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

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

1. 
   Rosalyn A. Juergens1,


2. 
   John Wrangle1,


3. 
   Frank P. Vendetti3,


4. 
   Sara C. Murphy1,


5. 
   Ming Zhao1,


6. 
   Barbara Coleman1,


7. 
   Rosa Sebree1,


8. 
   Kristen Rodgers2,


9. 
   Craig M. Hooker1,


10. 
    Noreli Franco1,


11. 
    Beverly Lee1,


12. 
    Salina Tsai4,


13. 
    Igor Espinoza Delgado5,


14. 
    Michelle A. Rudek1,


15. 
    Steven A. Belinsky6,


16. 
    James G. Herman1,


17. 
    Stephen B. Baylin1,


18. 
    Malcolm V. Brock2 and


19. 
    Charles M. Rudin1
    

+ Author Affiliations

1. 
   
   
   
   Authors’ Affiliations:¹Department of Oncology, ²Department of Surgery, ³Anti-Cancer Drug Development Graduate Training Program, and ⁴Department of Radiology, Johns Hopkins University, Baltimore, Maryland; ⁵Investigational Drug Branch, National Cancer Institute, Bethesda, Maryland; and ⁶Lovelace Respiratory Research Institute, Albuquerque, New Mexico
   
   

1. 
   Corresponding Authors:
   Charles M. Rudin, MD, PhD, Johns Hopkins University, Cancer Research Building 2, Room 544, 1550 Orleans Street, Baltimore, MD 21231. E-mail: rudin@jhmi.edu; or Malcolm V. Brock, MD, Johns Hopkins University, Cancer Research Building 1, Room 542, 1650 Orleans Street, Baltimore, MD 21231. E-mail: mbrock1@jhmi.edu
   

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; 1(7); OF1–OF10. ©2011 AACR.

• 
  Received August 26, 2011.


• 
  Revision received September 26, 2011.


• 
  Accepted October 3, 2011.

• ©2011 American Association for Cancer Research.

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