Abstract 4592: Etirinotecan pegol accumulates in breast cancer brain metastases and prolongs survival in an experimental model of brain metastases of human triple negative breast cancer
Authors: Nounou Mohamed , Hoch Ute , Adkins Chris E. , Terrell Tori B. , Villalba Heidi , Eldon Michael E. , Lockman Paul R. 
Published: May 2015

Abstract
Background: Breast cancer brain metastases (BCBM) remain a challenging consequence of advanced breast cancer. The blood-brain barrier prevents many chemotherapeutic agents used to control systemic disease from reaching effective concentration in brain metastases. Etirinotecan pegol (EP) is the first long acting topoisomerase 1 inhibitor that provides continuous exposure to SN38 with reduced peak concentrations, which results in a better efficacy and safety profile than irinotecan (IRN). EP resulted in a RECIST response rate of 39% (7/18) in patients with metastatic TNBC. Here we present encouraging brain metastases distribution and survival results for EP in an experimental mouse model of TNBC brain metastasis using IRN as a control.
Methods: For efficacy, mice with established MDA-MB-231Br BCBM (treatment started 21 days after intracardiac injection of MDA-MB-231Br Luc cells) were treated IV with vehicle, 50 mg/kg IRN, or 50 mg/kg EP q7d. Efficacy was assessed using bioluminescent imaging and survival. After reaching the study endpoint, brain samples were harvested, sectioned, and analyzed for size and number of metastases. For brain metastases distribution, mice with established MDA-MB-231 brain metastases received 50 mg/kg 14C-EP or 14C-IRN. At planned times, animals were sacrificed and brain was harvested, sectioned, and mounted on slides for quantitation of radioactivity in brain metastases and brain tumor distant tissue (BDT).
Results: In the efficacy study, tumor bioluminescence in vehicle and IRN treated animals steadily increased. Vehicle animals died on days 16-23 post start of treatment and IRN animals died on day 21, leading to a median survival of 21 days in both groups. In contrast, bioluminescence decreased in EP treated animals over time, and 50% of animals survived to the end of study on day 70. Based on microscopic assessment of brain sections, EP treated animals had significantly reduced number of tumors per brain slice (0.5 for EP vs. 14.5 for IRN), and significantly smaller lesion size (0.04 mm2 for EP vs. 0.25 mm2 for IRN). Radiographic quantitation of brain sections confirmed that EP preferentially distributes into brain metastases compared to BDT. Brain metastases concentrations after EP were &gt;4-fold higher compared to IRN treatment.
Conclusions: EP shows promising efficacy in an experimental model of breast cancer brain metastases. EP selectively penetrates the compromised blood-brain barrier at the metastatic lesion, reduces the size and number of metastatic lesions, and prolongs survival. Plasma SN38 trough concentrations observed in this study are achieved clinically with the 145 mg/m2 q21d EP regimen used in the Phase 3 BEACON study in patients with metastatic BC. Assessment of the clinical relevance of these data is planned in the subset of BEACON patients with brain metastases.
Citation Format: Mohamed Nounou, Ute Hoch, Chris E. Adkins, Tori B. Terrell, Heidi Villalba, Michael E. Eldon, Paul R. Lockman. Etirinotecan pegol accumulates in breast cancer brain metastases and prolongs survival in an experimental model of brain metastases of human triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4592. doi:10.1158/1538-7445.AM2014-4592