Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study

Summary

Background

Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer.

Methods

Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m² on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681.

Findings

ORRs for the motesanib group and the placebo group did not differ significantly (49% vs 41%; absolute difference 8% [95% CI −6 to 22]; p=0·31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature.

Interpretation

Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population.

Funding

Amgen.

Introduction

Metastatic breast cancer is an incurable disease. Conventional chemotherapy with or without endocrine therapy is associated with a median survival of about 2 years, and less than 3% of patients survive in the longer term after treatment.¹ The development of new treatment strategies is therefore essential to improving outcomes for patients with metastatic breast cancer.

One of the most promising avenues for treating cancer is the development of new anti-neoplastic agents that target tumour vascular endothelium. The observation that the degree of tumour angiogenesis correlates with survival in patients2, 3, 4 with breast cancer has led to a search for pro-angiogenic molecules responsible for mediating new vessel formation. Numerous factors have been identified, including members of the basic fibroblast growth factor family, transforming growth factor β1, platelet-derived growth factor, angiopoietin 1 and, especially, vascular endothelial growth factor (VEGF); probably the most potent and selective mitogen for endothelial cells.⁵ Therefore, agents that inhibit angiogenesis and specifically target VEGF or its receptors (VEGFR) might have therapeutic importance for the treatment of breast cancer. Bevacizumab, a monoclonal antibody that blocks the VEGF ligand, was initially approved in combination with weekly paclitaxel for the treatment of metastatic breast cancer.⁶ Although bevacizumab plus weekly paclitaxel prolongs progression-free survival (PFS) compared with paclitaxel alone, it does not prolong overall survival. Recently, the US Food and Drug Administration (FDA) decided to retract the approval of bevacizumab for metastatic breast cancer, since the findings of the E2100 study, which led to the drug's initial licensing in this setting, were not supported by the findings of two subsequent phase 3 trials (AVADO⁷ and RIBBON-1⁸). Therefore, there is a need to investigate new agents that inhibit angiogenesis in patients with locally recurrent or metastatic breast cancer.

Motesanib is an orally administered small-molecule VEGFR tyrosine-kinase inhibitor (TKI) and antagonist of VEGFR1, VEGFR2, and VEGFR3, and it also inhibits PDGFR and KIT, which might confer direct antitumour activity. The spectrum of kinase inhibition by motesanib seems to be different from the other small-molecule VEGFR inhibitors.⁹ This molecule also has a half-life (6–7 h) that is shorter than most of the other VEGFR inhibitors.¹⁰ These molecular and pharmacokinetic properties could lead to potential differences in the efficacy and safety profile of motesanib. A clinical programme is ongoing to assess motesanib in combination with other therapies for the treatment of solid tumours, including non-small-cell lung cancer and metastatic breast cancer. We designed a randomised, placebo-controlled trial to investigate the effectiveness of motesanib compared with open-label bevacizumab or placebo, all in combination with weekly paclitaxel, in patients with HER2-negative locally recurrent or metastatic breast cancer.