title: Combination epigenetic therapy has efficacy in patients with refractory advanced non-small cell lung cancer.
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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland 21231, USA.
authors.forename: Rosalyn A
authors.initials: RA
authors.lastname: Juergens
authors.forename: John
authors.initials: J
authors.lastname: Wrangle
authors.forename: Frank P
authors.initials: FP
authors.lastname: Vendetti
authors.forename: Sara C
authors.initials: SC
authors.lastname: Murphy
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Barbara
authors.initials: B
authors.lastname: Coleman
authors.forename: Rosa
authors.initials: R
authors.lastname: Sebree
authors.forename: Kristen
authors.initials: K
authors.lastname: Rodgers
authors.forename: Craig M
authors.initials: CM
authors.lastname: Hooker
authors.forename: Noreli
authors.initials: N
authors.lastname: Franco
authors.forename: Beverly
authors.initials: B
authors.lastname: Lee
authors.forename: Salina
authors.initials: S
authors.lastname: Tsai
authors.forename: Igor Espinoza
authors.initials: IE
authors.lastname: Delgado
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Steven A
authors.initials: SA
authors.lastname: Belinsky
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D019175:DNA Methylation / Q000187:drug effects; D018450:Disease Progression; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic; D005260:Female; D015316:Genetic Therapy; D006657:Histones / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D001549:Benzamides; D014408:Biomarkers, Tumor; D006657:Histones; D011725:Pyridines; C118739:entinostat; D001374:Azacitidine