Phase 1b Study of Trebananib Plus Paclitaxel and Trastuzumab in Patients With HER2-Positive Locally Recurrent or Metastatic Breast Cancer

Introduction: Trebananib, a peptide-Fc fusion protein, blocks angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. Trebananib plus trastuzumab and paclitaxel was evaluated in human epidermal growth factor receptor 2–positive breast cancer in an open-label phase 1b clinical study. Patients and Methods: Women with human epidermal growth factor receptor 2–positive breast cancer received weekly paclitaxel (80 mg/m²), trastuzumab (8 mg/m² then 6 mg/kg every 3 weeks), and intravenous trebananib (10 mg/kg or 30 mg/kg weekly) beginning week 2. The primary end point was the incidence of dose-limiting toxicities. Secondary end points included incidence of adverse events (AEs), pharmacokinetics, and tumor response (objective response and duration of response). Results: Forty women were enrolled; 2 experienced dose-limiting toxicities (grade 3 ocular transient ischemic attack [10 mg/kg cohort] and grade 3 elevation in γ-glutamyl transferase [30 mg/kg cohort]). The most common treatment-emergent AEs were peripheral edema (n = 28), diarrhea (n = 27), alopecia (n = 26), fatigue (n = 24), and nausea (n = 24). Maximum observed concentration and area under the concentration–time curve increased proportionally with the trebananib dose. Objective response was confirmed in 31 patients. In the 10 mg/kg cohort, 16 patients (80%) experienced partial response, and none experienced complete response. In the 30 mg/kg cohort, 12 patients (71%) experienced partial response and 3 (18%) experienced complete response. Median (95% confidence interval) duration of response in the 10 and 30 mg/kg cohorts was 12.6 (4.3-20.2) and 16.6 (8.2-not estimable) months, respectively. Conclusion: This phase 1b study showed that trebananib was tolerated with manageable AEs at a dose up to 30 mg/kg weekly. Trebananib demonstrated anticancer activity, as indicated by objective response and duration of response. Given the potential interactions between human epidermal growth factor receptor 2 (HER2) signaling and angiogenesis, we investigated the angiopoietin (Ang) 1/Ang2 inhibitor trebananib plus trastuzumab and paclitaxel in HER2-positive breast cancer. Forty women received trebananib (10 or 30 mg/kg) plus trastuzumab and paclitaxel. The combination demonstrated acceptable toxicity and antitumor response in HER2-positive locally recurrent/metastatic breast cancer.