Select Excerpts from the Interview*

 Track 2

DR LOVE: What are the implications of the ECOG-E2100 trial comparing paclitaxel to paclitaxel plus bevacizumab?

DR SEIDMAN: ECOG-E2100 was a pivotal study. This is the kind of information you take home and interject into your practice the very next week. Here, we’re looking at targeted therapy, where one doesn’t necessarily need to test for the target. Docs who have been treating patients with metastatic breast cancer already are well aware of using targeted therapy in the form of trastuzumab.

In a sense, we now have a new targeted, better-tolerated, rationally designed biologic therapy that doesn’t require testing of the tumor. I believe the design of E2100 (3.1) was an appropriate one, using weekly paclitaxel as the control arm — a regimen very close to my heart on the heels of CALGB-9840 — in which we showed the superiority of weekly paclitaxel in terms of causing a higher response rate and a longer time to progression than conventional paclitaxel (Seidman 2004;[3.2]).

ECOG-E2100 showed us that the addition of bevacizumab to weekly paclitaxel not only improved the response rate (Miller 2005a), as was observed in the prior study with capecitabine (Miller 2005b), but unlike the study with capecitabine, now we had an increase in time to progression of about five months (3.2). The additional costs in terms of toxicity were fairly modest, with some increase in hypertension and proteinuria (Miller 2005a; [3.3]). Also, a slight increase in the risk of Grade III neuropathy was seen with bevacizumab (Miller 2005a; [3.3]).

 Track 3

DR LOVE: What’s your take on the clinical implications of ECOG-E2100 in terms of daily practice?

DR SEIDMAN: It has already made an impact on our daily practice at Memorial Sloan-Kettering. I believe the data speak very loudly for themselves. This is the kind of data where one doesn’t go back and say, “Well, I’m looking forward to six months from now when the FDA approves this.”

This is the kind of information where we feel almost an ethical imperative to come back and integrate it into practice, the benefit being so substantial.

For me, it’s a no-brainer for a patient who would appropriately receive a taxane as monotherapy as first-line treatment of metastatic disease. That woman should also receive bevacizumab, provided she has no serious contraindications — brain metastases, uncontrolled hypertension or significant proteinuria.

DR LOVE: You mentioned using bevacizumab with taxane monotherapy. Does that include docetaxel and nanoparticle albumin-bound (nab) paclitaxel?

DR SEIDMAN: The data that exist to date are with paclitaxel. We have a history, though, that tells us, for example, with the integration of trastuzumab, that with few exceptions, what worked with trastuzumab and paclitaxel also worked with trastuzumab and docetaxel.

So do we really need to repeat every single experiment — for example, the use of bevacizumab with weekly docetaxel, since it worked with paclitaxel I think probably not. I would rather not see the reproduction of all of these same Phase III studies over again with docetaxel that were done with paclitaxel. I would ditto the same sentiment for nab paclitaxel with bevacizumab.

DR LOVE: Would you want to see some Phase II or safety data with docetaxel or nab paclitaxel combined with bevacizumab?

DR SEIDMAN: Yes, I clearly want to see some safety data first. We’ve learned to expect the unexpected. There certainly could be differences in patterns of toxicity, based simply on the vehicles of those agents and how they might interact with bevacizumab.

At Memorial, we’re about to embark on a trial in which we will be comparing every three-week, every two-week and weekly dosing of nab paclitaxel with bevacizumab as first-line therapy and also trastuzumab for patients with HER2-positive disease. We’re looking at a nab paclitaxel schedule question and also the safety of the co-administration of bevacizumab.

 Track 5

DR LOVE: Would you continue bevacizumab upon disease progression?

DR SEIDMAN: I hope we don’t repeat the same mistake I believe we made in the development of trastuzumab — to not definitively ask the research question: “Is this an agent I should continue beyond the point of disease progression?”

Although it was talked about for many years and it was attempted to determine whether trastuzumab might be valuable to use beyond progression, we simply don’t know the answer to that question on a clinical basis. Most of us have developed a bias to continue trastuzumab for all practical purposes.

I believe that with bevacizumab, we have an opportunity to learn from the lessons of the past and to design trials early on that look at the duration of therapy question. If your patient progresses after her first-line taxane/bevacizumab regimen, should you continue bevacizumab for the next course or the course after and combine it with agents such as vinorelbine, gemcitabine and capecitabine? I honestly don’t know the answer to that question.

DR LOVE: Are there active discussions right now in the cooperative groups about a trial like that, looking at bevacizumab or not on progression?

DR SEIDMAN: There are discussions, and in thinking about this question, one of the reasons such trials have been thought, perhaps, not to be feasible relates to the half-life of the antibody and the need for a wash-out period. The argument with trastuzumab is that if you randomly assign patients to a do-notcontinue- trastuzumab arm, pharmacologically, they’re still getting trastuzumab many weeks after the last dose.

There is no really good way around that issue, but I still believe it’s a clinically relevant question to ask: Does stopping the antibody, as opposed to continuing it with the next regimen, make a difference? If there is a pharmacologic effect, it may translate early on into no difference at the first follow-up or the first set of scans. But presumably, if continuing the antibody — in this case bevacizumab — makes a difference and it’s a big enough difference, you may see that even regardless of the fact that the antibody will hang around for many weeks after you discontinue it.

 Track 6 - 7

DR LOVE: Can you discuss what we know about nab paclitaxel?

DR SEIDMAN: Nab paclitaxel basically is paclitaxel formulated without Cremophor. It was tested in the clinic in a large randomized trial involving about 450 women (Gradishar 2005), and there does seem to be a differential effect apart from the obvious advantage of not having to use premedications to avoid the hypersensitivity reactions — no need for corticosteroids or antihistamines (3.4).

The administration of 260 mg/m² nab paclitaxel caused a higher response rate and a longer time to progression than the conventional 175 mg/m² three-hour infusion, every three-week regimen of Cremophor-based paclitaxel (Gradishar 2005; [3.4]). In my mind, this represents a real step forward.

There was less Grade III and IV neutropenia with 260 mg/m² of nab paclitaxel compared to 175 mg/m² of paclitaxel (3.4), although this really didn’t translate into a difference in febrile neutropenia, which was low in both arms. There was a 10 percent incidence of Grade III neuropathy with nab paclitaxel, versus a two percent incidence with Cremophor-based paclitaxel (Gradishar 2005; [3.4]). This may not be all that surprising, given the differences in the doses that were used.

There was an apparent, fairly rapid reversibility of the Grade III neuropathy. The 10 percent of the population who experienced that degree of neuropathy seemed to have a median time to resolution back to baseline of about three weeks (Gradishar 2005), perhaps almost by the next cycle. Reversibility seemed to take longer in the patients randomly assigned to Cremophor-based paclitaxel.

I’m very intrigued by the data from the US Oncology Group Joanne Blum has reported. A weekly regimen of nab paclitaxel — administered in a population of patients who are already taxane-exposed to either paclitaxel or docetaxel and many, but not all, of whom have some pre-existing neuropathy — seemed not to cause a lot of severe neuropathy, particularly the 100 mg/m² three weeks- on and one-week-off regimen (Blum 2004).

 Track 8

DR LOVE: How would you compare the efficacy of weekly nab paclitaxel compared to weekly paclitaxel?

DR SEIDMAN: That’s a good question. Right now, it’s really hard to do. The US Oncology Group treated nice-sized populations with their weekly regimen. There were about 70 patients at the 100 mg/m² dose (Blum 2004), and at the other dose — the 125 mg/m² dose — in the range of about 100 patients (O’Shaughnessy 2004). Since that’s a nice sample size in terms of Phase II data, what we can say is that weekly nab paclitaxel has activity in patients with prior taxane exposure and even with prior recent taxane exposure.

Most of the data supporting the use of weekly Cremophor-based paclitaxel are not in the same population but are in women who haven’t had prior taxanes with a well-described activity with that approach from Phase II and the Phase III randomized trial (Seidman 2004).

The randomized Phase II trial with docetaxel, published in the Annals of Oncology by Tabernero (Tabernero 2004), is too difficult to compare with these data. My sense, and this is a real “guesstimation,” is that I wouldn’t expect weekly nab paclitaxel to be inferior to docetaxel.

There clearly are no direct comparisons, and I’m not sure I think that the appetite is very strong in the cooperative groups to do these kinds of trials. I believe there are too many other interesting targeted agents that beg asking questions rather than how nab paclitaxel weekly stacks up to weekly docetaxel.

 Track 10

DR LOVE: Based on the current research data, where do you see the role of nab paclitaxel in a clinical setting?

DR SEIDMAN: The ability to deliver drugs more safely offers a real potential benefit. Even if the randomized trial, perhaps, didn’t show a higher response rate or a modestly longer time to progression compared to paclitaxel (O’Shaughnessy 2003), simply not having to premedicate and not having to worry about serious allergic reactions, in my mind, would make nab paclitaxel the obvious choice.

The issue that comes around with the emergence of any new drug is always cost. There is a cost differential right now, since Cremophor-based paclitaxel is generically available. It’s not a trivial differential. Even at Memorial Sloan- Kettering, this is a consideration for the pharmacy budget.

We have guidelines for the use of nab paclitaxel, and the guidelines tend to reflect the data. In scenarios that are parallel to those where nab paclitaxel’s efficacy was shown — in the first-line and second-line setting — when one would use paclitaxel, then I’m very motivated to substitute nab paclitaxel.

DR LOVE: Have you utilized nab paclitaxel in the adjuvant setting, particularly in patients who may be having problems with Cremophor-based paclitaxel or docetaxel?

DR SEIDMAN: I have used nab paclitaxel a handful of times so far in the adjuvant setting. The scenarios are all memorable — patients who have had strong allergic histories to other agents. One scenario involved a woman with bipolar disease who becomes manic with steroid exposure, to the point where I spoke with her psychiatrist about the need to avoid corticosteroids.

With appropriate permission from our Pharmacy and Therapeutics committee, I was granted the approval to use nab paclitaxel in the adjuvant setting. This was a nice thing that allowed us to administer appropriate anthracycline and taxane-based adjuvant therapy without having to use corticosteroids.

Select publications