Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non–Small Cell Lung Cancer Academic Article uri icon

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abstract

  • UNLABELLED: 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.

authors

  • Juergens, Rosalyn
  • Wrangle, John
  • Vendetti, Frank P
  • Murphy, Sara C
  • Zhao, Ming
  • Coleman, Barbara
  • Sebree, Rosa
  • Rodgers, Kristen
  • Hooker, Craig M
  • Franco, Noreli
  • Lee, Beverly
  • Tsai, Salina
  • Delgado, Igor Espinoza
  • Rudek, Michelle A
  • Belinsky, Steven A
  • Herman, James G
  • Baylin, Stephen B
  • Brock, Malcolm V
  • Rudin, Charles M

publication date

  • December 2011

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