Breast Cancer Update 2006 (7)

DR TRIPATHY: The main endpoint of ECOG-E2100, progression-free survival, was significantly prolonged with the combination of bevacizumab and paclitaxel compared to paclitaxel alone. The hazard rates indicate a more robust improvement than we’ve seen with single chemotherapy compared to chemotherapy doublets.

Much attention has been given to the survival difference, which was statistically significant when initially presented at ASCO but was not significant at the next two presentations at ECCO and San Antonio. It’s important to remember that the number of events was nowhere near what was projected for that analysis. So although survival is an important endpoint, I don’t believe the trial had enough power to demonstrate whether a survival advantage exists. In the end, data on overall survival will be important in deciding whether to use bevacizumab. But right now, you have to go with the data on progression-free survival.

I have tried to practice the way the trial was designed, using bevacizumab for patients only as first-line therapy. I use it with paclitaxel, and I tend to reserve it either for patients who are symptomatic or for those who may not be symptomatic but whose disease trajectory is such that I would predict they might become symptomatic soon. It’s a judgment call.

In terms of whether or not we might want to generalize this and combine it with other chemotherapeutic drugs, I believe that’s a reasonable consideration. For patients who have already received a taxane in the adjuvant setting, should we use a drug like capecitabine? I believe it would be reasonable.

Breast Cancer Update — Think Tank Issue 2, 2006

DR RUGO: In addition to evaluating the combination of capecitabine/bevacizumab, another research strategy is to combine endocrine therapy with bevacizumab. Some interesting data indicate that estrogen may directly modulate angiogenesis through effects on endothelial cells in both physiologic and pathologic conditions. We also have data indicating that antiestrogen therapy blocks VEGF expression and estrogen-induced angiogenesis may be blocked by antiestrogen therapy.

Rakesh Jain’s group in Boston has observed an androgen-dependent tumor model and shown that castration, interestingly, leads to initial vascular regression, and then a second wave of angiogenesis occurs with vascular regrowth in this murine tumor model.

So a hypothesis was generated that anti-VEGF therapy may overcome this resistance of the second wave of angiogenesis seen with endocrine therapy in animal models and could improve the efficacy of standard hormone therapy in hormone receptor-positive metastatic breast cancer.

In the study presented by Dr Traina at ASCO this year, 43 patients received bevacizumab at 15 mg/kg every three weeks and letrozole at 2.5 mg per day. The combination appeared to be well tolerated. The drug-related toxicities were expected and only seen in a small number of patients. The efficacy analysis, which wasn’t the primary goal, was confounded by the long duration of prestudy aromatase inhibitor therapy in most patients, although it did appear that a number might have benefited from the therapy.

We have planned a Phase III study within CALGB and the Intergroup in patients with hormone receptor-positive disease. The patients will be randomly assigned to endocrine therapy with placebo or bevacizumab (administered every three weeks) as first-line therapy.

Breast Cancer Update — Think Tank Issue 2, 2006

DR WILLIAM J GRADISHAR: Right now, we have positive data from ECOG-E2100. By that, I’m emphasizing the fact that it’s used in the first-line setting. I have no reason to believe bevacizumab in conjunction with other agents, as first-line therapy, wouldn’t have a similar benefit. I don’t believe we will see people restricting themselves to the use of bevacizumab with paclitaxel alone, but we don’t have a lot of Phase II data for combining bevacizumab with a variety of different agents.

That said, the experience with trastuzumab is similar — we had preclinical models that guided us and then the Phase II trials followed. They all were consistent in that they demonstrated an incremental improvement when you combined the given agent with trastuzumab. I believe that when bevacizumab is combined with other chemotherapy agents, we will see the same improvement in outcome that we’ve seen in ECOG-E2100.

Breast Cancer Update 2005 (9)

DR BURSTEIN: We have data for bevacizumab in combination with paclitaxel. We certainly use a lot of weekly paclitaxel as first-line treatment for advanced breast cancer, so for patients who are already receiving paclitaxel, I believe this is clearly the regimen of choice.

The challenge is how to treat patients in the second- and third-line settings. At present, there really are only minimal data to indicate that bevacizumab is beneficial for such patients. Another challenge is what to do for those women who received anthracyclines and taxanes in the adjuvant setting.

Do you rechallenge them with paclitaxel and bevacizumab? There are two halves to that question. The first is, does bevacizumab actually help these women? We haven’t seen the data as yet broken out as a function of prior taxane therapy. The second half of the question is should you give the taxane again? Again, we don’t have good answers. If it’s been more than a year, it’s probably reasonable to give the paclitaxel again.

Occasionally, we recommend our vinorelbine regimen, because of our Phase II experience with vinorelbine plus bevacizumab.

Some people administer capecitabine plus bevacizumab, because, of course, there are safety data for that. On the other hand, those data don’t really suggest that particular combination does all that much compared to capecitabine alone. We’re all looking forward to more studies, more Phase II trials, to really try and understand how best to utilize this drug for metastatic disease.

Breast Cancer Update — Think Tank Issue 2, 2006

DR RUGO: ECOG-E2100 is a significant advance. Having participated in the initial capecitabine/bevacizumab trial and also having used bevacizumab in a variety of clinical research settings, we’ve been convinced for a long time that it has clinical benefit.

ECOG-E2100 produced two important implications. One is that we can, potentially, help patients in the metastatic setting with first-line therapy in combination with a taxane. The second is that it allowed us to move bevacizumab into trials in the early adjuvant setting, as well as into the neoadjuvant setting, which potentially allows us to identify the patient population most likely to benefit from bevacizumab.

Breast Cancer Update 2006 (7)

DR CARLSON: It’s reasonable to offer patients with triple-negative disease chemotherapy and bevacizumab as first-line therapy. The best evidence we have is with paclitaxel/bevacizumab. Kathy Miller’s ECOG study that evaluated capecitabine with or without bevacizumab showed a slightly higher response rate using the combination but no advantage in terms of relapse-free survival and overall survival.

We may be seeing specific drug effects and different drug interactions between bevacizumab and chemotherapy. It may be a result of different patient populations. The patients in the capecitabine study were treated in the second-line setting, not the first-line setting, as with paclitaxel and bevacizumab.

Breast Cancer Update 2006 (8)

DR BURSTEIN: For patients with triple-negative tumors we don’t have a target, so the work focused on optimizing chemotherapy. Some trials are evaluating adding products like capecitabine, and some are evaluating platinum-based chemotherapy. Additionally, there is interest in other biological approaches, and probably the one that is furthest along has been to add bevacizumab to the treatment of these patients. ECOG-E2100 indicated that the patients with ER-negative, HER2-negative disease did handsomely with paclitaxel and bevacizumab. So that is a reasonable patient population in which to try optimizing chemotherapy and other biological approaches.

For a woman with visceral, triple-negative metastatic disease that is extensive and symptomatic, obviously, we will administer chemotherapy. Most frequently, I use paclitaxel with bevacizumab for patients like that.

I find the data from ECOG-E2100 compelling — we can do better than using chemotherapy alone by adding bevacizumab treatment. I like the idea of using a relatively exciting biological therapy. The other point is that few women who walk in the door are chemotherapy naïve at that point.

Breast Cancer Update 2006 (8)

DR ROBERT B LIVINGSTON: We do not have hard evidence that one chemotherapy regimen is better than another chemotherapy regimen for the patient with serious, moderately symptomatic triple-negative metastatic disease. I believe most of us would be inclined to use anthracycline-based therapy if the patient hadn’t received it previously or if it had been more than a year since completion of her adjuvant treatment.

Many of us would be inclined to use a combination rather than a single agent, and I’m one of those because these patients have particularly aggressive disease and tend to experience short times to progression. The delay in time to progression that one sees with combinations may be important for patients with this type of disease.

At both my earlier institutional affiliations in Seattle and in the Southwest Oncology Group, we have been exploring antitubulin combinations, investigating combinations of vinorelbine and a taxane, either docetaxel or paclitaxel. Most recently, I’ve been involved in a trial with nab paclitaxel and vinorelbine. Those combinations are active. What I can honestly tell you is they’re probably not more active than somebody else’s choice of docetaxel and capecitabine or gemcitabine-based therapy.

The only patient right now, outside of a study, for whom I would probably urge the use of bevacizumab is this type of individual, because we do have evidence that the taxanes are as active, if not more active, than any other drugs. We do have evidence that weekly paclitaxel, which is the best way to administer the drug, is potentiated by the use of bevacizumab.

And we do have, in the triple negatives, a group of patients for whom, right now, no targeted therapy is available, except bevacizumab, that we can justify on the basis of a randomized trial. So if I were seeing such a patient in the clinic today, I would talk to her about a taxane-based treatment program, in all likelihood, and I would recommend that she also receive bevacizumab.

Interview, September 2006

DR GEORGE W SLEDGE JR: In ECOG-E2100 the progression-free survivals are now approximately a year for the combination of bevacizumab and paclitaxel. If we saw progression-free survivals in the same ballpark in the XCaliBr trial evaluating bevacizumab and capecitabine as first-line therapy, I believe we’d all find that very exciting, and it would certainly suggest that we might be able to combine bevacizumab successfully with other chemotherapeutic agents in a more up-front population.

It becomes important in an era when patients are receiving more and more of their therapy in the adjuvant setting, or more intensive chemotherapy in the adjuvant setting, so that drugs like capecitabine might be a preferential first choice for many patients in the front-line metastatic setting.

Breast Cancer Update — Think Tank Issue 2, 2006

DR HUDIS: I believe any patient with Stage IV breast cancer who is healthy enough to receive bevacizumab deserves a shot at capecitabine. I don’t buy the argument that it only works in the first-line setting and that it only works with paclitaxel.

The reasons I say that are, first, the drug has been extensively used with a variety of other chemotherapy agents. I don’t have to see safety data for a drug specifically in patients with breast cancer to call it safe. We have a lot of safety data for the 5-FU/bevacizumab combination.

Second, I thought the capecitabine/bevacizumab trial by Dr Miller was a positive signal. It showed a doubling of the response rate, but it did not achieve its primary endpoint of progression-free survival. The third reason is that you can see two patients in a clinic who are both ready to receive first-line therapy but have extraordinarily different prior chemotherapy experiences and exposure. For all these reasons, I offer bevacizumab, essentially, to all eligible patients with a line of therapy at some point in time.

Breast Cancer Update — Think Tank Issue 2, 2006

DR RUGO: We need the data from the ongoing RIBBON 1 and RIBBON 2 trials. The trials randomly assign patients either in the first- or second-line setting to receive chemotherapy with placebo or bevacizumab, and then they allow a crossover. The potential exists to obtain a lot of information. We have a menu of chemotherapy agents to choose from in those settings.

Breast Cancer Update 2006 (7)

DR CARLSON: Capecitabine is often the chemotherapeutic agent that I use as first-line therapy. Capecitabine has efficacy that is in the ballpark of any single agent, and I tend to treat metastatic breast cancer that’s not in visceral crisis with single-agent therapy.

The toxicity profile of capecitabine is favorable, and the women appreciate being able to take an oral medication, not having to go to the infusion center and not having to come back as frequently. It’s an agent that, at doses that are typically used, is associated with a predictable toxicity experience. I use 1,000 mg/m² twice daily — two weeks out of three weeks.

It’s very important that capecitabine does not cause alopecia. If you’re going to use sequential single agents, it’s always nice to start with an agent that doesn’t cause alopecia. If the woman already has established alopecia, you don’t gain from the nonalopecia properties of the new therapy. That’s often an important component of treatment of metastatic disease.

The other reason I often will lead with capecitabine is that many of these women, because it’s the first-line therapy, have recently been diagnosed with their metastasis. They will go through all the turmoil and psychic trauma of the new diagnosis, and in that context, often it is easier to start with an agent that has acceptable toxicity, so they can become used to the chronic nature of the disease and the need for ongoing chemotherapy with an agent that has good efficacy and doesn’t affect their quality of life to a major degree.

Breast Cancer Update 2005 (8)

DR VICENTE VALERO: There are two combination regimens that have proved to be superior to single-agent taxane therapy for metastatic disease. One is gemcitabine with paclitaxel, which was compared to paclitaxel alone. The data were presented at ASCO, showing an improvement in time to progression and preliminary evidence of an increase in overall survival.

The other study compared docetaxel with capecitabine to docetaxel alone and also showed a time to progression and overall survival advantage.

Based on the evidence, both of these combinations are reasonable for first-line chemotherapy of metastatic disease. However, in some patients, sequential chemotherapy is our preference.

I tend to use more sequential single-agent chemotherapy, but I believe the role of combination chemotherapy in some instances is well documented by the two studies I just mentioned.

For women who have symptomatic breast cancer with visceral involvement, it is essential to have a response to alleviate the symptoms and improve their quality of life. For those patients, despite the enhancement of the adverse events, I strongly consider combination chemotherapy.

Breast Cancer Update 2006 (6)

DR OSBORNE: In some ways, I believe nanoparticle albumin-bound (nab) paclitaxel is a little safer compared to the other taxanes. I’d also be interested to see how it does, for example, combined with trastuzumab for HER2-positive disease or combined with other chemotherapy regimens to see if the hint that it might be better in the metastatic setting plays out in the adjuvant setting.

The attractive thing about it is that you don’t have to administer premedication.

For patients who are on this drug for a long period of time, that’s a big advantage. Dexamethasone premedication can cause its own side effects. I haven’t used nab paclitaxel all that often yet, but I like it and I’m anxious to see how it’s going to be incorporated earlier in the management of the disease.

Breast Cancer Update 2006 (6)

DR HENDERSON: I am enthusiastic about nab paclitaxel. I have a bias in that I was very involved in the development of doxorubicin HCL liposome injection and it, like nab paclitaxel, has a delivery system that increases the amount of drug that actually reaches the tumor.

The issue of dose of chemotherapy has been a complicated one in cancer. When we examine dose in animal models, we clearly see a dose effect, and in leukemia we see an advantage with higher doses. Almost every oncologist has been taught as part of his or her earliest training that dose is a critical factor.

However, in most dose studies it’s difficult to demonstrate that dose makes a lot of difference, high-dose chemotherapy in bone marrow transplant being a case in point. I believe the reason we have been unable to show that dose is so important is that we are examining the dose we administer rather than the dose that reaches the tumor.

With a delivery system, you change the distribution of drug so that less goes to the normal tissue and more — a higher dose — reaches the tumor itself. That’s what happens with doxorubicin HCL liposome injection and nab paclitaxel. In both cases we can show that elegantly in preclinical models. Showing that in the human, of course, is more difficult because it’s not so easy to biopsy a tumor and measure the drug level.

We know that we can administer higher doses. In CALGB-9342, which studied paclitaxel doses of 175 mg/m², 210 mg/m² and 250 mg/m² in patients with metastatic breast cancer, we saw no significant effect from escalating the paclitaxel dose. However, there was some marginal effect from the higher doses and a suggestion of a longer time to tumor progression.

In fact, some of the analyses reached statistical significance as an endpoint. I believe with nab paclitaxel we are seeing that we can give higher doses and that patients tolerate higher doses.

In the preclinical models, mice tolerate higher doses of nab paclitaxel than paclitaxel delivered in Cremophor^®. In addition, because of the way the albumin interacts with the paclitaxel, higher doses were delivered to the tumor. I believe that’s why they were able to show a significantly better outcome with nab paclitaxel. It’s an interesting step forward.

Breast Cancer Update 2006 (3)

DR GRADISHAR: In terms of first-line taxanes in the metastatic setting, the data are still more abundant with both paclitaxel and docetaxel than with nab paclitaxel, so if basing a decision on the length of experience, those agents have been around for a longer time.

Next page