Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer

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

Research output: Contribution to journalArticlepeer-review

454 Scopus citations

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 bloodbased biomarker that correlates with clinical benefit.

Original languageEnglish (US)
Pages (from-to)598-607
Number of pages10
JournalCancer discovery
Volume1
Issue number7
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Oncology

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