title: Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy.
abstract: OBJECTIVE
  Histone deacetylase inhibitors (HDACis) have been shown to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) linked to epigenetic changes and epithelial-mesenchymal transition (EMT) state. This randomized phase II study evaluated the outcome of erlotinib with and without the isoform selective HDACi, entinostat.
  
  
  METHODS
  Previously treated patients with stage IIIB/IV non-small-cell lung cancer, no prior EGFR-TKIs, and performance status ≤ 2 were randomly administered erlotinib 150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 28 days (EE) or erlotinib plus placebo (EP). The primary end point was 4-month progression-free survival (PFS) rate with additional end points including 6-month PFS rate, PFS, and overall survival (OS). Exploratory analyses included EMT- and EGFR-related biomarker analysis on archival tissue.
  
  
  RESULTS
  One hundred thirty-two patients were enrolled (EE, 67; EP, 65). The 4-month PFS rate was comparable for both groups (EE, 18% v EP, 20%; P = .7). In the subset of patients with high E-cadherin levels, OS was longer in the EE group compared with the EP group (9.4 v 5.4 months; hazard ratio, 0.35; 95% CI, 0.13 to 0.92; P = .03) with a corresponding trend toward increased PFS. The adverse event (AE) profile was acceptable, with rash, fatigue, diarrhea, and nausea the most common AEs in both groups.
  
  
  CONCLUSIONS
  Erlotinib combined with entinostat did not improve the outcomes of patients in the overall study population when compared with erlotinib monotherapy. High E-cadherin expression levels at time of diagnosis indicate an increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a biomarker-driven validation study.
authors.affiliation: University of Colorado Cancer Center, 12801 E 17th Ave, Mail Stop 8117, Aurora, CO 80045, USA.
authors.forename: Samir E
authors.initials: SE
authors.lastname: Witta
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jotte
authors.forename: Katrik
authors.initials: K
authors.lastname: Konduri
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Neubauer
authors.forename: Alexander I
authors.initials: AI
authors.lastname: Spira
authors.forename: Robert L
authors.initials: RL
authors.lastname: Ruxer
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bunn
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000069347:Erlotinib Hydrochloride; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage*; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D015820:Cadherins; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines; D011799:Quinazolines; C118739:entinostat; D000069347:Erlotinib Hydrochloride