehler
authors.affiliation: Department of Research Oncology, King's College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Spicer
authors.affiliation: Department of Medicine, University of Chicago, Chicago.
authors.forename: R
authors.initials: R
authors.lastname: Salgia
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston.
authors.forename: G
authors.initials: G
authors.lastname: Shapiro
authors.affiliation: Department of Clinical Research, Synta Pharmaceuticals Corp., Lexington, USA.
authors.forename: E
authors.initials: E
authors.lastname: Sheldon
authors.affiliation: Department of Clinical Research, Synta Pharmaceuticals Corp., Lexington, USA.
authors.forename: F
authors.initials: F
authors.lastname: Teofilovici
authors.affiliation: Department of Clinical Research, Synta Pharmaceuticals Corp., Lexington, USA.
authors.forename: V
authors.initials: V
authors.lastname: Vukovic
authors.affiliation: Department of Cancer Studies, University of Leicester, Leicester, UK.
authors.forename: D
authors.initials: D
authors.lastname: Fennell
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D018841:HSP90 Heat-Shock Proteins; C117307:KRAS protein, human; C533237:STA 9090; D043823:Taxoids; D014230:Triazoles; D000077143:Docetaxel; D007770:L-Lactate Dehydrogenase; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HSP90 inhibitor; adenocarcinoma; advanced NSCLC; docetaxel; ganetespib