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



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/m2on 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-Ahighpopulations.



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-Ahighsubgroup. 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%).



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.



ClinicalTrials.gov NCT01663727.
Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, London, HA6 2RN, UK. Electronic address: david.miles@doctors.org.uk.
David
D
Miles
University of Edinburgh and Cancer Services, NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK.
David
D
Cameron
Oncology Department, Dnipropetrovsk Medical Academy, Multiprofile Clinical Hospital, #449102, Blizhnaya Str, Dnipropetrovsk, Ukraine.
Igor
I
Bondarenko
NN Blokhin Cancer Centre, Kashirskoye Schosse 23, Moscow, 115478, Russia.
Lyudmila
L
Manzyuk
Centro Hemato Oncológico Panama, Marbella Edificio Royal Center, 5to. Piso Torre B, Panama City, Panama.
Juan Carlos
JC
Alcedo
Medical Oncology Department, National Oncology Institute, Gorgas & Juan de Arco Street, Ancon, PO Box 0816-04433, Panama City, Panama.
Roberto Ivan
RI
Lopez
Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
Seock-Ah
SA
Im
Oncology and Haematology Service, Grand Hôpital de Charleroi, Grand Rue 3, 6000, Charleroi, Belgium.
Jean-Luc
JL
Canon
Lviv State Oncological Regional Treatment and Diagnostic Center, 2a Hashek Str, Lviv, 79031, Ukraine.
Yaroslav
Y
Shparyk
Sarah Cannon Research Institute and Tennessee Oncology, PLCC, 3322 West End Avenue, Suite 900TN, Nashville, TN, 37203, USA.
Denise A
DA
Yardley
Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuou-ku, Osaka, 540-0006, Japan.
Norikazu
N
Masuda
Center for Breast Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, South Korea.
Jungsil
J
Ro
Virginia Cancer Specialists Research Institute, US Oncology, 1635 N. George Mason, Suite 170, Arlington, VA, 22205, USA.
Neelima
N
Denduluri
Biostatistics Oncology, Pharma Development, F. Hoffmann-La Roche, Building 670, Malzgasse 30, 4070 Basel, Switzerland.
Stanislas
S
Hubeaux
Global Development BioOncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Cheng
C
Quah
Global Development BioOncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA.
Carlos
C
Bais
Baylor Charles A. Sammons Cancer Center, US Oncology and Texas Oncology, 3410 Worth Street, Suite 400, Dallas, TX, 75246, USA.
Joyce
J
O'Shaughnessy
D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D017239:Paclitaxel / Q000008:administration & dosage; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D017239:Paclitaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D042461:Vascular Endothelial Growth Factor A; C508053:ERBB2 protein, human
Bevacizumab; Biomarker; Double-blind; Metastatic breast cancer; Predictive; Prospective; VEGF-A; Weekly paclitaxel