INTERVIEW WITH DR. MARK PEGRAM

DR. LOVE: What about the schedule of Herceptin?

DR. PEGRAM: We have, like many others, been compelled to switch to triple-dose Herceptin every three weeks, especially in Los Angeles where patients often come from great distances into town, and the traffic is very bad. And when we discuss Brian Leyland-Jones' results from the pharmacokinetic studies of the triple dose, every-three-week schedule with the patients, many of them have wanted to opt for that treatment, and it's been successful in our hands so far. We haven't had any problem with that schedule.
Many of the cooperative groups now, looking at Herceptin treatments, are also adopting the every-three-week triple dose schedule. For example, the BCIRG, in their large adjuvant Herceptin trial, will be giving Herceptin following the chemotherapy treatment on an every-three-week schedule. I think some of the North American cooperative group Herceptin adjuvant studies are doing the same thing.

DR. LOVE: But yet at this point, we really don't have comparative data, clinically, do we?

DR. PEGRAM: No, we don't. We just have this pilot study from Canada, where they had approximately, I think, 30 patients that were treated with Taxol-Herceptin. And their response rates were on the order of what we saw with the Herceptin pivotal trial with Taxol-Herceptin. But you're right. There aren't large randomized trials. The largest experience in terms of safety will actually come from these Herceptin adjuvant trials. There are going to be hundreds of patients treated on the every-three-week schedule over the next couple of years, just on those studies alone, and probably thousands in the community that have already been treated on an every-three-week schedule. I know that safety data is being collected on all of those patients to assure that this is going to be a good schedule.

DR. LOVE: And efficacy, at least in the adjuvant setting?

DR. PEGRAM: I'm not too concerned about efficacy from a theoretical point of view. The peak Herceptin blood levels are actually higher on the every-three-week schedule. The area under the curve of Herceptin concentration over time is actually higher on the every-three-week schedule. And the trough levels, that is, the level of Herceptin in the blood stream right before the next scheduled dose, is the same as on the weekly schedule. So, in terms of efficacy, since there's actually more Herceptin on board, if anything, you know, there could be greater efficacy. I don't think that's necessarily going to be the case, but certainly there's no theoretical reason to expect that the efficacy would be any less.

DR. LOVE: How about duration? How long do you continue Herceptin, whether it's alone or with chemotherapy?

DR. PEGRAM: Well, at UCLA, we have a number of patients who are on Herceptin and, sadly, progress. It's been our practice to try to get more information about synergy between other therapies and Herceptin. So, with that goal in mind, we've been keeping patients on Herceptin treatment, and then switching the underlying chemotherapy or hormonal therapy or whatever else we can come up with. As I mentioned before, we're also very interested in looking at other Herceptin combinations like with Tarceva. We also have a Herceptin-Avastin study that we have just put forward to our IRB Committee for consideration. This will be a study targeting HER2 and angiogenesis - it's a simultaneously in breast cancer. I think there's a lot of potential for novel combinations with Herceptin, so in general, it's been our practice to keep patients on Herceptin and then add in new agents.

DR. LOVE: Is this indefinitely?

DR. PEGRAM: Well, there's no clinical information to guide that decision. Clearly, in metastatic breast cancer patients, there comes a point where it's clear to the patients and the doctors that medical therapy is just no longer working. In those patients, we encourage them to consider hospice treatment and that sort of thing. So, if the disease is really at its end stage, we certainly do stop treatments at our institute. But while patients enjoy a good performance status, if they're not having any side effects from the Herceptin, if they're enjoying the every-three-week schedule, and it's not a big burden for them to come to the clinic, then we've just been keeping it on board. In the absence of data, we've kind of been a little bit shy to take it away, because although it may not be preventing progression, it may be slowing it. We just don't know the clinical answers yet.

DR. LOVE: Now, I just want to try to define within what you've just said, what you would consider pretty widely accepted and what is something that maybe your group in particular is doing. Because my take in having talked to different people, both who have specifically been involved with Herceptin and not, is that pretty much what everyone agrees upon is that the patient should be continued at least up until progression?

DR. PEGRAM: Sure.

DR. LOVE: That's where the debate comes in about whether you continue beyond progression.

DR. PEGRAM: Right.

DR. LOVE: But I've seen some patterns-of-care data that suggest that in the community sometimes physicians just stop Herceptin before progression.

DR. PEGRAM: I think that if one does that, they are really off the map. There's no data to support that. I want to emphasize that all of the Herceptin clinical trials that led to FDA approval of Herceptin were using Herceptin until progression. So, for example, the survival benefit that was seen with Herceptin in the randomized chemotherapy-Herceptin study, if we would have stopped the Herceptin before progression, maybe we wouldn't have had a survival benefit with those patients. So I'm very worried about stopping it prematurely. I think there's strong logic to continue it at least until progression, and that's the basis for all of the Herceptin clinical trial data to date.
Now, after progression, I absolutely agree. What I was quoting you before is our institutional practice, and I can only speak for UCLA. There's no clinical data and, consequently, a number of experts, whose opinions I respect a great deal, stop it at the time of progression.Thinking along the lines of conventional medical oncology history for the past 25-30 years with chemotherapy drugs and hormonal therapy drugs, when they stop working, they stop working for good, and there's no point in keeping them on board. I think that there's different ways to look at this problem and, in the absence of clinical data, there is going to be clinical judgment and personal preference involved. That's why we're getting these different opinions. There's no data to guide us. In the absence of data, I think our group is maybe a little conservative being afraid to stop it. While other groups don't want to continue it for fear that it's an extra burden for the patient to go through weekly or every-three-week treatments IV, when there's not a clear clinical benefit.

DR. LOVE: What about the strategy of continuing Herceptin but stopping the chemotherapy within that, or giving a chemo-holiday within that?

DR. PEGRAM: We do that all the time. In fact, that's the way the 648 pivotal trial was conducted. Patients received six cycles of chemotherapy and stopped the chemotherapy, but continued single-agent Herceptin until progression. And that's certainly my practice. Off study, I do chemotherapy until maximal response. Then I usually give one or two extra cycles beyond the best response, and then stop the chemotherapy and continue Herceptin alone. Absolutely.

DR. LOVE: So, it's not just six cycles, it's up until you feel that they've plateaued?

DR. PEGRAM: Yes. There are these rare patients, even in 648. We had a small fraction of patients who got treatment beyond six cycles, because you do see the occasional patient with the slow but progressive, ongoing response, even beyond six cycles. Doesn't happen very often. Most patients have their responses within the second or third cycle and by the sixth, they're done. But every once in a while, I do have patients that stay on chemotherapy longer than, let's say, six cycles as long as they're continuing to have a clear shrinkage of their tumor on radiographic studies and as long as they are coping with the side effects of chemotherapy satisfactorily. Then it's reasonable to continue the chemo until you see the maximum response.

DR. LOVE: Now, a common clinical presentation from metastatic disease is a woman who's had prior ACT adjuvant therapy. In a HER2-positive patient like that, what do you generally do?

DR. PEGRAM: I look for a study. But off study, we're very impressed by the small pilot trial done at the Dana-Farber by Bernstein and colleagues, showing a very high response rate to Navelbine-Herceptin. I think that's as reasonable as any combination. Certainly, vinorelbine is clinically well tolerated. It's fairly easy on the patients, as chemotherapy goes. And once you've used up, so to speak, Adriamycin and taxanes, it is attractive to move on to a different class of drugs. In that case, Navelbine, I think, is a logical choice.

DR. LOVE: You mentioned the possibility of using hormone therapy and Herceptin together.

DR. PEGRAM: Sure. Absolutely. There's scientific rationale on the basis of studies done by my colleague, Dr. Rich Pietras at UCLA, who has studied combinations of tamoxifen and Herceptin in animal models. Also, more recently, he's looked at combinations of Faslodex plus Herceptin in animal models with really striking beneficial results. So there may be some basis for a future clinical trial investigating Faslodex plus Herceptin. As you know, there is an Arimidex-Herceptin trial that's ongoing right now. It's accruing as we speak. The difficulty about these types of trials is the fact that most HER2-positive patients are ER-negative. So, it's hard to get enough colleagues to find enough centers who are willing to collaborate on these studies, to get enough patients to get an answer. But the answers will come in time.

DR. LOVE: But have you ever used that strategy outside of a protocol?

DR. PEGRAM: Sure. Absolutely. I have patients, ER-positive, and especially if they don't have bulky visceral disease with organ dysfunction, where I have used either tamoxifen or aromatase inhibitors in combination with Herceptin, and I have seen clinical responses, anecdotally. Now, were they responding to the Herceptin or were they responding to the hormone agent anyway? I don't know in those cases. I certainly have anecdotes before the Herceptin era, where HER2-positive patients anecdotally had responses to hormone therapy. It doesn't happen very often, but it does happen. The association between HER2 and hormone resistance is real. I believe it's very real, but it's not complete resistance. So, in the right clinical scenario, it's reasonable to consider hormone-Herceptin combinations.

DR. LOVE: Any biologic reason to think there might be synergy there?

DR. PEGRAM: Oh, absolutely. In fact, there's a paper presented at the AACR in 1999 from a group at Yale showing just that. In cell line models, they were able to demonstrate synergy between tamoxifen and Herceptin. we've confirmed that with our in vivo animal studies, where we see the same thing.

DR. LOVE: What actually is going on? Is there interaction between the estrogen receptor and the HER2?

DR. PEGRAM: There certainly is. Rich Pietras and I, with Dennis Slamon, published a paper a few years ago in the literature, where we were able to demonstrate that there is cross talk between the HER family signal pathway and the estrogen receptor. In particular, the estrogen receptor is downregulated by HER2 or signaling through HER2 and, by blocking HER2, you may be able to restore hormone sensitivity by relieving this estrogen receptor downregulation phenomenon.

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