Efficacy and Safety of Bevacizumab in Metastatic Colorectal Cancer: Pooled Analysis From Seven Randomized Controlled Trials

Abstract

Purpose. This analysis pooled individual patient data from randomized controlled trials (RCTs) to more thoroughly examine clinical outcomes when adding bevacizumab to chemotherapy for patients with metastatic colorectal cancer (mCRC). Patients and Methods. Patient data were pooled from the first-line AVF2107, NO16966, ARTIST, AVF0780, AVF2192, and AGITG MAX RCTs and the second-line E3200 RCT. All analyses were based on the intent-to-treat population. To assess differences in time-to-event variables by treatment (chemotherapy with or without placebo vs. chemotherapy plus bevacizumab), stratified random-effects (overall) and fixed-effects (subgroup comparisons) models were used to estimate pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results. The analysis population comprised 3,763 patients (1,773 chemotherapy with or without placebo; 1,990 chemotherapy plus bevacizumab). The addition of bevacizumab to chemotherapy was associated with statistically significant increases in overall survival (OS; HR, 0.80; 95% CI, 0.71-0.90) and progression-free survival (PFS; HR, 0.57; 95% CI, 0.46 -0.71). The effects on OS and PFS across subgroups defined by chemotherapy backbone (oxaliplatin-based, irinotecanbased), extent of disease (liver metastases only, extensive disease), age (Ͻ65, Ն65 years), Eastern Cooperative Oncology Group performance status (0, Ն1), and KRAS status (wildtype, mutant) were consistent with the overall analysis. Incidence rates of grade Ն3 hypertension, proteinuria, bleeding, wound-healing complications, gastrointestinal perforations, and thromboembolic events were increased with bevacizumab treatment. Conclusion. The use of bevacizumab with chemotherapy resulted in statistically significant increases in OS and PFS for patients with mCRC. The PFS benefit extended across the clinically relevant subgroups examined. The observed safety profile of bevacizumab was consistent with that reported in individual trials. The Oncologist 2013;18:1004 -1012 Implications for Practice: Several randomized trials of bevacizumab have been conducted to address specific questions regarding its use for patients with metastatic colorectal cancer (mCRC); however, because of their sample size limitations, subgroup analyses are frequently of limited power. By pooling individual patient data from seven randomized trials, more comprehensive analyses of the efficacy and safety of bevacizumab were made possible because of the large number of included patients. In addition, outcomes in clinically relevant subgroups were examined, and the data from these subgroups were consistent with those reported in the overall analyses. The results of this pooled analysis help further the clinician's understanding of the overall risks and benefits associated with adding bevacizumab to chemotherapy for patients with mCRC.

Tumor-Specific Uptake of Fluorescent Bevacizumab–IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study

“…Successful and specific imaging has been performed in patients with melanoma, renal cell cancer, neuroendocrine tumors, and breast cancer using 111 In-and 89 Zr-radiolabeled bevacizumab (11,(15)(16)(17)(18)(19). In these studies, a systemic total microdose of 4.5 mg labeled bevacizumab, that is, 30 nmol adhering to the definition of microdosing for proteins according to FDA/EMEA guidelines (20) and as described separately for proteins by Kummar and colleagues (21), was used, which is subtherapeutic compared with the therapeutic dose of 5 to 15 mg/kg bodyweight (22)(23)(24). In a recent PET imaging study with 89 Zr-bevacizumab in 23 patients with primary breast cancer, 25 of 26 tumors (96%) were visualized by PET 4 days after 89 Zr-bevacizumab tracer injection with tumor-to-normal tissue ratios of 1.4:10.3 (19).…”

Neoadjuvant therapy of bevacizumab in combination with oxaliplatin and capecitabine (XELOX) for patients with metastatic colorectal cancer with unresectable liver metastases: a phase II, open‐label, single‐arm, noncomparative trial

“…21 Bevacizumab (Avastin; F. HoffmannLa Roche Ltd., Genentech, Inc., San Francisco, CA, USA) is one such humanized recombinant monoclonal antibody that binds to and blocks the activity of all isoforms of vascular endothelial growth factor-A (VEGF-A). 22,23 Studies show that bevacizumab in combination with commonly used chemotherapeutic agents demonstrates a higher response rate (RR), progression-free survival (PFS) and overall survival (OS) versus chemotherapy alone in patients with mCRC, 22,[24][25][26] along with an acceptable safety profile in patients with unresectable mCRC. 27 According to the National Cancer Institute, neoadjuvant therapy can be given as the first step to shrink a tumor before the main treatment, which is usually surgery.…”

Efficacy of continuing anti-angiogenic agents in the second-line treatment for metastatic colon cancer depending on the KRAS mutation status: a meta-analysis

“…Эффективность добавления бевацизумаба к химиотерапии в 1-й линии доказана несколькими исследованиями, при этом ран-домизированных исследований, посвященных данному вопросу (именно популяции больных с мутацией гена KRAS), не проводилось. Однако по данным анализа 2 ис-следований (с доступными данными по статусу гена KRAS), опубликованного в 2013 г., бевацизумаб эффек-тивен в отношении ВБП в 1-й линии вне зависимости от мутационного статуса [7].…”