Tumor angiogenesis, an important step in breast cancer development, invasion, progression, and metastasis, is regulated by the expression of proangiogenic factors such as vascular endothelial growth factor (VEGF).[1-6] Higher levels of VEGF expression are associated with poor clinical outcomes and decreased survival in patients with breast cancer.[5-8] It follows that VEGF might prove useful as a potential target for drug development in this disease.[9-11]
Bevacizumab (Avastin), is a humanized anti-VEGF antibody that is approved by the US Food and Drug Administration for the first-line treatment of metastatic HER2-negative, breast cancer in combination with paclitaxel(Drug information on paclitaxel). In this review, we will discuss the development of bevacizumab(Drug information on bevacizumab) and the data pertaining to its use in the treatment of advanced breast cancer.
Studies of a murine anti-VEGF antibody demonstrated tumor growth inhibition and improved survival in xenograft models of cancer.[12-14] The humanized version of this anti-VEGF antibody (bevacizumab) is composed of a human immunoglobulin backbone and an antigen-binding region from the murine monoclonal antibody. Bevacizumab recognizes and neutralizes all isoforms of human VEGF-A, thereby preventing the growth factor from interacting with the VEGF receptor and abrogating the downstream biologic activity of VEGF.[15,16]
Phase I trials demonstrated that bevacizumab is generally well tolerated and has predictable pharmacokinetics, both alone and in combination with chemotherapy.[17,18] A phase I/II trial was conducted in patients with metastatic breast cancer (MBC) to determine the safety and efficacy of the drug. A total of 75 patients with disease progression after at least one conventional chemotherapy regimen were given bevacizumab at escalating doses of 3, 10, and 20 mg/kg every 2 weeks. The overall response rate was 9.3%, and the median duration of response was 5.5 months in this patient population. Approximately 17% of patients had either stable disease or an ongoing objective response. The median time to progression was 2.4 months, and median survival was 10.2 months.
The toxicity profile observed for bevacizumab differed from that typically experienced with cytotoxic chemotherapy. Adverse events leading to drug discontinuation included proteinuria, nephrotic syndrome, hypertensive encephalopathy, and headache associated with nausea and vomiting. Headache was the dose-limiting toxicity observed at 20 mg/kg, and therefore, 10 mg/kg was chosen as the optimal dose of bevacizumab in breast cancer. At 10 mg/kg, the most common grade 3/4 adverse events included hypertension, dyspnea, asthenia, and myalgia. Grade 3/4 proteinuria occurred in two of the 72 patients evaluated (2.8%). Thrombotic events occurred in three patients, and two patients experienced congestive heart failure (CHF).
Bevacizumab in Combination With Chemotherapy
Bevacizumab demonstrated modest clinical benefit as monotherapy. It is thought that anti-VEGF agents may act to normalize tortuous tumor vasculature, thereby reducing interstitial fluid pressure and facilitating drug delivery to solid tumors. A number of preclinical studies have suggested synergy between antiangiogenic therapy and chemotherapy. Here, we review the large, randomized, phase III trials and select phase II studies that test bevacizumab-chemotherapy combinations.
• Capecitabine and Bevacizumab in MBC—In the first published randomized phase III trial of bevacizumab, 462 eligible patients had anthracycline- and taxane-resistant disease, and progression or recurrence of disease after at least one chemotherapy regimen. Capecitabine(Drug information on capecitabine) (Xeloda) was administered at the same dose and schedule for both treatment arms (2,500 mg/m2/d twice daily for 2 of 3 weeks). Patients randomized to the combination arm received bevacizumab at 15 mg/kg IV every 3 weeks. The primary endpoint of the trial was progression-free survival (PFS).
The addition of bevacizumab to capecitabine increased the response rate from 9.1% to 19.8% (P = .001). However, the combination did not significantly increase PFS when compared to capecitabine monotherapy (4.86 vs 4.17 months, hazard ratio = 0.98, 95% confidence interval = 0.77–1.25; P = .857). The bevacizumab combination was well tolerated and did not appear to worsen capecitabine-related toxicity for this pretreated population. Bevacizumab-related toxicities included hypertension (grade 3: 17.9% vs 0.5% for single-agent capecitabine), thromboembolic events (grades 2–4: 6.9% vs 5.6%), proteinuria (grades 1–4: 22.3% vs 7.4%), and minor bleeding. Nine patients developed grade 3/4 CHF or cardiomyopathy: seven in the combination arm (3.1%) and two in the single-agent capecitabine arm (0.9%). Grade 3 or serious bleeding was uncommon and did not differ between therapies.
It was suggested that the activity of bevacizumab may have been obfuscated by the degree of prior therapy in this patient population with refractory disease. Advanced stages of cancer may have redundant angiogenic pathways, making the inhibition of a single receptor pathway inadequate for significant clinical benefit.
A multicenter, phase II study (XCALIBr: Xeloda in Combination with Avastin as first-Line treatment for HER2-negative metastatic Breast cancer) subsequently tested the combination of bevacizumab (15 mg/kg every 3 weeks) with capecitabine (1,000 mg/m2 twice daily for 2 of 3 weeks) as first-line treatment for 106 patients with metastatic breast cancer. This trial met its primary endpoint, an increase in time to progression from 4 months (capecitabine monotherapy) to 5.7 months (capecitabine and bevacizumab). The combination also demonstrated improved response rate compared to capecitabine monotherapy. An unplanned, subset analysis of efficacy based on hormone receptor status suggested greater activity in patients with estrogen receptor–positive disease. This finding is hypothesis-generating and will be studied further, as there is no ready explanation for this observation.
• Paclitaxel and Bevacizumab in MBC—The Eastern Cooperative Oncology Group (ECOG) trial 2100 randomized patients to weekly paclitaxel, with or without bevacizumab, as first-line therapy for locally recurrent breast cancer or MBC. Evidence has suggested that taxanes have antiangiogenic activity when administered at a low weekly dose.[24,25] Therefore, the combination of weekly paclitaxel and bevacizumab was selected for its dual antiangiogenic inhibition.
A total of 722 patients were enrolled on this trial. Paclitaxel was given at 90 mg/m2 weekly for 3 of 4 weeks. Patients who were randomized to the combination arm received bevacizumab at 10 mg/kg every 2 weeks. Patients with HER2-positive breast cancer were excluded from this trial, unless they had been previously treated with trastuzumab(Drug information on trastuzumab) (Herceptin). Pertinent exclusion criteria included the presence of brain metastases and significant underlying heart disease. Patients were permitted to have received adjuvant taxane therapy if a disease-free interval of > 12 months had elapsed. (Two-thirds of patients had received prior adjuvant therapy, and approximately 20% had previous taxane exposure.) Patients were stratified according to prognostic factors such as disease-free interval, number of metastatic sites, prior adjuvant therapy, and hormone receptor status. PFS was the primary endpoint.
Patients receiving paclitaxel with bevacizumab showed a significant improvement in PFS compared with those receiving paclitaxel alone (median = 11.8 vs 5.9 months; hazard ratio for progression = 0.60; P < .001). Similarly, the combination arm demonstrated a higher overall response rate than the single-agent arm (36.9% vs 21.2%, P < .001). The overall survival rate, however, was similar in the two groups (median = 26.7 vs 25.2 months; hazard ratio = 0.88; P = .16). ECOG 2100 demonstrated the efficacy of bevacizumab in combination with paclitaxel, and provided additional safety data. Patients in the combination arm experienced more grade 3/4 hypertension (14.8% vs 0%; P < .001), proteinuria (3.6% vs 0%; P < .001), headache (2.2% vs 0.0%, P = .008), and cerebrovascular ischemia (1.9% vs 0.0%, P = .02) than patients in the single-agent arm. The investigators observed no increased thromboembolic events or episodes of CHF in the combination arm. Quality-of-life measures using the Functional Assessment of Cancer Therapy (FACT)-Breast Cancer and FACT-General surveys were no different between treatment arms or time points.
• Docetaxel and Bevacizumab in MBC—Docetaxel is a commonly used taxane with efficacy against breast cancer. The AVADO (AVastin And DOcetaxel(Drug information on docetaxel)) trial was a randomized, double-blind, placebo-controlled, phase III study comparing the efficacy of docetaxel with or without bevacizumab for the treatment of patients with locally recurrent or MBC. Patients were randomized to one of three treatment arms: (1) docetaxel at 100 mg/m2 every 3 weeks, (2) docetaxel plus bevacizumab at 15 mg/kg every 3 weeks, and (3) docetaxel plus bevacizumab at 7.5 mg/kg every 3 weeks. Patients received a maximum of nine cycles of chemotherapy, but earlier discontinuation was permitted—a noteworthy design difference from ECOG 2100. Placebo or bevacizumab was continued until disease progression. All patients had the option of receiving bevacizumab in combination with their second-line chemotherapy.
The primary study endpoint was PFS, and the protocol-specified primary analysis was an unstratified comparison of PFS between each of the bevacizumab-containing arms and the control arm. The study was not powered to detect a difference between the two bevacizumab doses.