Randomized phase II trial of erlotinib with and without entinostat in patients with advanced non-small-cell lung cancer who progressed on prior chemotherapy

Samir E. Witta, Robert M. Jotte, Katrik Konduri, Marcus A. Neubauer, Alexander I. Spira, Robert L. Ruxer, Marileila Varella-Garcia, Paul A. Bunn, Fred R. Hirsch

Research output: Contribution to journalArticlepeer-review

140 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2248-2255
Number of pages8
JournalJournal of Clinical Oncology
Volume30
Issue number18
DOIs
StatePublished - Jun 20 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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