Abstract OT1-01-03: A phase II multi-center study of BGB324 in combination with pembrolizumab in patients with previously treated, locally advanced and unresectable or metastatic triple negative breast cancer (TNBC) or triple negative inflammatory breast cancer (TN-IBC)
Authors: Yule M , Wnuk-Lipinska K , Davidsen K , Blø M , Hodneland L , Engelsen A , Kang J , Lie M , Bougnaud S , Aguilera K , Ahmed L , Rybicka A , Milde Nævdal E , Deyna P , Boniecka A , Straume O , Thiery J-P , Chouaib S , Brekken RA , Gausdal G , Lorens JB 
Published: February 2018

Abstract
Background. The AXL receptor tyrosine kinase is associated with poor overall survival in breast cancer. AXL signaling is an important regulator of tumor plasticity related to epithelial-to-mesenchymal transition (EMT) and stem cell traits that drive metastasis and drug resistance. Upregulation of AXL has been associated with reduced response to anti-PD-1 therapy. Signaling via AXL is also a key suppressor of the anti-tumor innate immune response, and AXL is expressed on several cells associated with the tumor immune microenvironment. Hence AXL signaling contributes uniquely to both tumor cell intrinsic and microenvironmental anti-tumor immune suppression mechanisms. We show that AXL is required for tumor immune evasion in the 4T1/Balb/C mammary adenocarcinoma model and that blocking AXL signaling with BGB324, a selective clinical-stage small molecule AXL kinase inhibitor, enhanced the effect of immune checkpoint blockade. BGB324 + anti-CTLA-4/anti-PD-1 treated tumors displayed enhanced infiltration of cytotoxic T lymphocytes and Natural Killer cells. Importantly, responding animals rejected orthotopic 4T1 tumor cell re-challenge, demonstrating sustained tumor immunity. These data provided a translational rationale for combining AXL targeted therapy with immune checkpoint inhibitors to enhance anti-cancer immune response.
Study Design. BGBC007 (NCT03184558) is an open-label, single arm, multi-center phase II study designed to assess the anti-tumor activity of BGB324 in combination with pembrolizumab in patients with previously treated, locally advanced and unresectable, or metastatic TNBC or TN-IBC. Secondary objectives include safety and pharmacokinetic profile of BGB324 and pembrolizumab in combination. A single arm, extension of Simon's 2-stage design is employed with an interim and final analysis. Up to 56 evaluable patients will be enrolled. Recruitment will be halted once 28 evaluable patients have been entered to determine the Objective Response Rate (ORR, complete response and partial response). If 5 or fewer responses are observed in up to 28 patients, the trial will be terminated in favor of the null for futility. If 11 or more responses are observed, then the trial will be stopped in favor of the alternative for demonstration of activity. If 6 to 10 patients have an observed response then a further 28 patients may be evaluated. This design provides an overall power of 80.6% to test the stated null and alternative hypothesis. BGB324 will be administered orally, once daily, in a fasted state. Days 1, 2 and 3 of BGB324 administration consists of a 'loading' dose of 400 mg followed by a dose of 200 mg daily. A fixed dose of 200 mg pembrolizumab will be given by intravenous infusion over 30 minutes every 3 weeks. BGB324 and pembrolizumab will be given until disease progression, unacceptable dose toxicity, or until 106 weeks (35 cycles). Efficacy endpoints including ORR, Duration of Response, Progression Free Survival are based on tumor imaging evaluation by RECIST 1.1. Tumor specimens will be taken to assess AXL and PD-L1 expression.
Citation Format: Yule M, Wnuk-Lipinska K, Davidsen K, Blø M, Hodneland L, Engelsen A, Kang J, Lie M, Bougnaud S, Aguilera K, Ahmed L, Rybicka A, Milde Nævdal E, Deyna P, Boniecka A, Straume O, Thiery J-P, Chouaib S, Brekken RA, Gausdal G, Lorens JB. A phase II multi-center study of BGB324 in combination with pembrolizumab in patients with previously treated, locally advanced and unresectable or metastatic triple negative breast cancer (TNBC) or triple negative inflammatory breast cancer (TN-IBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-01-03.