Abstract 4719: Synergistic anticancer activity of triple combinations of eribulin, palbociclib and fulvestrant in hormone dependent patient-derived xenograft (PDX) models of human breast cancer
Authors: Boisferon Marc Hillairet de , Chatel Elodie Marie Dit , Nomoto Kenichi , Littlefield Bruce A. 
Published: August 2019

Abstract
Eribulin is a pharmaceutically optimized analog of the marine natural product halichondrin B. As its clinically formulated mesylate salt (Halaven®), eribulin is used for treatment of certain patients with advanced breast cancer and liposarcoma. Mechanistically, eribulin combines cytotoxic tubulin-based antimitotic effects with non-cytotoxic effects on tumor biology, including vascular remodeling, increased perfusion, mitigation of hypoxia and reversal of epithelial to mesenchymal transition (EMT). Reversal of EMT involves cell differentiation pathways that impinge on the G1/S cell cycle boundary. Since estrogenic signaling also impinges on the G1/S boundary, we asked if eribulin could combine advantageously with inhibitors of cyclin dependent kinases and hormonal agents that disrupt estrogenic signaling. Using PDX models of hormone receptor positive (HR+) breast cancer, we previously showed that combining eribulin and palbociclib is considerably more effective than either agent alone, using a “palbociclib holiday” strategy of withholding daily palbociclib doses the day before and the day of weekly eribulin doses to avoid possible cell cycle based antagonism. Here, we ask if the palbociclib holiday is strictly necessary for robust eribulin + palbociclib combination activity, and if triple combinations of eribulin, palbociclib and fulvestrant result in even better anticancer activity than doublet dosing. For the holiday/no holiday comparison, 0.125 mg/kg eribulin was dosed iv Q7Dx3, with palbociclib dosed po either at 150 mg/kg or 107 mg/kg on Q1Dx5[x3 weeks] (holiday) or Q1Dx21 (no holiday) schedules, respectively, resulting in equal palbociclib dose intensities for the 2 schedules. Results showed that synergism was seen in combination with or without palbociclib holiday, but superior results occur with holiday. Using the holiday strategy, we next investigated triple combinations of eribulin, palbociclib and fulvestrant. As single agents at the minimally effective doses selected, eribulin, palbociclib and fulvestrant led to treated/control values (T/C%) of 64%, 63% and 48%, respectively. Combining eribulin and palbociclib led to markedly superior anticancer activity (T/C 23%). Combining eribulin and fulvestrant also led to superior activity (T/C 22%), as did combining fulvestrant and palbociclib (T/C 19%). The triple combination generated the most robust activity at T/C 8%. By mouse RECIST criteria, 10%, 10% and 20% partial responses (PR) were observed for each doublet (fulvestrant/palbociclib, fulvestrant/eribulin, palbociclib/eribulin), respectively. In contrast, 90% PR was seen for the triple combination. These preclinical results support clinical exploration of eribulin, palbociclib and fulvestrant triple combinations for appropriate patients with HR+ breast cancers.
Citation Format: Marc Hillairet de Boisferon, Elodie Marie Dit Chatel, Kenichi Nomoto, Bruce A. Littlefield. Synergistic anticancer activity of triple combinations of eribulin, palbociclib and fulvestrant in hormone dependent patient-derived xenograft (PDX) models of human breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4719.