Following initial phase I trials evaluating dosing and tolerability in a variety of advanced solid tumors, investigators looked at the safety and efficacy of single agent bevacizumab in a phase II trial (33). In this study, 75 women with previously treated, metastatic breast cancer (70% receiving two or more prior chemotherapy regimens) were assigned to receive single-agent bevacizumab at escalating doses starting at 3 mg/kg IV every other week, up to 20 mg/kg every other week. The overall response rate in this pretreated population was 9.3% (confirmed response rate 6.7%), with a median duration of confirmed response of 5.5 months, and a reported 17% of patients with stable disease or better after five months of therapy. The drug was well tolerated at all doses, with increased incidence of headache, nausea, and vomiting at the 20 mg/kg dose. The most substantial toxicity was hypertension (seen in 23% of participants, 18.6% requiring treatment) and proteinuria (1+ in 12.5%, 2+ in 2.7%, and 3+ in 8.3). Four patients (5.3%) discontinued the drug because of adverse events (AEs) (one patient with hypertensive encepha-lopathy, one with proteinuria, one with nephritic syndrome, and one with headache, nausea, and vomiting) (Table 1). There were no reported episodes of significant bleeding in these patients. Axillary/subclavian venous thrombosis was seen in two patients with indwelling central catheters, but no episodes of lower extremity venous thrombosis or pulmonary embolus were observed. On the basis of these findings, the authors concluded that bevacizumab was active as monotherapy in metastatic breast cancer, with an acceptable toxicity profile,
TABLE 1 Serious Adverse Events Seen with Bevacizumaba
Hypertension, including hypertensive crisis Proteinuria including nephrotic syndrome
Thrombosis (venous and arterial)-including cerebral and myocardial infarction, transient ischemic attacks (TIA), and deep venous thrombosis Bleeding and hemorrhage Impaired wound healing Congestive heart failureb aResults from multiple clinical trials including studies in colorectal cancer, non-small cell lung cancer, renal cell carcinoma, and breast cancer.
bSeen only in patients receiving anthracyclines and/or left chest-wall irradiation.
supporting the initiation of trials investigating its use in combination with other chemotherapy agents in similar patients.
The theory that targeting angiogenesis could improve the efficacy of traditional chemotherapy has been proposed for several years, based largely on preclinical studies demonstrating a synergistic effect when these two approaches are combined (34,35). There are various theories as to how combining these agents could promote increased efficacy of one another when used in vivo. Anti-VEGF treatments may help to "normalize" the chaotic architecture of blood vessels associated with tumors, reducing vascular permeability and interstitial fluid pressure within the tumor itself, potentially improving drug delivery (i.e., cytotoxic agents) to the cancer (36). The fact that antiangiogenesis agents and traditional chemotherapy agents work by very different mechanisms to arrest tumor growth also argues in favor of combining these approaches to achieve maximum disease control. The first large trial investigating combined antiangiogenic and cytotoxic agents in breast cancer patients was a randomized phase III, study comparing responses with capecitabine plus bevacizumab to capecitabine alone (37). This study reported by Miller et al. enrolled 462 women with metastatic breast cancer, all receiving prior chemotherapy, and randomized them to receive either single-agent capecitabine (2500 mg/m /day twice daily for 14 days, followed by a seven day rest period) or the combination of capecitabine plus bevacizumab (15 mg/kg IV every three weeks). Patients continued therapy for a maximum of 35 cycles or until disease progression or toxicity warranted their withdrawal from the study. Patients in the combination arm could continue bevacizumab alone at disease progression—those on capecitabine monotherapy were not permitted to crossover to receive bevacizumab at any time during the trial. There was a reported doubling in the objective response rate (ORR) from 9.1% in the single-agent arm to 19.8% in the combination arm, which reached statistical significance (P = 0.001). Unfortunately, the results for progression-free survival (PFS) and OS were not similarly impacted. They reported a PFS of 4.86 months versus 4.17 months [hazard ration = 0.98, (95% CI 0.77-1.25), P = 0.857] and OS of 15.1 months versus 14.5 months. The addition of bevacizumab did not impact the frequency or severity of capecitabine-related toxicities, but was related to several AEs by itself. Hypertension and proteinuria were reported at higher frequency in the combination arm; there were no reported grade 4 events for either. Four patients discontinued bevacizumab due to hypertension, and two discontinued the treatment due to grade 3 proteinuria. Bevacizumab was associated with an increase in minor mucosal bleeding, with significantly higher numbers of grades 1 and 2 epistaxis occurring in the combination arm. There were no reported grade 4 bleeding events, and each arm reported only one grade 3 event. The incidence of thrombosis and thromboembolic events was infrequent and similar in both treatment arms. There was an apparent increase in congestive heart failure in the combination arm (nine patients developed grade 3 or 4 events) versus the control arm (two similar events), the significance of which was uncertain, but did warrant further evaluation. These findings clearly indicate that the addition of bevacizumab to capecitabine does increase response rates in this population of pre-treated patients with a reasonable profile for both safety and tolerability. However, there was no survival benefit derived from the combination in this study a finding that left doubt in the minds of many as to the exact role for bevaci-zumab in this setting. Timing may be a crucial issue in these patients, as many received multiple lines of prior chemotherapy before receiving bevacizumab in this study. If this is true, then earlier treatment in the first-line metastatic or even the adjuvant settings may hold greater potential for angiogenesis-inhibitors to truly make an impact in disease-free and survival outcomes.
Fortunately, the disappointing results in the initial phase III study did not discourage researchers from looking to answer this very question. If timing were an essential element of the angiogenesis cascade, then perhaps blocking this pathway in first-line metastatic disease may show improvements in ORR, PFS, and OS compared to the patients in the prior phase III study who had received prior therapy for their disease. This lead to a second phase III trial (E2100) investigating the role of bevacizumab in metastatic breast cancer (38). This intergroup study enrolled 722 women with locally recurrent or metastatic breast cancer and randomized them to receive either single agent, weekly paclitaxel (90 mg/m2 intravenously days 1, 8, and 15 every four weeks) or the same dose/schedule of paclitaxel plus bevacizumab (10 mg/kg days 1 and 8). At the time of first interim analysis (with updates), the authors were able to report a stunning benefit not only in overall response rates, but now for the first time in PFS and in OS (39). Overall response rates were significantly improved in the combination arm (29.9% vs. 13.8%; P < 0.0001) and in the subset of patients with measurable disease (34.3% vs. 16.4%; P < 0.0001). With an interim reporting of 484 events, PFS was also improved (11.4 months vs. 6.11 months; HR = 0.51, P < 0.001). The current data regarding OS is still immature and will require further observation before a trend is identified. Toxicity and tolerability data reported are consistent with prior studies, showing higher rates of hypertension and proteinuria in those patients receiving bevacizumab. These findings now support the role of bevacizumab in the treatment of advanced breast cancer, providing the impetus for further studies to investigate and hopefully refine the use of this potentially powerful agent.
While data from E2100 continue to accumulate, work on exploring the role of bevacizumab in the adjuvant setting is already under way. Many have held that if Folkman's theories were true, then the most beneficial use of antiangiogenesis agents would take place in adjuvant treatment. There is concern, however, regarding potential cardiac-toxicities that could develop in the adjuvant setting, particularly in patients receiving anthracyclines with bevacizumab (Table 2). An Eastern Cooperative Oncology Group (ECOG) pilot trial (E2104) will look specifically at this issue in patients with lymph node-positive, resected primary breast cancers. By design the study will look to evaluate the incidence of clinical congestive heart failure in the adjuvant setting with the use of these agents, with secondary
TABLE 2 Reported Incidence of Congestive Heart Failure with Bevacizumab
Observed incidence of congestive heart failure
Bevacizumab monotherapy in breast cancer 2/75 patients (2.7%)—both received prior doxorubicin
Capecitabine +/- bevacizumab in breast cancer E2100—bevacizumab + paclitaxel in breast cancer AML
(1-beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab) Neoadjuvant AT + bevacizumab inflammatory breast Doxorubicin + bevacizumab metastatic sarcomas
Preliminary data showing 1 /342 (0.3%)
6% incidence of CHF
Note: AT, doxorubicin and docetaxel.
Abbreviations: AML, acute myeloid leukemia; CHF, congestive heart failure; LVEF, left-ventricular ejection fraction. Source: Adapted from Refs. 29, 38, 40, 62, 63, 82, 83.
endpoints looking at changes in left ventricular ejection fraction (LVEF) and non-cardiac toxicity. Patients will be assigned to either standard dose-dense combination doxorubicin/cyclophosphamide plus initial bevacizumab (10 mg/kg IV days every two weeks) or the dose-dense combination doxorubicin/cyclophosphamide without the addition of bevacizumab. Both arms will then go on to receive paclitaxel (175mg/m2 IV every two weeks) with bevacizumab (10 mg/kg IV every two weeks) for four cycles, followed by single-agent bevacizumab (10 mg/ kg IV every two weeks) for an additional 18 cycles in the up-front arm, and/or additional 22 cycles in the remaining arm. Interim data from this trial has not yet been reported.
A definitive adjuvant trial has also been proposed and is currently awaiting final approval and activation from advisory committees. E5103 is a similarly designed adjuvant trial that will look at the impact of bevacizumab in combination with every three-week doxorubicin plus cyclophosphamide (AC), followed by weekly paclitaxel (T) in women with earlier stages of breast cancer. Once this study is initiated, the data on up-front bevacizumab will accumulate, providing the much needed answer to the critical questions of timing in the application of antiangiogenesis therapies in breast cancer. While these studies continue to collect data, several other phase II trials have looked at combining bevacizumab with other agents, including docetaxel in neoadjuvant (40) and advanced disease (41) vinorelibine (42), and letrozole (43). Investigators have also looked at the role of bevacizumab in combination with doxorubicin and docetaxel in the treatment of inflammatory and locally advanced breast cancer with promising findings based on several surrogate markers (44). Trials such as these will continue to provide data, hopefully determining the right combinations and schedules of agents that work best in conjunction with bevacizumab in breast cancer patients.
Angiogenesis is a complex process comprised of multiple signaling pathways. Many of these pathways are redundant, with several ligand-receptor combinations resulting in the same eventual down-stream cascade of events. This observation has lead many to speculate that simultaneous blockade of multiple pathways might have an even greater impact on halting angiogenesis and slowing tumor growth and progression. Early work in this area discovered a link between the expression of human epidermal growth factor receptor 2 (HER2) and increased transcriptional regulation of VEGF (45). With the known impact of HER2 overexpression in breast cancer, efforts turned to evaluate not only the role of this receptor in angiogenesis, but also the possible additional effect on this process if blocked. The addition of a specific neutralizing anti-erbB2/neu monoclonal antibody in vitro to human breast cancer cell lines overexpressing this receptor resulted in the dose-dependent reduction of VEGF protein expression (46). This, combined with evidence that HER2 gene amplification correlated with higher levels of angiogenesis in breast cancer (47), and the development of a more malignant phenotype in breast cancer patients (48) lead to the proposed combination of anti-HER2 and anti-VEGF antibodies. Pegram et al. (49) first proposed this combined modality approach in 2002, and followed with a phase I trial employing bevacizumab and the anti-HER2 antibody trastuzumab (Herceptin®; Genentech, San Francisco, California, U.S.A.) (50). In this study, nine patients with HER2 overexpressing, metastatic or recurrent breast cancer received trastuzumab (4 mg/kg loading dose, then 2 mg/kg IV weekly) plus bevacizumab (10 mg/kg IV every 14 days) until progression. The authors reported one complete response (CR) and four partial reponses (PRs) and two patients with stable disease. There were no grade III/IV AEs observed, and pharmacokinetic studies did not reveal the alteration of levels of either antibodies with co-administration. Thus, this combination appears safe, well tolerated, and active in breast cancer patients over-expressing HER2. Phase II trials are currently ongoing to provide additional data in this area.
There is similar preclinical evidence suggesting an interaction between EGFR and VEGF in the angiogenesis signaling cascade. EGFR may transcriptionally up-regulate VEGF expression (51), and subsequent blockade of these receptors with antibodies (4,46), or blocking their associated tyrosine kinase signaling mechanisms (52) has been showed to decrease VEGF transcription and expression. Combined blockade of EGFR and VEGF has been evaluated in several solid malignancies with mixed results reported thus far. ZD6474, a dual inhibitor of the VEGF-receptor 2-tyrosine kinase and EGFR-associated tyrosine kinase, has shown impressive preclinical efficacy in blocking the formation of atypical ductal hyper-plasia and carcinoma-in-situ in laboratory rats treated with 7,12-dimethylben-z[a]anthracene (53). In a phase II trial, single-agent ZD6474 was administered to 46 women with previously treated metastatic breast cancer (54). While this agent was well-tolerated with minimal reported toxicity, there were no objective responses seen in any of the dosing cohorts evaluated. Current studies are now evaluating the tyrosine kinase inhibitor erlotinib in combination with bevacizumab in patients with metastatic breast cancer (55). More work will obviously need to be done in this area before any definitive conclusions can be drawn about the synergy or efficacy of these agents in combination.
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