Combination Epigenetic Therapy Has Efficacy in Patients With Refractory Advanced Non-Small Cell Lung Cancer

Cancer Discov. 2011 Dec;1(7):598-607. doi: 10.1158/2159-8290.CD-11-0214. Epub 2011 Nov 9.

Abstract

Epigenetic alterations are strongly associated with the development of cancer. We conducted a phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non-small cell lung cancer. This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy. Median survival in the entire cohort was 6.4 months (95% CI 3.8-9.2), comparing favorably with existing therapeutic options. Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035). Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.

Significance: This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Azacitidine / administration & dosage
  • Azacitidine / adverse effects
  • Benzamides / administration & dosage
  • Benzamides / adverse effects
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Non-Small-Cell Lung / drug therapy
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / therapy*
  • Cohort Studies
  • Combined Modality Therapy
  • DNA Methylation / drug effects
  • Disease Progression
  • Disease-Free Survival
  • Epigenesis, Genetic
  • Female
  • Genetic Therapy
  • Histones / metabolism
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / therapy*
  • Male
  • Middle Aged
  • Pyridines / administration & dosage
  • Pyridines / adverse effects

Substances

  • Benzamides
  • Biomarkers, Tumor
  • Histones
  • Pyridines
  • entinostat
  • Azacitidine