title: Phase I/II trial of vorinostat (SAHA) and erlotinib for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations after erlotinib progression.
abstract: OBJECTIVE
  Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors.
  
  
  METHODS
  We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation.
  
  
  RESULTS
  A total of 33 patients were enrolled in the phase I-II trial. The maximum tolerated dose was erlotinib 150 mg p.o., QD, and 400mg p.o., QD, on days 1-7 and 15-21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC 95%: 18.0-37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43-8.45) and overall survival (OS) 10.3 months (95% CI: 2.4-18.1).
  
  
  CONCLUSIONS
  Full dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression.
authors.affiliation: Medical Oncology Department, Hospital Clinic Barcelona-ICMHO, Barcelona, Spain. Electronic address: nreguart@clinic.ub.es.
authors.forename: Noemi
authors.initials: N
authors.lastname: Reguart
authors.affiliation: Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain; Pangaea Biotech, Hospital Universitario Quirón, Dexeus, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.affiliation: Medical Oncology Department, Centre Sanitari i Universitari de Bellvitge, Institut Català d'Oncologia-ICO, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Cardenal
authors.affiliation: Medical Oncology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
authors.forename: Andres F
authors.initials: AF
authors.lastname: Cardona
authors.affiliation: Medical Oncology Department, Hospital Clínico Lozano Blesa, Zaragoza, Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Isla
authors.affiliation: Medical Oncology Department, Centre Sanitari i Universitari de Bellvitge, Institut Català d'Oncologia-ICO, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Palmero
authors.affiliation: Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain.
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.affiliation: Phase I, Early Clinical Trials Unit, University Hospital of Antwerp-UZA, Belgium.
authors.forename: Christian
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
authors.forename: M Cinta
authors.initials: MC
authors.lastname: Pallarès
authors.affiliation: Medical Oncology Department, Hospital Clínico Universitario, Valencia, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Insa
authors.affiliation: Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain.
authors.forename: Enric
authors.initials: E
authors.lastname: Carcereny
authors.affiliation: Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
authors.forename: Margarita
authors.initials: M
authors.lastname: Majem
authors.affiliation: Medical Oncology Department, Hospital La Paz, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: De Castro
authors.affiliation: Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Queralt
authors.affiliation: Pangaea Biotech, Hospital Universitario Quirón, Dexeus, Barcelona, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Molina
authors.affiliation: Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain; Pangaea Biotech, Hospital Universitario Quirón, Dexeus, Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D018450:Disease Progression; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011799:Quinazolines / Q000008:administration & dosage; D016896:Treatment Outcome; D000077337:Vorinostat
chemical_list: D006877:Hydroxamic Acids; D011799:Quinazolines; D000077337:Vorinostat; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR mutations; Erlotinib; Histone deacetylase inhibitors; NSCLC; TKIs resistance; Vorinostat