A phase I clinical trial of bavituximab and paclitaxel in patients with HER2 negative metastatic breast cancer

Abstract

Bavituximab is a chimeric monoclonal antibody that targets phosphatidylserine (PS). PS is externalized on cells in the tumor microenvironment when exposed to hypoxia and/or other physiological stressors. On attaching to PS, bavituximab is thought to promote antitumor immunity through its effects on PS receptors in monocytes, and myeloid-derived suppressor cells, as well as trigger antitumor effects by inducing an antibody-dependent cellular cytotoxicity on tumor-associated endothelial cells. We conducted a phase I clinical trial of bavituximab in combination with paclitaxel in patients with HER2-negative metastatic breast cancer. Patients were treated with weekly paclitaxel (80 mg/m 2 for 3/4 weeks) and weekly bavituximab (3 mg/kg for 4/4 weeks). Correlative studies included the measurement of circulating microparticles, endothelial cells, and apoptotic tumor cells by flow cytometry. Fourteen patients with metastatic breast cancer were enrolled; all were evaluable for toxicity and 13 were evaluable for response. Treatment resulted in an overall response rate (RR) of 85% with a median progression-free survival (PFS) of 7.3 months. Bone pain, fatigue, headache, and neutropenia were the most common adverse effects. Infusion-related reactions were the most common adverse event related to bavituximab therapy. Correlative studies showed an increase in the PS-expressing apoptotic circulating tumor cells in response to bavituximab, but not with paclitaxel. No changes in the number of circulating endothelial cells or apoptotic endothelial cells were observed with therapy. Platelet and monocyte-derived microparticles decreased after initiation of bavituximab. Bavituximab in combination with paclitaxel is well tolerated for treatment of patients with metastatic breast cancer with promising results observed in terms of clinical RRs and PFS. The toxicity profile of bavituximab is notable for manageable infusion-related reactions with no evidence for increased thrombogenicity. Recent preclinical data suggest that bavituximab can also promote antitumor immune activity that should be explored in future clinical trials.

Exposure of phosphatidylserine on the cell surface

“…117 This treatment appears promising. [118][119][120] Recent reports suggest that the PtdSer in the tumor-associated endothelial cells and the PtdSer exposed on tumor cells after treatment with anticancer drugs create an immune-suppressive tumor environment; the antibody against PtdSer reverses this effect, creating anti-tumor immunity. 121 It will be interesting to study whether the flippase and scramblases discussed in this review are involved in the PtdSer exposure on tumor-associated endothelial cells.…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…44 More recently, a phase I clinical trial with bavituximab in combination with paclitaxel has shown more promising results among 14 HER2-negative metastatic breast cancer patients, with an 85% response rate. 45 In addition, an ongoing phase III trial involving the treatment of advanced non-small-cell lung cancer with bavituximab and docetaxel is currently in progress. 46 Collectively, these studies highlight the potential of targeting and manipulating the extracellular phospholipid code therapeutically in cancer settings.…”

Preclinical Evaluation of Sequential Combination of Oncolytic Adenovirus Delta-24-RGD and Phosphatidylserine-Targeting Antibody in Pancreatic Ductal Adenocarcinoma

“…This offers an opportunity for combination therapy with PS-targeting antibodies. PS targeting antibodies, including Bavituximab and 1N11 have been evaluated in metastatic breast and lung cancers in phase 1 clinical trials showing promising results (12, 13). In this study, we tested the combination of Delta-24-RGD and 1N11, a fully human PS targeting antibody similar to Bavituximab, by using a sequential combination strategy.…”

“…Recent data from an animal model of melanoma demonstrated that combining PS-targeting antibodies improved the effectiveness of immune checkpoint inhibitors, suggesting that antibodies to PS can reverse its immune dampening signals (11). PS targeting antibodies, Bavituximab, have also been raised to target PS-expressing tumor cells and investigated in phase I clinical trials of several solid tumors systems including metastatic breast and lung cancers (12, 13). Together, these studies suggest that anti-PS antibodies could augment the anti-cancer effects of oncolytic virus therapy.…”