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Tracks 1-3, 6

DR LOVE: Mark, can you comment on the use of bevacizumab for patients with HER2-negative metastatic disease?

DR PEGRAM: I was impressed by the ECOG-E2100 data (Miller 2005a). The hazard ratio is reminiscent of our experience in the pivotal trial of trastuzumab as first-line therapy for HER2-positive metastatic disease (Slamon 2001). Moreover, if you look at the one-year survival outcome differences, you see that they also fall right on top of the one-year survival differences that were recorded early on in the trastuzumab pivotal trial.

Clearly we have demonstration of efficacy in terms of improved time to tumor progression. The overall survival data are not yet mature for that data set, but I would expect they should be this year. The last time Kathy Miller updated that data set, I believe only about 30 percent of the final number of survival events had occurred (Miller 2005a). So we’ll have to wait for the final analysis.

DR LOVE: What about the use of bevacizumab as second-line therapy?

DR PEGRAM: That question is being addressed in the ongoing RIBBON 2 study. Patients on that study are able to select from a menu of different chemotherapy options at the investigator’s discretion, and then they are randomly assigned to bevacizumab or placebo in the second-line setting. Short of any data from such a trial, I probably would not routinely recommend bevacizumab in a second-line setting because we have literally no data to support it at this time.

DR LEYLAND-JONES: In terms of activity in the second-line setting, Mark is absolutely right. We have no data, but I have the feeling we will be seeing significant activity with bevacizumab in the second- and third-line settings for metastatic disease.

DR WINER: I don’t believe you can think of this as another combination therapy like a taxane with capecitabine or gemcitabine. It’s important to recognize that a previous randomized trial of bevacizumab with capecitabine in the second-line setting was largely negative, although a hint of activity was evident (Miller 2005b).

I don’t believe we should be too rigid about defining first- and second-line therapy because so much of this depends on what someone has received in the adjuvant setting. A woman who received adjuvant TAC or ACpaclitaxel nine months ago and now has a relapse is technically in the first-line setting and far more refractory than many who are in the second-line setting who might not have received adjuvant chemotherapy.

So for the woman who received adjuvant AC a few years ago and capecitabine as her first-line regimen, I’m willing to try paclitaxel and bevacizumab, recognizing that ECOG-E2100 limited eligibility to patients who had not received chemotherapy in the metastatic setting.

DR LOVE: Aman, what are your thoughts on this controversy?

DR BUZDAR: I don’t believe there is much controversy. The data clearly demonstrated that inclusion of a biologic with paclitaxel substantially improved the response rate and time to progression (Miller 2005a). This is a viable positive lead, and we need to discuss it with every patient who meets those eligibility criteria.

The next generation of trials will answer more clearly whether in the second-and third-line settings the inclusion of bevacizumab will enhance the response rate.

DR LOVE: Would you consider combination chemotherapy (a taxane and capecitabine) and bevacizumab for a patient with rapidly progressive visceral disease?

DR BUZDAR: I would not because the safety data are not available. We don’t know which dose of each drug we should use for that combination. That is not an appropriate recommendation outside of the context of a clinical trial.

DR LOVE: Matt, what are your thoughts?

DR ELLIS: If ECOG-E2100 does not show an overall survival advantage, then bevacizumab is another palliative drug for the treatment of metastatic breast cancer with the potential to relieve symptoms. If that were the case, I would not use bevacizumab for asymptomatic patients because they have no symptoms to palliate. I would probably reserve it for patients who are heavily symptomatic with visceral crisis, for whom response is critical. If bevacizumab improves survival, my view will change.

DR BUZDAR: Let’s say that no survival advantage is demonstrated. Still, in metastatic disease, the idea is to control the disease for as long as possible. If you start with a combination therapy of biologics and chemotherapy and you control the disease in a much higher number of patients for a much longer period, that is a major achievement from the patient perspective, even though long-term survival may not be affected.

DR DICKLER: We have a lot to learn about bevacizumab. As we learn more about how it works and how to appropriately select patients, then we’ll better know with whom we should use it.

Right now, however, I believe stringent rules about which line of therapy to use it in don’t make a lot of sense, and toxicity is an issue that must be considered with this drug. Side effects include hypertension, which can be significant. Some patients require two drugs to control their blood pressure, but it is controllable. I’ve also had patients develop nephrotic-range proteinuria, and I monitor the urine protein-to-creatinine ratio every few months.

DR LOVE: Joe, if a patient who received adjuvant AC develops asymptomatic metastatic disease that is treated with capecitabine and then develops symptoms from her metastatic disease, what would you recommend?

DR SPARANO: I would absolutely offer that patient paclitaxel and bevacizumab.

DR ELLIS: So would I, probably.

DR WINER: As would I.

Tracks 7-8

DR LOVE: MJ, let’s talk about the most recently available taxane, nab paclitaxel. Can you comment on the shorter infusion time for nab?

DR JAHANZEB: From the practice standpoint, chair time is an issue, so this is an advantage. Patients don’t want to sit for an infusion any longer than necessary. Not having to administer premedications is another advantage with nab paclitaxel.

Also, the lack of allergic reactions and the shorter duration of neuropathy are desirable (Gradishar 2005).

Cost is the only remaining issue with nab paclitaxel from a practitioner’s standpoint. That has been the reason, I believe, for slower uptake. Otherwise, it’s a good advance in terms of making a widely used drug better with respect to its efficacy and toxicity.

DR LOVE: Let me quickly poll the group. If the cost of nab paclitaxel were exactly the same as paclitaxel, would you use paclitaxel? Show of hands is unanimous with one exception. Eric, you are the only one not raising a hand.

DR WINER: Show me the Phase III trial that has compared nab paclitaxel to weekly paclitaxel. I believe the claim that the neuropathy is of shorter duration is based on a very small number of patients. I’m not aware of any symptom complex that is typically more severe but goes away more quickly with one drug versus another.

DR LOVE: From a quality-of-life point of view, Eric, how much of an advantage are the shorter infusion time and lack of premedications?

DR WINER: If you’re talking about weekly versus weekly, weekly paclitaxel is administered over an hour, which is not a tremendously long time. The need for ongoing steroid premedication when you’re using weekly paclitaxel is something that one can question. Maybe nab paclitaxel will be a better drug, but it’s important to investigate further.

DR LOVE: Rowan?

DR CHLEBOWSKI: Up to now, docetaxel at 100 mg/m² every three weeks hasn’t been beaten by anything in the metastatic disease setting, but it has been tied by weekly paclitaxel.

The presentation by Gradishar at the 2006 San Antonio Breast Cancer Symposium was a Phase II trial, but an apparently substantial improvement occurred in the primary study endpoint, which was objective response, with weekly nab paclitaxel compared to every three-week docetaxel (Gradishar 2006). This is impressive.

DR LOVE: Maura, can you discuss your research experience with dose-dense ACnab paclitaxel?

DR DICKLER: We have a feasibility study (MSKCC-06019) evaluating bevacizumab in the adjuvant setting, which is using dose-dense ACdose-dense nab paclitaxel. The trial is currently accruing. Approximately 45 people have enrolled, and many haven’t finished receiving the nab paclitaxel. I hope we’ll have more information by ASCO.

DR LOVE: The US Oncology trial indicated that you need growth factors in that situation.

DR DICKLER: Correct. When they conducted their small pilot trial, they didn’t use pegfilgrastim with nab paclitaxel at 260 mg/m² every two weeks. I believe a third of the patients couldn’t receive nab paclitaxel on time (Robert 2005). We’ve also conducted a study at Memorial Sloan-Kettering in which we tried to avoid pegfilgrastim with dose-dense treatment, and we could not administer the treatment on time. It required delays.

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