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Role of Bevacizumab for Patients with HER2-Negative Metastatic Disease
Track 17
 DR LOVE: Eric, can you comment on how you approach the patient
with triple-negative breast cancer who develops cancer relapse soon after
receiving adjuvant chemotherapy? |
DR WINER: Typically, I would administer bevacizumab and weekly paclitaxel,
with the exception of a patient who had a particularly short disease-free
interval (less than one year) and had received a taxane in the adjuvant setting.
In that situation, we don’t have a clear answer, and I would be inclined to use
another chemotherapeutic agent with bevacizumab. I would pick an agent
for which we have toxicity data because from an efficacy standpoint, I don’t
believe we can answer the question.
DR SWAIN: I would use paclitaxel and bevacizumab. The patients in ECOG-E2100
who had received adjuvant taxanes were required to have had a disease-free
interval of at least 12 months, and they derived a significant benefit from
paclitaxel and bevacizumab (Miller 2007; [2.1]).
DR SLEDGE: Approximately one in five patients entering the trial had received
an adjuvant taxane one year or more in the past. The hazard ratio for those
patients was the best hazard ratio of any subgroup in the forest plot, almost as if
bevacizumab in that setting is at least partially reversing taxane resistance.
DR LOVE: George, what is your algorithm for first-line therapy for the patient
with progressive, hormone-insensitive, indolent disease?
DR SLEDGE: I believe this is a case in which you sit down and discuss the
factors with the patient. Eleven-month progression-free survival is pretty good
in the metastatic setting. I would add that I do not see a whole lot of evidence
that we should be using bevacizumab further along. We have no evidence for
benefit with this agent for anything other than front-line metastatic disease in
breast cancer. If I were going to use bevacizumab for a patient, I would use it
up front.
Track 20
| DR LOVE: Joyce, can you discuss the use of bevacizumab as second- or
third-line therapy for metastatic disease? |
DR O’SHAUGHNESSY: In Kathy Miller’s trial of capecitabine with or
without bevacizumab for patients previously treated for metastatic disease,
the response rate was higher with the combination (Miller 2005), but not
progression-free survival.
The concern I’ve always had about these later-line trials, though, is that when your endpoint is to change the median progression-free survival, you have to positively affect 50 percent or more of your patients because if only one third of your patients are benefiting, you won’t change your median.
The other data that I find especially interesting are Mark Pegram’s with trastuzumab-pretreated patients. I agree we have to wait for the RIBBON 2 trial data to be sure, but I believe that at least some data support the use of later-line bevacizumab.
DR LOVE: Eric, what about the issue of how one defines first and second line?
DR WINER: I believe we are a little rigid about this because, depending on
what someone received in the adjuvant setting, patients in the second-line
metastatic setting may have received far less therapy than patients who are
being treated in the first-line setting.
I agree with George and would be inclined to use bevacizumab earlier rather than later. That said, for the patient who decides to take capecitabine at the first line in the metastatic setting, I am not uncomfortable using paclitaxel/bevacizumab as the second-line regimen, but I stop it there.
I want to make one other point regarding median time to progression. Median time to progression is a surrogate for the whole curve, so when you obtain a p-value for that Kaplan-Meier curve, it’s on the entire curve — it’s not only about the median. It’s convenient to talk about the median, but sometimes you can have a significant p-value and no difference in the median.
Track 21
| DR LOVE: George, where are we heading with bevacizumab dosing? |
DR SLEDGE: The dose of bevacizumab is controversial primarily because
of the issue of cost. We chose the dose of bevacizumab to use in our Phase
III trial based on a Phase II trial in which we evaluated three dose levels
(Cobleigh 2003).
We began with three milligrams per kilogram, followed by 10 milligrams per kilogram and then 20 milligrams per kilogram. We noted a slightly higher response rate at 10 compared to three. The 20-mg/kg dose produced horrendous migraines. That is the dose-limiting toxicity of bevacizumab.
From the Phase I trials, we know that doses as low as one milligram per kilogram are pretty effective at “Hoovering” up all of the circulating VEGF — so who knows?
Maybe there’s a difference intratumorally in the tumor microenvironment. We were able to measure VEGF only at the circulating level — and there you eliminate it all at a fairly low dose.
DR LOVE: What about side effects and toxicity with different doses?
DR SLEDGE: I believe there’s probably a range in which you’re
not going to discern much difference. More toxicity occurs at a certain
level — not only with bevacizumab but also with a fair number of small-molecule
receptor tyrosine kinase inhibitors — at which migraine and
hypertension rates begin to increase.
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TOPICS
Adjuvant Chemotherapy for Patients with HER2-Negative Disease
Adjuvant Systemic Therapy for Patients with HER2-Positive Disease
Adjuvant Therapy for Elderly Patients with HER2-Positive Disease
Adjuvant Trial Evaluating Trastuzumab and/or Lapatinib in HER2-Positive Disease
- Select publications
Role of Bevacizumab for Patients with HER2-Negative Metastatic Disease
Adjuvant Trial Combining Bevacizumab with Trastuzumab
Optimizing First-Line Systemic Therapy for Patients with ER-Positive, HER2-Positive Metastatic Disease
- Select publications
Breast Cancer Update:
A CME Audio Series and Activity
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