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

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

CONSORT diagram describing numbers and treatment of non–small-cell lung cancer patients enrolled in ENCORE–401 (Entinostat Combinations Overcoming Resistance–401). AE, adverse event; PD, progressive disease.

Fig 2.

Kaplan-Meier estimates of (A) progression-free survival (PFS) in the full, randomly assigned patient population; (B) overall survival (OS) in the full, randomly assigned patient population; (C) PFS in a subset of E-cadherinLO (immunohistochemistry [IHC], 0, +1, +2) patients; (D) PFS in a subset of E-cadherinHI (IHC, +3) patients; (E) OS in E-cadherinLO (IHC, 0, +1, +2) patients; and (F) OS in E-cadherinHI (IHC, +3) patients.

Fig 3.

Forest plot of median overall survival and associated hazard ratios by biomarker status. Ecad, E-cadherin; EGFR, epidermal growth factor receptor; FISH, fluorescent in situ hybridization; KRAS, Kirsten rat sarcoma viral oncogene homolog.

Fig A1.

(A-F) Immunohistochemistry analysis of E-cadherin expression in archival tissue samples from patients enrolled onto ENCORE-401 (Entinostat Combinations Overcoming Resistance–401). Two examples of each assigned immunohistochemistry score are provided with designations of +1 and +2 as E-cadherinLO and +3 as E-cadherinHI.