Background: Entinostat (E) an HDAC inhibitor, and Lapatinib (L) given in combination induces FOXO3a and mediates Bim1 expression in HER2+ cell lines resulting in apoptosis [Lee et al. BCRT 2014], providing rationale for this NCI/CTEP sponsored phase 1b trial of E and L +/- T in mHER2+ breast cancer. Methods: A 3+3 phase 1b design was used to determine MTD. Group 1 received E and L. Group 2 received E, L and T. MTD was E 15mg q 2 wks, L 1250mg q 28 days (Group 1), E 12mg q 2 wks, L 1000 mg q 28 days and T 8mg/kg -> 6mg/kg q 3 wks (Group 2); 11 pts received E, L and T at MTD in an expansion cohort. Results: 37 pts were enrolled (15 Group 1, 11 Group 2, and 11 dose expansion); 18 had evaluable circulating tumor cells (isolated using ApoCell’s ApoStream technology) with Akt, HER2, EGFR for further correlative analysis. Median age was 52 (26-72 yo), received 3 (1-15 lines) previous therapies; 13 pts in Group 1, and 19 pts in Group 2/expansion had evaluable response to date. Total 9(24%) pts had clinical benefit (CB=CR, PR, SD at 6mo), 7(54%) pts with prior lapatinib had CB. CBR in metastatic IBC was 23%. Efficacy and toxicity summarized in table 1. Final clinical and correlative results will be reported at presentation. Conclusions: The entinostat, lapatinib and trastuzumab (ELT) regimen was safe and effective in pts who progressed on trastuzumab, even in those with prior lapatinib exposure. These results justify further evaluation of entinostat in combination with HER2 targeted therapy to overcome resistance. Clinical trial information: NCT01434303

CR: complete response, PR: partial response, SD: stable disease at 4 mo, (*):* number of pts; L: lapatinib