Abstract
e14545 Background: Preclinical studies showed the synergistic effect of entinostat with epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in NSCLC cell lines. Entinostat (SNDX-275, Syndax Pharmaceuticals) is an oral, class 1 isoform selective HDACi that restores the expression of e-cadherin and sensitivity to EGFR-TKI in NSCLC cell lines. The aim of this study was to determine the safety and feasibility of combining entinostat with erlotinib in advanced NSCLC patients in order to determine the recommended Phase 2 dose. Methods: Patients with recurrent or metastatic NSCLC whose tumors progressed on prior chemotherapy were treated with either 5 or 10mg orally of entinostat once every two weeks and erlotinib 150mg daily. Results: A total of 9 patients were enrolled (3 at entinostat 5mg; 6 at 10mg). Characteristics: Sex: M/F: 6/3; Age range: 46–84 yrs; ECOG PS: 0–1; Smoking status: 1/8 (never/current or prior smokers); Number of prior treatments: 1–2. There was one DLT of grade 3 asthenia. This occurred in one of the six patients in the 10mg dose cohort. The most common adverse events were anorexia, and asthenia. This was more often noted in elderly patients. Of the 9 evaluable patients, one patient had a confirmed partial response and remains on study (>5 cycles) and another patient had stable disease for 8 months. Pharmacokinetic analysis has been completed with both drugs exhibiting levels comparable to historical data. No drug:drug interaction was observed. EGFR FISH, EGFR mutation, and epithelial-to-mesenchymal marker analysis is in progress. Conclusions: This study has established the safety and a recommended phase 2 dose of 10 mg of entinostat once every other week in combination with 150 mg daily of erlotinib in a 28-day cycle in advanced NSCLC patients. A randomized, double blinded phase 2 study has been initiated with 43 patients enrolled to date. [Table: see text]
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