Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation

Eur J Cancer. 2017 Jan:70:146-155. doi: 10.1016/j.ejca.2016.09.024. Epub 2016 Nov 4.

Abstract

Aim: MERiDiAN evaluated plasma vascular endothelial growth factor-A (pVEGF-A) prospectively as a predictive biomarker for bevacizumab efficacy in metastatic breast cancer (mBC).

Methods: In this double-blind placebo-controlled randomised phase III trial, eligible patients had HER2-negative mBC previously untreated with chemotherapy. pVEGF-A was measured before randomisation to paclitaxel 90 mg/m2 on days 1, 8 and 15 with either placebo or bevacizumab 10 mg/kg on days 1 and 15, repeated every 4 weeks until disease progression, unacceptable toxicity or consent withdrawal. Stratification factors were baseline pVEGF-A, prior adjuvant chemotherapy, hormone receptor status and geographic region. Co-primary end-points were investigator-assessed progression-free survival (PFS) in the intent-to-treat and pVEGF-Ahigh populations.

Results: Of 481 patients randomised (242 placebo-paclitaxel; 239 bevacizumab-paclitaxel), 471 received study treatment. The stratified PFS hazard ratio was 0.68 (99% confidence interval, 0.51-0.91; log-rank p = 0.0007) in the intent-to-treat population (median 8.8 months with placebo-paclitaxel versus 11.0 months with bevacizumab-paclitaxel) and 0.64 (96% confidence interval, 0.47-0.88; log-rank p = 0.0038) in the pVEGF-Ahigh subgroup. The PFS treatment-by-VEGF-A interaction p value (secondary end-point) was 0.4619. Bevacizumab was associated with increased incidences of bleeding (all grades: 45% versus 27% with placebo), neutropenia (all grades: 39% versus 29%; grade ≥3: 25% versus 13%) and hypertension (all grades: 31% versus 13%; grade ≥3: 11% versus 4%).

Conclusion: The significant PFS improvement with bevacizumab is consistent with previous placebo-controlled first-line trials in mBC. Results do not support using baseline pVEGF-A to identify patients benefitting most from bevacizumab.

Clinical trials registration: ClinicalTrials.gov NCT01663727.

Keywords: Bevacizumab; Biomarker; Double-blind; Metastatic breast cancer; Predictive; Prospective; VEGF-A; Weekly paclitaxel.

Publication types

  • Clinical Trial, Phase III
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Angiogenesis Inhibitors / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Bevacizumab / administration & dosage
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / diagnosis
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Disease-Free Survival
  • Double-Blind Method
  • Female
  • Humans
  • Middle Aged
  • Molecular Targeted Therapy / methods*
  • Paclitaxel / administration & dosage
  • Prospective Studies
  • Receptor, ErbB-2 / metabolism
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism
  • Young Adult

Substances

  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Paclitaxel

Associated data

  • ClinicalTrials.gov/NCT01663727