Therapeutic impact of Nintedanib with paclitaxel and/or a PD-L1 antibody in preclinical models of orthotopic primary or metastatic triple negative breast cancer

Elaine Reguera-Nuñez,Shan Man,Robert S Kerbel,Annabelle Chow,Frank Hilberg,Ping Xu

doi:10.1186/s13046-018-0999-5

Abstract

BackgroundTriple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy. We evaluated various combinations of three different drugs: nintedanib, an antiangiogenic TKI targeting VEGF receptors, paclitaxel (PTX), or a PD-L1 antibody, using models of orthotopic primary or advanced metastatic TNBC involving a metastatic variant of the MDA-MB-231 human cell line (called LM2–4) in SCID mice and two mouse lines (EMT-6 and a drug-resistant variant, EMT-6/CDDP) in immunocompetent mice. These drugs were selected based on the following: PTX is approved for TNBC; nintedanib combined with docetaxel has shown phase III clinical trial success, albeit in NSCLC; VEGF can act as local immunosuppressive factor; and PD-L1 antibody plus taxane therapy was recently reported to have encouraging phase III trial benefit in TNBC.MethodsStatistical analyses were performed with ANOVA followed by Tukey’s Multiple Comparison Test or with Kruskal-Wallis test followed by Dunn’s Multiple Comparison Test. Survival curves were analyzed using a Log-rank (Mantel Cox) test. Differences were considered statistically significant when p values were < 0.05.ResultsToxicity analyses showed that nintedanib is well tolerated when administered 5-days ON 2-days OFF; PTX toxicity differed in mice, varied with cell lines used and may have influenced median survival in the metastatic EMT6/CDDP model; while toxicity of PD-L1 therapy depended on the cell lines and treatment settings tested. In the LM2–4 system, combining nintedanib with PTX enhanced overall antitumor efficacy in both primary and metastatic treatment settings. In immunocompetent mice, combining nintedanib or PTX with the PD-L1 antibody improved overall antitumor efficacy. Using the advanced metastatic EMT-6/CDDP model, optimal efficacy results were obtained using the triple combination.ConclusionsThese results suggest circumstances where nintedanib plus PTX may be potentially effective in treating TNBC, and nintedanib with PTX may improve PD-L1 therapy of metastatic TNBC.

Highlights

Triple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy
The rationale is that this would allow us to include in the study an immune checkpoint inhibitor, a decision mainly based on clinical results that emerged during the course of our experiments with LM2–4 suggesting the potential benefit of targeting Programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in TNBC [61]
Nintedanib combined with paclitaxel delays growth of LM2–4 human breast cancer xenograft and improves median survival Based on preliminary results of nintedanib combined with paclitaxel in a phase I trial treating early human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients [34], we decided to analyze the impact of nintedanib on advanced metastatic disease, both alone and combined with maximum-tolerated dose (MTD) paclitaxel in the LM2–4 model

Summary

Introduction

Triple negative breast cancer (TNBC) is an aggressive malignancy with poor prognosis, in part because of the current lack of any approved molecularly targeted therapy. We evaluated various combinations of three different drugs: nintedanib, an antiangiogenic TKI targeting VEGF receptors, paclitaxel (PTX), or a PD-L1 antibody, using models of orthotopic primary or advanced metastatic TNBC involving a metastatic variant of the MDA-MB-231 human cell line (called LM2–4) in SCID mice and two mouse lines (EMT-6 and a drug-resistant variant, EMT-6/CDDP) in immunocompetent mice These drugs were selected based on the following: PTX is approved for TNBC; nintedanib combined with docetaxel has shown phase III clinical trial success, albeit in NSCLC; VEGF can act as local immunosuppressive factor; and PD-L1 antibody plus taxane therapy was recently reported to have encouraging phase III trial benefit in TNBC. The most common malignancy in women worldwide, consists of four main subtypes: luminal A, luminal B, HER2-positive, and triple negative This subgroup classification is based on expression of hormone receptors and overexpression of the human epidermal growth factor receptor 2 (HER2). The subtype of TNBC can have a significant impact on relative sensitivity to a particular drug or therapy such as cisplatin chemotherapy [1] and immunotherapy [4]

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