David Miles1, David Cameron2, Igor Bondarenko3, Lyudmila Manzyuk4, Juan Carlos Alcedo5, Roberto Ivan Lopez6, Seock-Ah Im7, Jean-Luc Canon8, Yaroslav Shparyk9, Denise A Yardley10, Norikazu Masuda11, Jungsil Ro12, Neelima Denduluri13, Stanislas Hubeaux14, Cheng Quah15, Carlos Bais15, Joyce O'Shaughnessy16. 1. Mount Vernon Cancer Centre, Rickmansworth Road, Northwood, London, HA6 2RN, UK. Electronic address: david.miles@doctors.org.uk. 2. University of Edinburgh and Cancer Services, NHS Lothian, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK. 3. Oncology Department, Dnipropetrovsk Medical Academy, Multiprofile Clinical Hospital, #449102, Blizhnaya Str, Dnipropetrovsk, Ukraine. 4. NN Blokhin Cancer Centre, Kashirskoye Schosse 23, Moscow, 115478, Russia. 5. Centro Hemato Oncológico Panama, Marbella Edificio Royal Center, 5to. Piso Torre B, Panama City, Panama. 6. Medical Oncology Department, National Oncology Institute, Gorgas & Juan de Arco Street, Ancon, PO Box 0816-04433, Panama City, Panama. 7. 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. 8. Oncology and Haematology Service, Grand Hôpital de Charleroi, Grand Rue 3, 6000, Charleroi, Belgium. 9. Lviv State Oncological Regional Treatment and Diagnostic Center, 2a Hashek Str, Lviv, 79031, Ukraine. 10. Sarah Cannon Research Institute and Tennessee Oncology, PLCC, 3322 West End Avenue, Suite 900TN, Nashville, TN, 37203, USA. 11. Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, 2-1-14, Hoenzaka, Chuou-ku, Osaka, 540-0006, Japan. 12. Center for Breast Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do, 10408, South Korea. 13. Virginia Cancer Specialists Research Institute, US Oncology, 1635 N. George Mason, Suite 170, Arlington, VA, 22205, USA. 14. Biostatistics Oncology, Pharma Development, F. Hoffmann-La Roche, Building 670, Malzgasse 30, 4070 Basel, Switzerland. 15. Global Development BioOncology, Genentech Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. 16. Baylor Charles A. Sammons Cancer Center, US Oncology and Texas Oncology, 3410 Worth Street, Suite 400, Dallas, TX, 75246, USA.
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 withchemotherapy. 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 (242placebo-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.
RCT Entities:
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.
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