You are here: Home: BCU 1 | 2006 Think Tank:  Section 4: Systemic Management of Metastatic Disease

Tracks 1-22

Track 1 Paclitaxel and bevacizumab for patients who have previously received adjuvant taxane therapy Track 2 Potential benefit of combining bevacizumab and capecitabine Track 3 Tolerability and efficacy of paclitaxel and bevacizumab as first-line therapy for metastatic disease Track 4 Potential rationale for the slow incorporation of bevacizumab into clinical practice Track 5 Weighing the costs of therapy versus the benefit to patients Track 6 Rationale for using bevacizumab beyond the first-line setting Track 7 Need for an ongoing dialogue about the rising cost of therapies Track 8 Trend for improvement in survival in ECOG-E2100 Track 9 Clinical use of bevacizumab in combination with capecitabine Track 10 Continuation of bevacizumab after disease progression Track 11 XCaliBr: Phase II study of capecitabine with bevacizumab followed by bevacizumab upon progression Track 12 Mechanisms of resistance to anti-angiogenic therapy Track 13 Importance of weighing overall societal costs versus the cost of an individual therapy Track 14 Potential biologic rationale for benefit of adjuvant bevacizumab Track 15 Evaluating the optimal duration of adjuvant bevacizumab Track 16 Potential benefit of fulvestrant in combination with aromatase inhibitors Track 17 Ovarian suppression and fulvestrant for premenopausal women Track 18 Biologic rationale for using a loading dose of fulvestrant Track 19 Sequencing hormonal therapy for premenopausal women with ER-positive metastatic disease Track 20 Influence of aromatase inhibitors on intratumoral estrogen levels Track 21 Incorporation of fulvestrant into the adjuvant setting Track 22 Potential role of fulvestrant after five years of an aromatase inhibitor

Select Excerpts from the Discussion

Tracks 1-2

DR LOVE: Dr Miller, would you comment on ECOG-E2100 and the treatment of patients who previously received an adjuvant taxane?

DR MILLER: This trial (Miller 2005a) specifically allowed patients who had had an adjuvant taxane as long as their disease-free interval was greater than 12 months. Approximately 18 percent of the patients were in this situation, and they were nicely matched between the two treatment groups.

The overall result in these patients was essentially a doubling of objective response rates, which translated into a highly significant, more than five-month improvement in progression-free survival. It’s certainly fair to wonder if those results held up in the patients who received taxane-containing adjuvant therapy.

We have evaluated a variety of subsets, including the subset that received previous taxane-based therapy. Their hazard ratio was 0.38, compared to 0.51 for the overall group. This translated into an improvement in their progression-free survival from four months to 12.4 months. So, if you’ve had an adjuvant taxane, you do gain substantial benefit from a taxane plus bevacizumab.

Toxicity in this trial was also favorable, with 15 to 16 percent of patients developing hypertension that needed therapy and no major differences in the chemotherapy-related toxicities. There were slight increases in fatigue and neuropathy, likely because patients were responding for longer durations, so they received more exposure to chemotherapy.

In whom would I not consider this combination? One obvious group is patients who were not eligible for the E2100 trial, who received an adjuvant taxane and relapsed in fewer than 12 months. Those patients actually were allowed to enroll in the previous randomized trial of capecitabine with or without bevacizumab as their first therapy (Miller 2005b).

This previous trial also found increases in response rate by adding bevacizumab to capecitabine but no difference in progression-free survival. There were, however, huge differences in the patient populations, particularly in the extent of previous chemotherapy. About a third of patients in E2100 were completely chemotherapy-naïve, including no adjuvant chemotherapy and much less exposure to previous taxanes.

I believe the biggest difference between the trials is a matter of timing — as breast cancers progress, they express a greater number and have greater redundancy in the proangiogenic pathways. This explanation fits the E2100 data nicely and is why, for this patient, I would strongly recommend a taxane and bevacizumab-containing regimen rather than some other chemotherapy combination and holding bevacizumab in reserve until further progression.

Tracks 3-5

DR LOVE: Many oncologists tell us they’re confused about where bevacizumab fits into the management of metastatic breast cancer. Does that surprise you, Kathy?

DR MILLER: It has surprised me from the day I presented these results. No other trial in first-line treatment for metastatic breast cancer has found this degree of improvement in outcome with this minimal toxicity (Miller 2005a). The only study that has come close is the original trastuzumab randomized trial (Slamon 2001), and that was hampered by a significant rate of congestive heart failure in one of the two arms.

I don’t recall anyone looking at those results and saying, “It’s only five months and we just don’t know where this fits in. We have so many other things to give patients.”

 

No other drugs were approved for breast cancer between then and the E2100 data. And this trial applies to a much larger subset of our patients. I quite honestly don’t understand the reluctance.

DR BURSTEIN: I like the E2100 study, and it’s an exciting proof of principle. I would use the regimen for treatment of the patient who had received an adjuvant taxane, but let me ask you to play it out a little more. For instance, we have trials of combination versus sequential chemotherapy with a statistically significant survival advantage. I have, in general, resisted those, believing that we should treat sequentially.

One of the challenges your two trials pose for me is that they suggest a relatively specific window during which bevacizumab is effective. Conceptually, I find it hard to imagine that the drug works in the first-line setting but not elsewhere.

DR MILLER: It may be hard to explain, but these are the data we have, and it does fit the biology. We also have data suggesting that increases in proangiogenic peptide expression result in a relative resistance to chemotherapy. These become more numerous as patients progress, and this makes inhibiting any single factor inherently less effective, which is different from the chemotherapy trials.

The other difference is that the chemotherapy trials usually have only found a progression-free survival improvement of two to three months at the cost of substantial increases in toxicity. I suspect we will have an overall survival improvement; it’s just too early to know yet.

This should not be taken as an assumption that no survival advantage exists, merely that it’s an effective therapy. We have to wait longer to get those results.

DR WINER: I, too, am enthusiastic about bevacizumab, but three issues have led people to be less enthusiastic. One is that this applies to a large subset of patients. I believe people would be happier if this could be targeted to a specific group. People are also less enthusiastic because of not knowing quite what to do with the results of the capecitabine trial. The third and very real issue is the cost.

DR HUDIS: Unfortunately, the cost got in everyone’s way. This is the first drug that forced a change in dispensing practices for our whole institution. We can’t write for it without pre-approval from the insurance company, and we’ve never had that for any agent in our setting.

The second issue, which we don’t talk much about, is that although the toxicities are manageable and those of us who used the drug got used to it, it represents a little bit of a change in practice patterns for oncologists. They’re suddenly paying attention to proteinuria and hypertension.

DR MILLER: I don’t deny that the cost is an issue. But the cost is not markedly different from the cost of trastuzumab when it was first available, and I don’t recall reluctance with that agent.

When I’ve heard people talk about their reluctance, they haven’t said, “If cost were not an issue, I would use it in a heartbeat.” So I think cost is one component of the reluctance but certainly not the only one.

DR SLEDGE: Physicians like to be able to say, “This drug will improve your survival by X months.” I think part of the problem with this drug is that we don’t have those survival data yet.

From a quality-of-life standpoint, those of us who have used it have found it to be an incredibly easy drug for patients, with truly trivial toxicity compared to every single chemotherapeutic agent in the therapeutic armamentarium. It also more than doubles the response rate.

DR OSBORNE: I believe the cost of this drug has perhaps crossed the line in the eyes of private practitioners. We’re beginning to realize there’s a limit.

Track 5

DR LOVE: Kathy, what has been your reaction to the discussions regarding the cost of bevacizumab?

DR MILLER: I am frustrated by the inconsistency in how we view costs of therapies. In many settings we routinely use growth factors and expensive supportive care agents for regimens that have a low risk, when the guidelines wouldn’t suggest it, and people order lots of horrendously expensive combined PET/CT scans, which don’t add to treatment.

So I have a problem hearing about the cost of one specific drug that had a huge benefit in this trial. I’m not arguing that we shouldn’t consider the costs. Of course, they’re important for all of our practices, our individual patients and our society. But to consider the costs in a vacuum only as they apply to one drug is a mistake.

Tracks 6-7

DR LOVE: Cliff, are you using capecitabine combined with bevacizumab?

DR HUDIS: Absolutely. The data are not really negative (Miller 2005b). The response rate is higher. A principle has been clearly established, in my mind, that bevacizumab adds to chemotherapy in a cohort of patients.

DR BURSTEIN: We should be in dialogue about where and how best to use these therapies, and I take Kathy’s point that the expense is not unique to this drug. There is a compelling reason to think we often overtreat in the way of PET scans, stereotactic radiosurgery the third or fourth time around for brain metastases, or unbelievable efforts at other supportive care, which have a relatively modest cost-effective gain. I believe we should engage in a serious dialogue about these issues.

Tracks 11-12

DR LOVE: George, what efforts are being made to determine the role of bevacizumab with other agents in the first- and second-line settings?

DR SLEDGE: The XCaliBr trial uses front-line capecitabine with bevacizumab for patients who have received basically any adjuvant chemotherapy.

This trial has recently been expanded to approximately 112 patients, and it should have decent confidence intervals for response rate and progression-free survival.

This trial also recommends that patients cross over to a second-line chemotherapy, either vinorelbine or paclitaxel, at the investigator and patient’s choice, with bevacizumab.

So we will obtain data from this trial in terms of second-line responses to either vinorelbine or paclitaxel with bevacizumab. The data should be available to us some time next year.

Resistance remains a big issue for anti-angiogenic therapy in just about every disease that we’ve evaluated it in to date, and it’s certainly not surprising that it will continue to be a problem.

Therefore, it’s not surprising that crossing over to another chemotherapy agent with bevacizumab is unlikely to make much difference.

Track 16

DR LOVE: John, do we have any information about combination hormonal therapy with fulvestrant and an aromatase inhibitor in the metastatic setting?

DR ROBERTSON: This is being evaluated in the ongoing SoFEA trial, in which the aromatase inhibitor is continued and fulvestrant is added on in the hope that by keeping down the estradiol level, more fulvestrant will compete with the receptor and perhaps give a better initial response or even longer-term control. But I’m not sure that we’re going to see the result of this study in our lifetime.

Theoretically, fulvestrant with an aromatase inhibitor is as good as any other option. The problem with this combined approach is that we have no human data for any combination. We have nothing to suggest that this combination will be better.

Track 18

DR LOVE: What’s the evidence supporting a loading dose of fulvestrant?

DR ROBERTSON: First, tamoxifen reaches a steady state at two weeks, whereas fulvestrant can take up to four or five months to reach a steady state.

Another issue, which I believe makes people slightly uncomfortable, is that in the second-line study, fulvestrant was just as good as anastrozole after tamoxifen (Howell 2002; Osborne 2002).

The first-line study, however, had two problems. Although it was a randomized study, 10 percent more people were assigned to fulvestrant versus tamoxifen.

In addition, in the intention-to-treat population, the time-to-progression curve for the initial fulvestrant arm drops down much more quickly than the curve for tamoxifen, and then, after the first six months, it runs parallel to tamoxifen. It makes one think that perhaps the drug is not on board in that first six months.

The question is: why would you see this in the first-line and not the second-line setting? You could argue that some of those patients in the second-line setting may be having a tamoxifen withdrawal effect while the fulvestrant levels are going up.

DR HAYES: I would argue that this drug clearly has a dose-response curve. Kent’s trials demonstrated that the lower dose had to be dropped because it was ineffective (Osborne 2002).

In addition, I don’t know any drug we use for which we don’t want to use the right dose. It’s clear from the pharmacokinetics of this drug that if you use the loading dose, you reach what should be acceptable levels faster. We don’t use a loading dose for tamoxifen because patients take it every day.

Track 21

DR LOVE: Hal, what investigational strategies are being pursued with fulvestrant?

DR BURSTEIN: We have a wealth of endocrine options coming forward. How to integrate fulvestrant is one of them. Many of us are starting to think about it in the adjuvant setting.

What’s disappointing is that we don’t really have a surrogate, short of a large, randomized, prospective study that will take a decade to finish, to tell us what to do with this drug.

It’s at the fundamental level of failure of what our laboratory correlative studies have allowed us to do so far because we’re still left having to resort to tremendously large studies to answer these questions. It’s a real barrier for more rapid integration.

The question is: fulvestrant with or without an aromatase inhibitor or fulvestrant after an aromatase inhibitor in the adjuvant setting or combinations thereof ?

Track 22

DR LOVE: Eric, can you talk about the delayed fulvestrant trial?

DR WINER: This is not fully hashed out by any means.

We’ve prepared a concept of a trial looking at fulvestrant in the extended adjuvant setting for women who have received five years of an aromatase inhibitor or who have received tamoxifen followed by some amount of an aromatase inhibitor.

The concept would be to compare fulvestrant with either no therapy or a placebo in those women and potentially allow women to start on the therapy even after a break of a year or two or three years, with the idea that whenever a woman with ER-positive breast cancer starts a new endocrine therapy, a benefit and a decrease in events may occur.

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