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Select Excerpts from the Interview
Track 2
DR LOVE: Can you describe Memorial’s Phase II trial of nab paclitaxel
combined with bevacizumab and the rationale behind its design?
DR SEIDMAN: It’s a randomized trial of weekly versus every two-week versus
every three-week nab paclitaxel with concurrent bevacizumab as first-line
therapy for metastatic breast cancer.
Following ECOG-E2100, and given the benefits of nab paclitaxel compared to paclitaxel (Miller 2005a; Gradishar 2005), we decided to evaluate in a randomized Phase II fashion the package insert dose of 260 mg/m2 of nab paclitaxel on a schedule of every three weeks versus the same dose on a dose-dense schedule of every two weeks with G-CSF versus a dose of 130 mg/m2 administered weekly, without interruption, in the CALGB-9840 manner (Seidman 2004). All the patients in this trial receive bevacizumab, and the target accrual is 225 patients, or 75 patients per arm.
We’ve completed our first interim safety analysis and, with approximately 20 patients per arm, so far no signal in any arm has indicated that we should stop accrual because of excessive toxicity.
Track 4
DR LOVE: What’s your take on the use of nab paclitaxel in clinical
practice?
DR SEIDMAN: The trial that led to the FDA approval of nab paclitaxel
convinced me that this agent, at 260 mg/m2, certainly is not less effective than
Cremophor-based paclitaxel at 175 mg/m2 (Gradishar 2005).
I find not having to administer premedications or corticosteroids, being able to infuse the drug over half an hour instead of three hours and not worrying about potential allergic reactions, which are occasionally life threatening, makes it a “no-brainer” in terms of which taxane I use.
Steroids are a double-edged sword in the sense that often, along with the prescription for steroids, I have to write a prescription for zolpidem because the patient can’t sleep well at night. Also, with weekly taxanes and weekly steroids, I do see steroid myopathy and occasionally diabetics who have trouble controlling their blood sugars. What I hear most that limits the use of nab paclitaxel is the pharmacoeconomics of the drug, and I don’t have a great response to that.
Track 6
DR LOVE: How do you incorporate bevacizumab into the management of
breast cancer outside of a clinical trial?
DR SEIDMAN: Currently, I generally follow the ECOG-E2100 paradigm
(Miller 2005a). For patients who are not participating in our AC/nab paclitaxel/bevacizumab pilot trial but for whom taxanes are appropriate, I use
paclitaxel and bevacizumab. Occasionally, I will have patients who have
received an adjuvant taxane within the past year and have relapsed, and my
inclination at that point is to use capecitabine and bevacizumab, based on
Kathy Miller’s reported Phase III trial (Miller 2005b). Those are probably the
two most common scenarios.
DR LOVE: Many people don’t use the combination of capecitabine and bevacizumab
because they consider the ECOG trial negative (Miller 2005b). How
do you respond to that?
DR SEIDMAN: Despite the doubling of the response rate, it does concern
me that the trial did not show a significant increase in the time to progression.
Certainly a difference is evident between that population and that of the
E2100 trial with regard to the extent of prior therapy.
I don’t see any reason to suspect that the addition of bevacizumab to one particular cytotoxic agent in breast cancer versus another will make a big difference in terms of efficacy. The RIBBON 1 trial, which allows a repertoire of commonly used chemotherapy regimens in the first-line setting, should inform us whether we need to worry about which agent we combine with bevacizumab (3.1).
DR LOVE: What do you think of George Sledge’s XCaliBr study, which
evaluated capecitabine/bevacizumab in the first-line setting?
DR SEIDMAN: That was a Phase II trial, and it’s hard to know what to make
of the data because it had no control arm. The nice thing about this trial is
that the efficacy at a lower dose of capecitabine was similar to what Miller
previously reported. In the XCaliBr trial (3.2) they used 1,000 mg/m2 twice
daily, whereas in the Phase III trial they used 1,250 mg/m2 twice daily.
Track 7
DR LOVE: Bevacizumab is now being studied in the adjuvant setting.
What are your thoughts on those trials?
DR SEIDMAN: First, the theoretical consideration is that with a smaller
volume of cancer, angiogenesis seems to be driven more by VEGF than other
growth factors, whereas with a larger tumor volume, a greater list of growth
factors seems to come into play. Thus we have every reason to hope and
believe that perturbing VEGF receptor activation will have a big impact in the
adjuvant setting.
DR LOVE: Your colleague Maura Dickler has reported data from a pilot trial combining bevacizumab with hormonal therapy. Where do you think that
is headed?
DR SEIDMAN: In the pilot trial, letrozole was administered with bevacizumab,
and the data certainly showed the feasibility of combining an aromatase inhibitor
with bevacizumab (Traina 2006). Given that cross talk occurs between
estrogen signaling and VEGF signaling, there’s certainly hope that intervening
earlier with anti-angiogenic therapy, before the patient gets to the point of
needing chemotherapy, might be beneficial.
Track 8
DR LOVE: What do you think about the data from the TAnDEM trial,
evaluating anastrozole with trastuzumab in the metastatic setting?
DR SEIDMAN: I first glimpsed those data after they were initially presented in
Istanbul at ESMO in September (Kaufman 2006). I was struck that the median
time to progression in the anastrozole-alone arm was 2.4 months, whereas
when combined with trastuzumab, the time to progression doubled to 4.8
months (Mackey 2006; [3.3]). Granted, this was ER-positive, HER2-positive
disease, but that duration of response to anastrozole alone doesn’t fit with
what I see clinically. I have many patients in my own practice who have ER-positive,
HER2-positive disease who do fine in the absence of trastuzumab.
The more important question is, if you use the combination of an aromatase inhibitor and trastuzumab early on for a patient with hormone-sensitive, metastatic breast cancer, what will be the implication of having already played your trastuzumab card when that patient ultimately develops hormone-refractory disease? We know that adding trastuzumab to chemotherapy, either paclitaxel or docetaxel, provides a survival advantage, so I’m not ready to change my practice based on the TAnDEM data.
Having said that, there are patients who come to me who are on antiestrogen therapy and trastuzumab, but usually their clinical story has some strange, unique aspect that makes me feel it’s an appropriate thing to do.
One example in which applying the TAnDEM data would make sense would be for the occasional patient who’s received adjuvant tamoxifen but not an aromatase inhibitor and then develops metastatic disease and is treated with chemotherapy and trastuzumab. Most of us are in the habit of stopping the chemotherapy at a certain point and just continuing trastuzumab, but in this case the patient has not received an aromatase inhibitor.
For me it would be a no-brainer at that point to use the chemotherapy and trastuzumab to maximum response, or to the point at which toxicity begins to accumulate, and then discontinue the chemotherapy and add the aromatase inhibitor.
Also, there are those patients who present with metastatic disease who have never received adjuvant therapy, yet you feel you should first treat them with chemotherapy and trastuzumab, even if they have ER-positive disease. This would be another example in which, perhaps, after administering the chemotherapy and trastuzumab, you should put the chemotherapy aside and use the aromatase inhibitor out back instead of up front.
Track 14
DR LOVE: Would you discuss Bill Gradishar’s presentation of the EFECT
trial and your thoughts on those data?
DR SEIDMAN: The EFECT trial randomly assigned patients with metastatic
breast cancer whose disease had progressed despite treatment with a nonsteroidal
aromatase inhibitor to the steroidal aromatase inhibitor exemestane or
to fulvestrant. Many of us have been using both of these approaches somewhat
indiscriminately, perhaps influenced more by patient preference, such as for a
monthly injection over taking a pill.
The EFECT findings afford us flexibility in our treatment options. I believe most clinicians will be influenced by patient preferences when choosing between an oral medication or a monthly injection. For many patients who are coming in monthly for a bisphosphonate, for example, an injection doesn’t demand much more of them in terms of the frequency of office visits.
This trial also employed a loading schedule for fulvestrant, which is what I tend to use in my own practice. When using fulvestrant, one should probably follow the design of this trial, starting with the 500-mg loading dose followed by a subsequent dose of 250 milligrams two weeks later and then 250 milligrams monthly.
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