Bevacizumab

Abstract

The tolerability profile of bevacizumab was generally acceptable in clinical trials in patients with advanced colorectal cancer, breast cancer, or NSCLC. In pooled analysis, the most common adverse events of any severity in patients receiving bevacizumab were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria. Most adverse events were mild to moderate in severity, and events such as hypertension, hemorrhage, or proteinuria were clinically manageable.The most common grade 3 or 4 adverse events in bevacizumab recipients were asthenia, pain, hypertension, diarrhea, and leukopenia. Bevacizumab is associated with an increased risk of gastrointestinal perforations in patients with metastatic colorectal cancer, hemoptysis in patients with advanced NSCLC (particularly those with squamous cell histology), wound healing complications, arterial thromboembolism, sensory neuropathy, and congestive heart failure. Such events have resulted in death, but are relatively uncommon.AbstractBevacizumab is a humanized recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumor growth.In patients receiving an irinotecan plus fluorouracil/leucovorin (IFL) regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab significantly increased overall survival by 4.7 months relative to IFL plus placebo. In the second-line treatment of advanced colorectal cancer, patients who received bevacizumab in combination with a fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen had an overall survival time that was 2 months longer than that in patients receiving FOLFOX4. Preliminary results indicated that bevacizumab significantly extended progression-free survival by 4.9 months in patients receiving paclitaxel for the first-line treatment of locally recurrent or metastatic breast cancer. The addition of bevacizumab to paclitaxel plus carboplatin in the first-line treatment of advanced NSCLC significantly prolonged overall survival by >2 months.Bevacizumab has acceptable tolerability in patients with advanced colorectal cancer, breast cancer, or NSCLC, with the majority of adverse events being generally mild and clinically manageable. Thus, bevacizumab provides a highly effective addition to standard chemotherapeutic regimens for advanced colorectal cancer, breast cancer, and NSCLC.Pharmacological PropertiesBevacizumab binds to soluble VEGF, preventing receptor binding, and inhibits VEGF-induced endothelial cell proliferation and migration in vitro. In vivo in murine xenografts, bevacizumab decreased tumor growth by ≈70–95% compared with control animals. In patients with rectal adenocarcinoma or inflammatory or locally advanced breast cancer, intravenous bevacizumab displayed antiangiogenic and antitumor effects.The single-dose pharmacokinetic profile of bevacizumab 0.1–10 mg/kg is linear, and an accumulation index of 1.4–2.9 has been observed after multiple doses of 3–20 mg/kg. The mean central volume of distribution of bevacizumab was 37.9–48.6 mL/kg during monotherapy, 34.3–56.8 mL/kg during coadministration with other antineoplastic agents, and was 22% greater in males than in females after correction for bodyweight.The clearance of bevacizumab is low (2.8–5.1 mL/kg/day with doses of 0.3–10 mg/kg) and varies with bodyweight, sex, and tumor burden. Bevacizumab 0.3–20 mg/kg has a long terminal elimination half-life (up to 22 day across a range of doses in multiple studies and ≈20 days in a population pharmacokinetic analysis), permitting administration at 2- or 3-week intervals.Therapeutic EfficacyIn chemotherapy-naive patients with metastatic colorectal cancer, the addition of bevacizumab to IFL treatment significantly increased median values for overall survival by 4.7 months, progression-free survival by 4.4 months, and response duration by 3.3 months and the objective response rate (ORR) 1.3-fold relative to IFL plus placebo. In addition, bevacizumab plus fluorouracil/leucovorin significantly improved median progression-free survival, although not overall survival, in patients with a poor prognosis who were unlikely candidates for irinotecan therapy. Bevacizumab combined with FOLFOX4 significantly increased median overall survival by 2 months, median progression-free survival by >2 months, and the ORR by 2-fold relative to FOLFOX4 alone in chemotherapy-experienced patients with advanced colorectal cancer.In preliminary results, first-line therapy with bevacizumab plus paclitaxel in patients with locally recurrent or metastatic breast cancer significantly increased median progression-free survival by 4.9 months and the ORR by almost 2-fold relative to paclitaxel monotherapy. In heavily pretreated patients, however, despite a significant 2-fold increase in ORR, the addition of bevacizumab to capecitabine did not demonstrate any significant increase in median progression-free or overall survival times relative to capecitabine alone.Bevacizumab combined with paclitaxel plus carboplatin significantly increased median overall survival by >2 months, median progression-free survival at 1 year by almost 2 months, and more than doubled the ORR relative to paclitaxel plus carboplatin in chemotherapy-naive patients with advanced nonsquamous cell NSCLC. as|Tolerability