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
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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.
Cancer discovery. 12/2011; 1(7):598-607.
