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Lung Cancer. 2014 May;84(2):161-7. doi: 10.1016/j.lungcan.2014.02.011. Epub 2014 Mar 2.

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.

Author information

1
Medical Oncology Department, Hospital Clinic Barcelona-ICMHO, Barcelona, Spain. Electronic address: nreguart@clinic.ub.es.
2
Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain; Pangaea Biotech, Hospital Universitario Quirón, Dexeus, Barcelona, Spain.
3
Medical Oncology Department, Centre Sanitari i Universitari de Bellvitge, Institut Català d'Oncologia-ICO, Hospitalet de Llobregat, Barcelona, Spain.
4
Medical Oncology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia.
5
Medical Oncology Department, Hospital Clínico Lozano Blesa, Zaragoza, Spain.
6
Medical Oncology Department, Hospital Germans Trías i Pujol, Institut Català d'Oncologia-ICO, Badalona, Barcelona, Spain.
7
Phase I, Early Clinical Trials Unit, University Hospital of Antwerp-UZA, Belgium.
8
Medical Oncology Department, Hospital de la Santa Creu I Sant Pau, Barcelona, Spain.
9
Medical Oncology Department, Hospital Clínico Universitario, Valencia, Spain.
10
Medical Oncology Department, Hospital La Paz, Madrid, Spain.
11
Pangaea Biotech, Hospital Universitario Quirón, Dexeus, Barcelona, Spain.

Abstract

OBJECTIVES:

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.

PATIENTS AND 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).

CONCLUSION:

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.

KEYWORDS:

EGFR mutations; Erlotinib; Histone deacetylase inhibitors; NSCLC; TKIs resistance; Vorinostat

PMID:
24636848
DOI:
10.1016/j.lungcan.2014.02.011
[Indexed for MEDLINE]
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