title: Carboplatin and Paclitaxel in combination with either vorinostat or placebo for first-line therapy of advanced non-small-cell lung cancer.
abstract: PURPOSE Vorinostat, a histone deacetylase inhibitor, exerts anticancer effects by both histone and nonhistone-mediated mechanisms. It also enhances the anticancer effects of platinum compounds and taxanes in non-small-cell lung cancer (NSCLC) cell lines. This phase II randomized, double-blinded, placebo-controlled study evaluated the efficacy of vorinostat in combination with carboplatin and paclitaxel in patients with advanced-stage NSCLC. PATIENTS AND METHODS Patients with previously untreated stage IIIB (ie, wet) or IV NSCLC were randomly assigned (2:1) to carboplatin (area under the curve, 6 mg/mL x min) and paclitaxel (200 mg/m(2) day 3) with either vorinostat (400 mg by mouth daily) or placebo. Vorinostat or placebo was given on days 1 through 14 of each 3-week cycle to a maximum of six cycles. The primary end point was comparison of the response rate. Results Ninety-four patients initiated protocol therapy. Baseline patient characteristics were similar between the two arms. The median number of cycles was four for both treatment arms. The confirmed response rate was 34% with vorinostat versus 12.5% with placebo (P = .02). There was a trend toward improvement in median progression-free survival (6.0 months v 4.1 months; P = .48) and overall survival (13.0 months v 9.7 months; P = .17) in the vorinostat arm. Grade 4 platelet toxicity was more common with vorinostat (18% v 3%; P < .05). Nausea, emesis, fatigue, dehydration, and hyponatremia also were more frequent with vorinostat. CONCLUSION Vorinostat enhances the efficacy of carboplatin and paclitaxel in patients with advanced NSCLC. HDAC inhibition is a promising therapeutic strategy for treatment of NSCLC.
authors.affiliation: Emory University, Winship Cancer Institute, 1365 Clifton Rd, C-3090, Atlanta, GA 30322, USA. suresh.ramalingam@emory.edu
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Michael L
authors.initials: ML
authors.lastname: Maitland
authors.forename: Paul
authors.initials: P
authors.lastname: Frankel
authors.forename: Athanassios E
authors.initials: AE
authors.lastname: Argiris
authors.forename: Marianna
authors.initials: M
authors.lastname: Koczywas
authors.forename: Barbara
authors.initials: B
authors.lastname: Gitlitz
authors.forename: Sachdev
authors.initials: S
authors.lastname: Thomas
authors.forename: Igor
authors.initials: I
authors.lastname: Espinoza-Delgado
authors.forename: Everett E
authors.initials: EE
authors.lastname: Vokes
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.forename: Chandra P
authors.initials: CP
authors.lastname: Belani
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000008:administration & dosage; D010919:Placebos; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D010919:Placebos; D000077337:Vorinostat; D016190:Carboplatin; D017239:Paclitaxel