PMID- 22508830
OWN - NLM
STAT- MEDLINE
DCOM- 20120816
LR  - 20220330
IS  - 1527-7755 (Electronic)
IS  - 0732-183X (Print)
IS  - 0732-183X (Linking)
VI  - 30
IP  - 18
DP  - 2012 Jun 20
TI  - Randomized phase II trial of erlotinib with and without entinostat in patients 
      with advanced non-small-cell lung cancer who progressed on prior chemotherapy.
PG  - 2248-55
LID - 10.1200/JCO.2011.38.9411 [doi]
AB  - PURPOSE: Histone deacetylase inhibitors (HDACis) have been shown to overcome 
      resistance to epidermal growth factor receptor tyrosine kinase inhibitors 
      (EGFR-TKIs) linked to epigenetic changes and epithelial-mesenchymal transition 
      (EMT) state. This randomized phase II study evaluated the outcome of erlotinib 
      with and without the isoform selective HDACi, entinostat. PATIENTS AND METHODS: 
      Previously treated patients with stage IIIB/IV non-small-cell lung cancer, no 
      prior EGFR-TKIs, and performance status </= 2 were randomly administered erlotinib 
      150 mg on days 1 through 28 plus entinostat 10 mg orally on days 1 and 15 every 
      28 days (EE) or erlotinib plus placebo (EP). The primary end point was 4-month 
      progression-free survival (PFS) rate with additional end points including 6-month 
      PFS rate, PFS, and overall survival (OS). Exploratory analyses included EMT- and 
      EGFR-related biomarker analysis on archival tissue. RESULTS: One hundred 
      thirty-two patients were enrolled (EE, 67; EP, 65). The 4-month PFS rate was 
      comparable for both groups (EE, 18% v EP, 20%; P = .7). In the subset of patients 
      with high E-cadherin levels, OS was longer in the EE group compared with the EP 
      group (9.4 v 5.4 months; hazard ratio, 0.35; 95% CI, 0.13 to 0.92; P = .03) with 
      a corresponding trend toward increased PFS. The adverse event (AE) profile was 
      acceptable, with rash, fatigue, diarrhea, and nausea the most common AEs in both 
      groups. CONCLUSION: Erlotinib combined with entinostat did not improve the 
      outcomes of patients in the overall study population when compared with erlotinib 
      monotherapy. High E-cadherin expression levels at time of diagnosis indicate an 
      increased sensitivity to HDACi/EGFR-TKI inhibition providing the basis for a 
      biomarker-driven validation study.
FAU - Witta, Samir E
AU  - Witta SE
AD  - University of Colorado Cancer Center, 12801 E 17th Ave, Mail Stop 8117, Aurora, 
      CO 80045, USA.
FAU - Jotte, Robert M
AU  - Jotte RM
FAU - Konduri, Katrik
AU  - Konduri K
FAU - Neubauer, Marcus A
AU  - Neubauer MA
FAU - Spira, Alexander I
AU  - Spira AI
FAU - Ruxer, Robert L
AU  - Ruxer RL
FAU - Varella-Garcia, Marileila
AU  - Varella-Garcia M
FAU - Bunn, Paul A Jr
AU  - Bunn PA Jr
FAU - Hirsch, Fred R
AU  - Hirsch FR
LA  - eng
GR  - P30 CA046934/CA/NCI NIH HHS/United States
GR  - U01 CA157715/CA/NCI NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20120416
PL  - United States
TA  - J Clin Oncol
JT  - Journal of clinical oncology : official journal of the American Society of 
      Clinical Oncology
JID - 8309333
RN  - 0 (Benzamides)
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (Cadherins)
RN  - 0 (Histone Deacetylase Inhibitors)
RN  - 0 (Pyridines)
RN  - 0 (Quinazolines)
RN  - 1ZNY4FKK9H (entinostat)
RN  - DA87705X9K (Erlotinib Hydrochloride)
SB  - IM
MH  - Aged
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Benzamides/*administration & dosage
MH  - Biomarkers, Tumor/metabolism
MH  - Cadherins/metabolism
MH  - Carcinoma, Non-Small-Cell Lung/*drug therapy
MH  - Erlotinib Hydrochloride
MH  - Female
MH  - Histone Deacetylase Inhibitors/*administration & dosage
MH  - Humans
MH  - Lung Neoplasms/*drug therapy
MH  - Male
MH  - Middle Aged
MH  - Pyridines/*administration & dosage
MH  - Quinazolines/*therapeutic use
PMC - PMC4798782
MID - NIHMS742858
COIS- Authors' disclosures of potential conflicts of interest and author contributions 
      are found at the end of this article.
EDAT- 2012/04/18 06:00
MHDA- 2012/08/17 06:00
PMCR- 2013/01/20
CRDT- 2012/04/18 06:00
PHST- 2012/04/18 06:00 [entrez]
PHST- 2012/04/18 06:00 [pubmed]
PHST- 2012/08/17 06:00 [medline]
PHST- 2013/01/20 00:00 [pmc-release]
AID - JCO.2011.38.9411 [pii]
AID - 89411 [pii]
AID - 10.1200/JCO.2011.38.9411 [doi]
PST - ppublish
SO  - J Clin Oncol. 2012 Jun 20;30(18):2248-55. doi: 10.1200/JCO.2011.38.9411. Epub 
      2012 Apr 16.