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JOURNAL CLUB - Oncology

At the end of this report, you can view Prof. David Miles' ASCO presentation on the AVADO study.

Editorial Overview:

John R. Mackey, MD, FRCPC

Professor of Oncology, University of Alberta, Edmonton, Alberta

Breast cancer affects approximately 21,000 Canadian women a year, and nearly 5400 die from metastatic disease. While mortality rates from breast cancer have declined significantly over the past 20 years—largely due to improvements in adjuvant therapy—a significant proportion of patients either present with metastatic disease or experience distant relapses after primary therapy. Median survival has improved to nearly three years from the diagnosis of distant metastases, but long-term survival remains infrequent: the goal of treatment of metastatic breast cancer (MBC) remains optimal palliation.

But how do we define optimal palliation? Clearly, laudable goals of therapy would be to prolong survival, maintain quality of life, improve tumour-related symptoms by controlling disease, and achieve each of the above with minimally toxic treatments. While overall survival (OS) in metastatic breast cancer (MBC) has improved modestly with the arrival of new systemic therapies, individual trials only rarely demonstrate improvements in OS—multiple lines of therapy, crossover to the experimental agents, the biological heterogeneity of breast cancer, and loss to follow-up dilute our ability to detect survival effects from first-line interventions. Similarly, quality of life (QOL) evaluations are diluted by loss of data when patients become ill, the difficulty in capturing disease- and treatment-related symptoms, the efficacy of modern supportive care options, and the difficulty in interpreting what a given change in QOL actually means to a patient.

Objective response rates do provide a measure of anticancer activity, but suffer from their inapplicability to patients with non-measurable disease, the knowledge that tumour size reduction is not necessarily related to improvement of a patient’s symptoms, and the growing awareness that many effective new biologics may benefit patients even without producing objective responses. Increasingly, clinical trialists and clinicians are therefore turning to prolongation of progression-free survival (PFS) as a clinically meaningful and readily evaluable end point. PFS reflects the interval of time during which patients are alive without progressive disease (i.e. the duration of cancer control). Assuming equitoxic options, patients and clinicians obviously prefer those regimens that provide the longest PFS.

Adding VEGF Inhibition to Standard Treatment Regimens

There is considerable interest in developing new and more effective treatments for MBC. Although there are many acceptable first-line cytotoxic options, for those women who warrant chemotherapy (i.e. life-threatening and/or visceral metastases, severe symptoms, exhausted hormonal therapies or hormone receptor-negative disease, reasonable performance status and adequate physiologic reserves), taxane therapy with paclitaxel or docetaxel remains an accepted standard of care.

Angiogenesis is the process of formation of new blood vessels. However, breast cancers have been shown to utilize this normal physiologic process to support tumour growth. Vascular endothelial growth factor (VEGF) is a central regulator of angiogenesis, and is frequently overexpressed within the breast cancer microenvironment. A direct correlation has also been found between intratumoural VEGF levels and poor breast cancer outcomes, including OS. Consequently, VEGF has been aggressively pursued as a breast cancer drug target, and inhibition of VEGF and its receptors have been shown to have important anti-tumour activity in preclinical models, and in increasing numbers of phase II MBC trials.

The most well-studied antiangiogenic in breast cancer is the humanized monoclonal antibody bevacizumab, which binds and clears VEGF. In the randomized, phase III E2100 study, a significant benefit in PFS was observed with bevacizumab plus paclitaxel vs. paclitaxel alone (Miller et al. N Engl J Med 2007;357:2666-76). The randomized phase II, double-blind, placebo-controlled AVADO (Avastin and Docetaxel in Metastatic Breast Cancer) study investigated the addition of bevacizumab to a different taxane, docetaxel, in women with MBC. The results of this trial were unveiled at ASCO 2008.

AVADO Review

As reported by Prof. David Miles, Mount Vernon Cancer Centre, Middlesex, UK, AVADO involved a total of 736 women from 104 different sites in 26 countries (including Canada). Patients were rapidly recruited between March 2006 and April 2007, producing a “bolus” of patients with similar durations of follow-up.

All patients were HER2-negative and none had received prior chemotherapy for locally recurrent or metastatic disease. However, prior adjuvant chemotherapy was allowed, provided six months or more had elapsed from the last dose and 12 months or greater had elapsed if the last dose was a taxane.

Table 1.

Patients were randomized into one of three treatment arms: docetaxel 100 mg/m² plus bevacizumab 7.5 mg/kg, both given every three weeks; docetaxel 100 mg/m² plus bevacizumab 15 mg/kg every three weeks (standard breast cancer dose); or docetaxel 100 mg/m² plus placebo every three weeks. Dose reductions of docetaxel to 75 mg/m² and to 60 mg/m² were allowed in the event of chemotherapy toxicity, and treatment was continued until disease progression, at which point all patients were eligible to receive bevacizumab with second-line chemotherapy. The primary end point was PFS, and the study was designed with 80% power to detect a risk reduction of 30% reported as a hazard ratio (HR) of 0.7.

At a median follow-up of 10.2 months, the intent-to-treat unstratified analysis indicated that the HR for PFS with low-dose bevacizumab was 0.79, which corresponds to a median PFS of 8.7 months. This compared to a median PFS of 8.0 months in the control arm (P=0.0318). For the higher-dose (standard breast cancer dose) bevacizumab arm, the HR was 0.72, corresponding to a median PFS of 8.8 months (P=0.0099). In other words, the risk for disease progression was reduced by 21% with low-dose bevacizumab and by 28% with the higher dose, as Prof. Miles noted. As he also pointed out, the HR reflects PFS rates over the entire course of the study, and not just at a single point in time when 50% of patients have reached this particular end point, as PFS rates are usually calculated.

AVADO study investigators also were required by the U.S. Food and Drug Administration (FDA) to stratify results by entry criteria and to censor results for any non-protocol treatment patients might have received prior to disease progression. In this FDA-mandated analysis, the HRs were more favourable than those in the unstratified analysis at 0.69 for the low-dose bevacizumab arm (P=0.0035) and 0.61 for the high-dose arm (P<0.0001) (Table 1).

Response rates (complete and partial) in all three arms were also quite robust—even in the placebo arm, where there was a 44% response rate, a reflection of the known anti-tumour activity of docetaxel. The response rate with low-dose bevacizumab was significantly higher at 55% (P=0.0295), and 63% in the high-dose bevacizumab arm (P=0.0001) (Table 2). Complete responses were seen in 3% of low-dose bevacizumab recipients, 1% of high-dose recipients and in 1% of placebo recipients, while partial responses were seen in 52%
ively.

Table 2.

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Because follow-up is relatively short at just over 10 months, there were only 50 deaths in the overall cohort, giving a one-year survival rate of 78% for the low-dose arm, 83% for the high-dose arm and 73% for the control arm. Final analysis of OS is planned in 2009.

Treatment Safety

According to Prof. Miles, safety was possibly one of the more important messages to emerge from the AVADO trial. There was a slightly higher incidence of grade 3 or higher adverse events (AEs) in the bevacizumab arms but AEs leading to death were equivalent across the three arms, and there was no excess of death in either of the bevacizumab arms. Specifically, rates of grade 3 and higher AEs occurred in approximately 74% of both arms containing bevacizumab and in 67% of patients receiving docetaxel alone.

Neutropenia occurred in <20% of patients in all three arms, while rates of febrile neutropenia were relatively low at 15.2% for low-dose bevacizumab, 16.6% for high-dose bevacizumab and 12% for the placebo arm (Table 3). Importantly, there were no differences in thrombotic events, wound healing complications or gastrointestinal perforation across the three arms of the study, while rates of hypertension were actually quite low.

Prof. Miles concluded that no new safety signals emerged from the AVADO study and physicians could be reassured that bevacizumab adds very little to the toxicities of the taxanes already widely used in MBC today.

Further Considerations

As reported by ECOG investigators, the E2100 trial provided earlier evidence that the combination of a VEGF inhibitor plus a taxane had good activity in MBC (N Engl J Med 2007;357:2666-76). In this study involving 722 patients, researchers used weekly paclitaxel and a single biweekly bevacizumab dose of 10 mg/kg. The E2100 investigators reported that the addition of bevacizumab to paclitaxel doubled PFS to 11.8 months compared with 5.9 months with paclitaxel alone (P<0.001).

There was much discussion regarding the reasons why PFS was appreciably longer in the E2100 study compared with AVADO. As suggested by ASCO discussant Dr. Kathy Albain, Loyola University, Chicago, Illinois, following Prof. Miles’ presentation, weekly paclitaxel in and of itself may have an antiangiogenic effect, essentially giving patients a “double hit” of angiogenic inhibition. Longer PFS rates were also seen in the docetaxel monotherapy arm of AVADO than have been previously reported in other clinical trials (eight months vs. six months). It is not known at this time if AVADO will show an OS advantage, given that all patients who fail on the taxane monotherapy arm will be given the oppo
acizumab, potentially diluting any survival benefit.

Table 3.

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questions and answers

Panel

Karen Gelmon, MD, FRCPC

Clinical Professor of Medicine, University of British Columbia, Vancouver, British Columbia

André Robidoux, MD, FRCPC

Professor, Department of Surgery, Université de Montréal, Scotia Chair in Breast Cancer Diagnosis and Treatment, CHUM-Hôtel-Dieu, Montreal, Quebec

John R. Mackey, MD, FRCPC

Professor of Medicine, University of Alberta, Edmonton, Alberta

Why is it important that oncologists continue to explore more effective combinations in the setting of locally advanced or MBC?

Dr. Mackey: There is still very much an unmet medical need for improved treatments for advanced breast cancer. Current standard therapies are of palliative benefit, and symptom control is often achieved with effective systemic therapy but median survival is generally still reported to be less than three years. Although a small percentage of patients will survive to 10 years, it is not clear to me that we are curing the disease.

Dr. Gelmon: Ultimately some studies have suggested a small survival benefit and improvement in PFS with some drugs but advances have been minimal and modest at best. So we need a treatment that more substantially affects OS for a greater number of women.

Dr. Robidoux: When I started practicing, breast cancer mortality was around 50%; now it’s around 25%, so mortality from breast cancer has really decreased over the past 20 years. But despite the fact that we have made significant improvements in the management of MBC, significant numbers of patients still die from it every year so there is a clear place for definitive improvement in the disease.

Could you comment on the mechanism of action of bevacizumab and how it may have enhanced outcomes in a variety of cancers to date, and now MBC?

Dr. Mackey: Bevacizumab binds VEGF and prevents the interaction of VEGF to its receptors (Flt-1 and KDR) on the surface of endothelial cells. The interaction of VEGF with its receptors leads to endothelial cell proliferation and new blood vessel formation in in vitro models of angiogenesis. Administration of bevacizumab to xenotransplant models of colon cancer in nude (athymic) mice caused reduction of microvascular growth and inhibition of metastatic disease progression. The mechanism of action of anti-VEGF therapy in general and bevacizumab in particular, however, is not fully understood. Predictive markers have not yet been identified. Bevacizumab has well-documented efficacy as part of first-line therapy in various malignancies ranging from colorectal to breast and lung cancer. Although it mainly exerts its efficacy in conjunction with conventional cytotoxic chemotherapy, several apparently VEGF-dependent malignancies such as renal cell cancer, ovarian cancer and glioblastoma have been shown to be susceptible to single-agent bevacizumab.

Dr. Gelmon: I think the answer is fairly straightforward. We think angiogenesis is important for the formation of new blood vessels feeding tumours and is important to tumour growth. Thus, blocking angiogenesis, which we usually do with bevacizumab in combination with chemotherapy, therefore will be effective in a wide variety of cancers. So assuming that is how bevacizumab works, it should fulfill its promise.

Dr. Robidoux: VEGF is a central regulator of angiogenesis so by disrupting the signal of VEGF, bevacizumab alters the survival of cancer cells and the implantation of new metastasis in patients with breast cancer. VEGF expression is demonstrated not only in breast cancer but in other cancers as well and is influenced by different oncogenes, so bevacizumab may also be useful in other cancers where VEGF is expressed.

Could you comment on the rapidity of response to the treatment protocol seen in AVADO and the fact that the response rate was much higher than that seen in E2100 to paclitaxel plus bevacizumab?

Dr. Mackey: Response rates went from 44% (in those with measurable disease) to 55% to 63% [for docetaxel alone, low-dose bevacizumab and high-dose bevacizumab, respectively].

Dr. Gelmon: I actually think the differences between the two studies were modest. And unless you’re comparing end points in the same trial, it’s hard to make cross-trial comparisons with slightly different patient populations and different regimens.

Dr. Robidoux: It is important to achieve a rapid response because if you do have a rapid response, you are likely to have a rapid improvement in symptoms and that could have an important impact on QOL for patients. A rapid response may also translate into an earlier and longer PFS.

Why is a high response rate important to demonstrate in MBC with any new protocol?

Dr. Mackey: In general, although not always, women with advanced breast cancer have symptoms, and these are often related to both the amount of cancer present and where it is located. So if a drug is able to achieve a good response, the tumour burden is reduced and in general, this goes hand-in-hand with improvements in symptoms.

Dr. Gelmon: I think ultimately survival or PFS—especially PFS—is more important than response rate. However, a response rate that goes in the same direction as PFS is encouraging, and certainly patients like to see a tumour shrink, as they are usually less symptomatic once a tumour shrinks, especially if a large tumour is causing problems for them.

Dr. Robidoux: For any protocol, a high response rate is a measure of the activity of the drug, especially for these new biological targeted therapies. But again, a high response rate will usually lead to an improvement in symptoms. It might also be an important primary end point to gain [approval] for a drug because some drugs in the past have received approval based on overall response rate. So for the introduction of new drugs, it’s an important end point as well.

AVADO measured PFS as a HR, which apparently measures the treatment effect over the entire study interval, whereas PFS is usually assessed when half of the patients have progressed. Could you comment on the use of HR in AVADO, and whether the PFS rates seen in this study were more robust because investigators measured HR of disease progression?

Dr. Mackey: My understanding of the statistical design was that it provided 80% power to detect a PFS HR of 0.7, i.e. a relative reduction in the risk of recurrence of 30%. This was achieved in the stratified analysis for both arms. Time of treatment assessment caused a sawtooth appearance of the curves, as seen in many studies where timing of response assessments are conducted as per protocol. Visually, the median time to progression occurs at just such a time.

Dr. Gelmon: When you look at it statistically, a median PFS is the point where 50% of patients have progressed. The HR looks at the entire curve, so it’s not just one point in time. Now both PFS and HR can be affected by other treatments or other variables, so it’s probably important to look at both. But because the HR looks at the entire curve and not just at one point, a lot of people think it’s preferable and HRs are increasingly reported. OS usually goes along with PFS and certainly for most patients, PFS is of importance. But keep in mind that subsequent treatments can affect OS and make it a harder end point to achieve.

All of Europe, Australia and the US have approved bevacizumab in the absence of mature OS data. Does this support the robustness of the PFS results?

Dr. Mackey: The study was designed to demonstrate an improvement in PFS, not to look at OS, except as a secondary end point. But there is a great debate among oncologists as to the value of an end point such as PFS for drug approval and in the Canadian context, there is no unanimity as to whether PFS is meaningful. However, if you talk to patients, what I tend to see is that if you can offer a drug that has a better duration of disease control—which is what PFS means—and hold the cancer at bay for a longer period of time, this is generally accompanied by better symptom control and patients want it. In addition, I think a PFS advantage may well have some effect on OS, although it is a poor surrogate end point for OS. But in general, drugs that have provided an OS advantage often look like they provide PFS advantages as well, but for a trial to prove an OS advantage would require thousands of patients.

Dr. Gelmon: It supports the fact that PFS is probably a clinically relevant end point, not just for the AVADO study, but for all studies.

Dr. Robidoux: PFS as an efficacy end point has been used in the past. Of course, OS is the gold standard, but coupled with a good overall response rate [and] with an improvement in QOL, PFS is reason enough why some drugs have been approved on PFS rates alone. There is also a strong economic rationale for approval of a drug in terms of the recurrences it may prevent. Patients can also remain active longer, and these are also important end points to consider as well. In AVADO, the OS data are not yet mature, but there was a trend in terms of improvement in survival in patients on the higher dose of bevacizumab, though we need further follow-up as there are no differences in survival as yet.

How do you interpret the safety findings of bevacizumab in MBC as seen in the AVADO study?

Dr. Mackey: Fortunately, one of the particularly important outcomes of the AVADO study was that there was very little incremental toxicity. To my surprise, the only significant increase in toxicity was in febrile neutropenia from 12% to 16%, unlike the E2100 approach, where arterial thrombotic events, hypertension, bleeding, fatigue and neuropathy were all substantially increased (albeit in an open-label study) [with bevacizumab].

Dr. Gelmon: I think the safety looked good; there was some hypertension and proteinuria, but overall, the protocol looked pretty good. Having said that, the safety of the regimen might be different in earlier disease because we would not have that many long-term safety issues in the metastatic setting as we might have in earlier disease. So we still need to confirm its safety in the adjuvant setting.

Dr. Robidoux: There was no real increase in toxicity in the bevacizumab-containing arms, so I think that the safety data are reassuring, at least with this combination with a taxane. I think the neutropenia and infections that were seen reflects more the side-effect profile of the taxanes, and overall, in terms of the other side effects, they seemed to be more related to the taxanes rather than bevacizumab so the study confirms the general safety of the VEGF inhibitors.

Are the taxanes and the regimens used in both AVADO and E2100 comparable, or do they differ in terms of their effectiveness or even toxicity profiles? How might these differences have affected outcomes in AVADO compared with those from E2100?

Dr. Mackey: In general, I think that every-three-weekly docetaxel and weekly paclitaxel are similarly effective backbone regimens, although they differ in toxicities (more neutropenia with docetaxel, more neuropathy with paclitaxel), and in chemotherapy chair time and outpatient department resource requirements. The more interesting question is whether the higher incremental toxicities seen in the E2100 study with the addition of bevacizumab to paclitaxel might reflect not only the increased duration of therapy, but whether the weekly paclitaxel is itself somewhat anti-angiogenic, and you are observing an interaction of two anti-angiogenic strategies to account for the substantially improved efficacy, as well as substantially increased toxicities.

Dr. Gelmon: We used to think the two taxanes were different in terms of efficacy but weekly paclitaxel and every-three-week docetaxel are pretty equivalent. There are differences in toxicity between the two taxanes and these differences might affect our ability to give long-term treatment. For example, paclitaxel causes more peripheral neuropathy, docetaxel more neutropenia and nail changes. But we might also be able to give fewer cycles of docetaxel than paclitaxel, which makes them different as well. It may be, however, that some toxicity, and in particular hypertension, is a surrogate marker of drug effect. Hypertension may help identify responders.

Dr. Robidoux: I do not think you can compare the two trials. They were quite different in design. AVADO was a double-blind, placebo-controlled trial, E2100 was not; the taxanes are somewhat different and the regimens were clearly different in the two trials; and even the patient population studied may have been somewhat different. What is important is that both trials are going in the same direction, and now we have a second trial that confirms the activity of bevacizumab when added to the taxane, so that is the important message.

If using bevacizumab in combination with a taxane, how would you select which taxane regimen to use?

Dr. Mackey: Unfortunately, the major differences in study design of E2100 (open-label and co-operative group level data with long-term follow-up but significant loss to follow-up) and AVADO (placebo-controlled registration trial, short follow-up of only 10 months) do not allow direct comparisons to say which is the better taxane/bevacizumab combination. In general, I think that every-three-weekly docetaxel and weekly paclitaxel are similarly effective backbone regimens, although they differ in toxicities (more neutropenia with docetaxel, more neuropathy with paclitaxel) and in chemotherapy chair time and outpatient department resource requirements. So ultimately, I think that the practical realities of the patient accessing the clinic and the availability of chair time are probably the key decision points.

Dr. Gelmon: We make a selection partially based on data and partially based on patient characteristics: how their bone marrow is; what they have tolerated in the past or can tolerate now; whether they can come in weekly or not. So those kinds of issues affect treatment selection.

Dr. Robidoux: I think I would prefer weekly paclitaxel but we are not sure which is the best taxane to give with bevacizumab. On the other hand, weekly visits may be more of a problem for some patients, so you have to consider patient needs as well. But in terms of efficacy, I think weekly paclitaxel is slightly more effective, even though it may be more cumbersome in terms of patient visits.

Now that two trials have shown encouraging findings in MBC with the combination of bevacizumab plus a taxane, how do you see the findings from these two studies changing the management of MBC?

Dr. Mackey: There are different hats that one can wear when interpreting a clinical trial. From the perspective of a clinical researcher, AVADO confirms the E2100 results, and provides level I evidence that angiogenesis is important in MBC and can improve clinical outcomes. The implications are that antiogenesis therapy should also improve outcomes in the neoadjuvant setting, and augurs well for improvements in the adjuvant setting in the three global bevacizumab trials BETH, BEATRICE and ECOG 5103. From the perspective of a practicing clinician, it depends on how the medical oncologist and the patient evaluate the merit of PFS advantages in the absence of proven OS benefits. And from the perspective of a health economist or a funding agency, it is unclear to me whether bevacizumab would achieve standard-defined thresholds for cost-effectiveness.

Dr. Gelmon: Both trials were positive so I think results support going forward with these regimens and exploring their use further in MBC. At the same time, it is a bit disappointing that there was not more of an effect, because the effect [of additional bevacizumab] was modest, but all in all, results are encouraging and I think there is a role for bevacizumab in this setting. The efficacy of bevacizumab in MBC may be improved in the future if we can determine which patients in terms of their pharmacogenomics and which tumours in terms of their genetic characteristics will respond to the treatment and therefore, treat the persons most likely to respond.

Dr. Robidoux: I think if bevacizumab was approved in Canada, it might change the way we approach patients with MBC; we might also introduce it a bit earlier as well, rather than wait for patients to fail on standard chemotherapy before we introduce something new. So it would give us the opportunity to test new drug protocols at a stage when they might be more effective rather than wait for patients to fail before we introduce a new regimen.

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