Present and future roles of bevacizumab in breast cancer
- H Cortés-Funes1
© BioMed Central Ltd 2007
Received: 23 May 2007
Published: 19 June 2007
Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been reported to be associated with a poor prognosis in primary breast cancer and other solid tumours . VEGF was observed to be one of the most important mediators of tumour angiogenesis in human breast cancer and was the only one linked to poor relapse-free survival .
VEGF affects tumour growth and metastasis in many forms of breast cancer, including invasive/noninvasive, node-negative/node-positive, inflammatory and metastatic disease. Also, VEGF expression has been observed across a number of disease-related variables, including hormonal and HER-2 status.
A complex relationship between oestrogen, the oestrogen-receptor subtypes, and VEGF has been seen in preclinical breast cancer models. Oestrogen modulates VEGF expression at the gene transcriptional level . VEGF expression in breast cancer cells promotes oestrogen-independent tumour growth in ovariectomized mice and VEGF-stimulated neovascularization, and contributed to tumour growth in both oestrogen-treated and nonoestrogen-treated mice. Tumour growth was highest in VEGF-expressing mice treated with oestrogen .
In multiple prospective and retrospective studies assessing blood and tumour samples in lung cancer patients, VEGF and angiogenesis have been associated with larger tumour size, increased rate of metastasis, recurrence of disease and poorer overall and disease-free survival [5–7]. Bevacizumab is a humanized recombinant antibody that prevents VEGF receptor binding, and inhibits angiogenesis and tumour growth. In patients receiving an irinotecan plus fluorouracil/leucovorin regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab significantly increased overall survival. 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 2 months longer than that in patients receiving FOLFOX4.
Bevacizumab has been tested in many tumours, proving efficacy when added to almost any chemotherapy regimen. It has been hypothesized that there are three main mechanisms by which bevacizumab exerts its antitumour activity: regression of existing tumour microvasculature, normalization of surviving mature tumour vasculature and inhibition of vessel regrowth and neovascularization as an effect with continuous treatment .
Based on preclinical findings that have shown the activity of bevacizumab in breast cancer, bevacizumab monotherapy was tested in a phase I/II dose escalation trial (AVF0776g) in metastatic breast cancer (MBC) with three doses (3, 10 and 20 mg/kg every 2 weeks) in 75 patients who had relapsed following at least one conventional chemotherapy regimen for metastatic disease. Combining data from the three arms, the overall response (OR) rate was 6.7%, the median duration of response (DR) was 5.6 months and overall survival (OS) was 10.2 months. Bevacizumab was well tolerated although four patients presented with headache with nausea and vomiting at the higher dose (dose limiting toxicity). Comparison of data from the three study arms indicated that a bevacizumab dose of 10 mg/kg every 2 weeks produced the best therapeutic ratio in this population of heavily pretreated patients .
Bevacizumab has since been studied in several phase II trials with different chemotherapy regimens (docetaxel, vinorelbine), targeted agents (trastuzumab, erlotinib) and hormonal therapies (letrozol), showing encouraging results and acceptable toxicity profiles in these combinations. Nowadays, there is evidence for efficacy of bevacizumab from two phase III trials (AVF2119g and E2100). The first phase III trial published (AVF2119g) compared a combination of bevacizumab (15 mg/kg every 3 weeks plus capecitabine 2,500 mg/m2 daily for 2 weeks of a 3-week cycle) versus capecitabine alone. A total of 462 women with MBC previously treated with an anthracycline and a taxane were randomized to any of the study arms. The primary study endpoint was progression-free survival (PFS) and secondary endpoints included the OR rate, DR and OS. There was no significant difference in PFS between the two arms. The proportion of progression-free patients at 6 months was 33.8% for the Xeloda-alone arm and 33.0% for the Xeloda plus bevacizumab arm. Median PFS was 4.17 and 4.86 months, respectively (HR = 0.98, P = 0.857). Overall survival data for the Xeloda-alone arm (14.5 months) compared with the Xeloda plus bevacizumab arm (15.1 months) was also not significant. Although the addition of bevacizumab to capecitabine did improve PFS nor OS, there was a significant increase in the OR rate in the capecitabine plus bevacizumab arm compared with the capecitabine-only arm when the data were analysed both by investigators (30.2% versus 19.1%; P = 0.006) and by an independent review facility (19.8% versus 9.1%; P = 0.001). However, no significant differences in PFS or in OS were found between the two arms. The combination was found to be well tolerated, with no increase in the frequency or severity of capecitabine-related adverse events in the bevacizumab-containing arm . In this study, although the addition of bevacizumab to capecitabine did not improve PFS (the primary endpoint), the OR rate doubled.
There have been a number of reasons hypothesized that could explain these observations. First of all, it has been demonstrated that VEGF inhibition is more effective in earlier disease, since in advanced disease there are also other angiogenic factors that are overexpressed .
Another reason could be that patients were heavily pretreated, having received both an anthracycline and a taxane prior to entering the trial. The other phase III trial (E2100) is an ongoing open-label, phase III trial in which bevacizumab is being evaluated in combination with weekly paclitaxel as first-line therapy for MBC. Patients recruited to this trial are less heavily pretreated than patients in AVF2119g. A total of 722 patients have been randomized to one of two arms: paclitaxel 90 mg/m2 alone every week for 3 weeks followed by 1 week without treatment or paclitaxel plus bevacizumab 10 mg/kg every 2 weeks. No crossover is permitted in this trial.
The objectives are to compare PFS, the OR rate and OS between the arms. Preliminary results from the first preplanned interim analysis showed a significant increase in median PFS in patients receiving bevacizumab plus paclitaxel compared with paclitaxel alone (11.4 versus 6.11 months; P < 0.0001). This PFS result was obtained following 89% of the required events. The OR rate for all patients was 29.9% (bevacizumab/paclitaxel) versus 13.8% (paclitaxel) (P < 0.0001), and was 37.7% (bevacizumab/paclitaxel) versus 16% (paclitaxel) (P < 0.0001) for patients with measurable disease only. The survival data are still immature .
Differences in the patient populations may help to explain the differences in results between the two phase III trials. Trial AVF2119 included a higher proportion of patients who had received chemotherapy, including those who had received both an anthracycline and a taxane. A greater number of HER2-positive patients were also enrolled in AVF2119, most of whom had previously received trastuzumab.
Trial AVF2119 patients were generally more heavily pretreated than those enrolled in the E2100 trial. This may partly explain why the significant response rate improvement seen in this trial did not translate into a PFS benefit. Showing these results, it can be hypothesized that bevacizumab should be used as early as possible to obtain the maximum benefit.
There are many other ongoing phase III trials that are testing the use of bevacizumab in combination with standard chemotherapy regimens. The AVADO trial is an ongoing randomized, double-blind, placebo-controlled, multicentre phase III trial that will randomize 705 patients to receive docetaxel at a dose of 100 mg/m2 every 3 weeks with either placebo, bevacizumab 7.5 mg/kg or bevacizumab 15 mg/kg. The primary trial endpoint will be PFS. Secondary endpoints will include the OR rate, duration of response, time to treatment failure, overall survival, safety and quality of life. Another trial exploring bevacizumab in combination with standard regimens is the RIBBON-1 study, a phase III trial to be conducted in countries worldwide that will investigate further combinations of bevacizumab and chemotherapy. The primary trial endpoint is PFS. Investigators will assign patients to a chemotherapy regimen, including specified regimens of anthracycline-based combination chemotherapy, taxane (docetaxel or Abraxane™) every 3 weeks, or Xeloda. Patients are then randomized to receive bevacizumab (15 mg/kg every 2 weeks) or placebo. Another combination that is also being explored is bevacizumab plus trastuzumab. There is a strong rational for combining both antibodies as the different factors that bevacizumab and trastuzumab inhibit play important roles in tumour growth and progression. It has been shown that activation of the HER family of receptors induces VEGF expression and angiogenesis in cancer cell models . These observations suggest that combined inhibition of VEGF and HER2 may enhance antitumour activity.
The feasibility of combining bevacizumab with trastuzumab was evaluated in the phase I, open-label AVF2473s trial. A total of nine patients with HER2-positive advanced or MBC were treated in one of three cohorts. Data from this trial led to the recommendation of bevacizumab 10 mg/kg every 2 weeks for use in combination with trastuzumab 2 mg/kg weekly (after a loading dose of 4 mg/kg) in phase II trials. The maximum tolerated dose was not reached. Analyses of pharmacokinetic parameters showed that coadministration of bevacizumab and trastuzumab does not alter the pharmacokinetics of either agent, indicating no interaction between the two agents. The combination was well tolerated, with no grade 3/4 adverse events . Recently presented at the San Antonio Breast Cancer Symposium 2006 have been the first efficacy data from an ongoing, nonrandomized, open-label, uncontrolled, phase II study trial (TORI-B-03) that explores the combination of bevacizumab plus trastuzumab for the first-line treatment of Her2-positive locally recurrent, surgically unresectable, or metastatic breast cancer. The interim data of 37 patients showed that the combination of both targeted agents induces an overall response rate of 54% with an acceptable safety profile without inducing the typical chemotherapy-related side effects.
There is currently running a phase III trial of bevacizumab, docetaxel and trastuzumab (AVEREL) in patients with previously untreated, HER2-positive MBC: 320 patients will be randomized to receive either docetaxel and trastuzumab or docetaxel, trastuzumab and bevacizumab until disease progression. Patients from the control arm will not be permitted to crossover to receive bevacizumab upon progression. The primary trial endpoint is PFS. Other endpoints include response rate, duration of response, OS and safety.
There is also evidence from phase II trials proving the efficacy of adding bevacizumab to other agents such as vinorelbine, erlotinib or letrozol. All this combinations have demonstrated encouraging results with acceptable toxicity profiles that warrant further exploration.
Besides the use of bevacizumab in the metastatic setting, it has been hypothesized that the greater benefit could be obtained when used in earlier stages. The progression of breast cancer is accompanied by the production of a wide array of proangiogenic growth factors that promote and support tumour growth. When tumours are small they secrete VEGF, which acts as a paracrine factor to induce endothelial cell proliferation and blood vessel formation, mediating tumour progression. As the tumour develops further, additional factors are also secreted . This evidence suggests that the inhibition of VEGF may be more beneficial in earlier stages, as neoadjuvant or adjuvant treatment. There are many trials, planned and ongoing, exploring bevacizumab in the neoadjuvant setting. An ongoing, phase II trial of bevacizumab in combination with docetaxel in the neoadjuvant setting (AVF2307s) is being conducted in patients with locally unresectable breast cancer with or without metastasis. Patients receive bevacizumab 10 mg/kg every 2 weeks and docetaxel 35 mg/m2 weekly for the first 6 weeks of an 8-week cycle. After two cycles, patients with stable disease or response, undergo surgery and radiotherapy, followed by further chemotherapy (not containing bevacizumab). The study objectives are to evaluate the efficacy and safety of neoadjuvant bevacizumab with docetaxel in breast cancer patients. Preliminary efficacy data showed that bevacizumab plus docetaxel reduces tumour vascular permeability and microvessel density . Combined response data for both study arms revealed seven complete responses (14.3%), 32 partial responses (65.3%), five patients with stable disease and a further five with progressive disease. This gave an OR rate of 79.6%, with no difference between the study arms. Both PFS and OS were 40 months in the docetaxel arm and neither had been reached in the docetaxel plus bevacizumab arm . TORI-B-02 is a phase II neoadjuvant trial currently being conducted at the University of California, Los Angeles. A total of 90 patients are being enrolled into four different treatment arms, in order to compare two different bevacizumab doses with placebo: Arm 1: bevacizumab 7.5 mg/kg, followed by six cycles of bevacizumab 7.5 mg/kg in combination with TAC (docetaxel, doxorubicin and cyclophosphamide) every 3 weeks; Arm 2: placebo 7.5 mg/kg, followed by six cycles of placebo 7.5 mg/kg in combination with TAC every 3 weeks; Arm 3: bevacizumab 15 mg/kg, followed by six cycles of bevacizumab 15 mg/kg in combination with TAC every 3 weeks; and Arm 4: placebo 15 mg/kg, followed by six cycles of placebo 15 mg/kg in combination with TAC every 3 weeks. Then, 28–42 days after receiving chemotherapy, patients eligible for surgery will undergo resection. After either receiving surgery or completing chemotherapy, patients in Arms 1 and 3 will receive bevacizumab at their previous dose until disease progression. Patients in Arms 2 and 4 will not receive further therapy before disease progression. The primary objectives of the TORI-B-02 trial are to evaluate the safety and toxicity of bevacizumab given as preoperative therapy to patients with stage II/III breast cancer in combination with the TAC regimen. Analysis of changes in HIF-1α levels will also be carried out, in order to compare tumour angiogenesis in patients given bevacizumab and placebo.
Other trial objectives include investigation of the clinical benefit of adding bevacizumab to TAC in the neoadjuvant setting. Parameters to be evaluated are the clinical objective response rate (complete response plus partial response), pathologic complete response rate and rate of breast-conserving surgery. As wound-healing complications have previously been reported in bevacizumab clinical trials, the effect of bevacizumab on postsurgical wound-healing will also be investigated as well as the rate of cardiac heart failure.
The most successful use of antiangiogenic therapy has been predicted to be in the adjuvant treatment, and there is a clear biologic basis and rationale for exploring bevacizumab in this clinical setting. A large proportion of patients with breast cancer have been reported to have primary tumours that overexpress VEGF, and overexpression of VEGF is associated with increased rates of relapse . The trials planned with bevacizumab in the adjuvant setting will confirm the efficacy of adding an antiangiogenic therapy to standard combinations.
The data from the trials currently ongoing will tell us the efficacy of combining bevacizumab with other drugs used in the metastatic setting, besides docetaxel or capecitabine, the exact role of bevacizumab in neoadjuvant and adjuvant settings, and perhaps it will be possible to identify which patients are most likely to benefit from VEGF-targeted therapies.
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