Abstract P4-14-22: A single-center, open-label phase 1b study of entinostat, and lapatinib alone, and in combination with and trastuzumab in patients with HER2+ metastatic breast cancer after progression on trastuzumab
Authors: Lim B , Jackson S , Alvarez RH , Ibrahim NK , Willey JS , Murthy RK , Booser DJ , Giordano SH , Barcenas CH , Brewster A , Walters RS , Brown PH , Tripathy D , Valero V , Ueno NT 
Published: May 2016

Abstract
Background: Our in vitro and in vivo preclinical data showed that entinostat enhances the efficacy of lapatinib in HER2 positive (HER2+) breast cancer cells via FOXO3-mediated Bim1 expression, which resulted in enhanced apoptosis in HER2 targeted therapy (lapatinib and trastuzumab)-resistant breast cancer (IBC and non-IBC) cells [Lee et al.]. Based on these findings, we conducted a phase 1b trial of entinostat to determine the maximal tolerated dose (MTD) in combination with lapatinib alone and in combination with lapatinib and trastuzumab for metastatic HER2+ breast cancer patients (pts), who progressed on trastuzumab.
Method: This was a single-center, open-label phase 1b study to evaluate the dose limiting toxicity (DLT) and determine MTD. 3+3 dose escalation schedule was used for Cohorts 1 and 2. Pts received lapatinib and entinostat (Cohort 1) or entinostat, lapatinib, and trastuzumab (Cohort 2). Initial dose of lapatinib 1250mg in Cohort 1 and 1000mg for Cohort 2 to match standard dose in combination with trastuzumab dose. In Cohort 1, entinostat was given PO on day 1 and 15 every 28 days cycle at dose levels 10 mg (level 0), 12 mg (level 1), or 15 mg (level 2). The dose levels for Cohort 2 were 12 mg (co-level 0) or 15 mg (co-level 1) on day 1 and 15 every 28 days cycle. While lapatinib and entinostat were given 28 days cycle due to entinostat dosing, the dosing of trastuzumab followed approved schedule every 21 days starting at 8mg/kg loading followed by 6mg/kg q 3 wks in Cohort 2 and 3. After the MTD of entinostat in cohort 2 was determined at 12mg, an expansion cohort of 10 pts (cohort 3) was conducted.
Results: Median age was 52 (26-69 yrs). Median number of prior trastuzumab-based regimens was 2 (1-6), 8 pts had lapatinib containing treatment prior to the trial, including 5 pts who had clinical benefit. 16 had ER+ and 13 ER negative, and 9 had IBC. Clinical efficacy and toxicity of treatment is summarized in table 1. Out of 14 pts who had clinical benefit (CR, PR, SD), 6 had IBC. Three pts are still on therapy (1CR, 1PR, 1SD).
Table 1. Clinical Efficacy, Toxicity of combination Receptor StatusResponseGrade 3 toxicityGrade 4 toxicityCohort 1HER2+/ER- (N=8) HER2+/ER+ (N=7)CR (N=1; 8M), SD (N=4;1,2,4M)Lapatinib dose reduction: 3 pts Rash (2) Abdominal pain + dyspnea (1)Entinostat dose reduction: 2pts Neutropenia (1 at 12mg, 1 at 15mg)Cohort 2/3HER2+/ER- (N=8) HER2+/ER+ (N=6)CR (N=2; 3,6M), PR (N=2;4,5M) SD (N=5;1,2,4,6M)Lapatinib dose reduction: 2 pts Diarrhea (N=1 at 12mg N=1 at 10mg) Entinostat dose reduction: 5 pts Neutropenia (N=2 at 12 mg) Leukopenia (N=1 at 12mg) Anemia (N=1 at 12mg)Entinostat dose reduction: 2pts Hypokalemia (N=1 at 12mg) Thrombocytopenia (N=1 at 15mg)CR: complete response, PR: partial response, SD: stable disease, N=number of pts, M=months
Conclusion: MTD was reached at 12mg q 2wkly entinostat, lapatinib 1000 mg daily and trastuzumab 8 mg/kg followed by 6mg/kg q 3 wks. This combination was safe and had promising clinical efficacy in patients with trastuzumab-resistant metastatic HER2+ breast cancer including IBC, warranting further study.
Citation Format: Lim B, Jackson S, Alvarez RH, Ibrahim NK, Willey JS, Murthy RK, Booser DJ, Giordano SH, Barcenas CH, Brewster A, Walters RS, Brown PH, Tripathy D, Valero V, Ueno NT. A single-center, open-label phase 1b study of entinostat, and lapatinib alone, and in combination with and trastuzumab in patients with HER2+ metastatic breast cancer after progression on trastuzumab. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-14-22.