Select Excerpts from the Discussion

Front-line management of HER2-positive metastatic disease

Track 26

DR LOVE: Melody, could you comment on the issue of trastuzumab monotherapy of metastatic disease?

DR COBLEIGH: In Chuck Vogel’s single-agent, up-front trastuzumab trial, the median survival for approximately 100 patients who received trastuzumab monotherapy was identical to the median survival of the patients who received chemotherapy in combination with trastuzumab in the randomized trial (Vogel 2002; Slamon 2001).

Therefore, I believe this option should be discussed with patients, and I frequently use it when there’s nonlife-threatening disease, which is most of the time.

Track 27

DR LOVE: What is your approach to postmenopausal patients with hormone receptor-positive, HER2-positive disease who relapse on an adjuvant aromatase inhibitor and have not received any anti-HER2 therapy?

DR BURRIS: This is a setting in which we have clinical trial experience with fulvestrant and trastuzumab, which has gone well. I have used this approach off study with a number of patients, based in part on data from UCLA demonstrating that fulvestrant may confer an advantage in this population of patients.

DR GRADISHAR: We typically administer an endocrine agent alone. We try to extend treatment with single-agent endocrine therapy for as long as we can, unless there’s a clear-cut advantage to do otherwise. While I believe the combination of fulvestrant and trastuzumab is reasonable, these patients often later receive chemotherapy with trastuzumab as doublet therapy.

DR LOVE: Andy, some people make the argument to use chemotherapy and trastuzumab up front in this situation because that’s the only approach in which a survival benefit has been demonstrated (Slamon 2001).

DR SEIDMAN: I believe that’s a reasonable argument. However, the scenario you presented represents a potential potpourri of clinical scenarios.

I would use either exemestane or fulvestrant, because there was a long disease-free interval without visceral disease that would have pushed me toward using chemotherapy and trastuzumab. Those are the variables that drive my decision the most.

DR SLEDGE: Prior endocrine therapy did not diminish the survival advantage in any way in the pivotal trastuzumab study (Slamon 2001), so you don’t compromise the patient’s eventual benefit from chemotherapy with trastuzumab by using endocrine therapy first.

DR SLAMON: I don’t believe you compromise it. The critical question is, do you add anything to it? The fact that single-agent, antihormonal therapy did so poorly in the TAnDEM trial surprised some people, but we would have predicted it based on the fact that they had HER2-positive disease (Mackey 2006).

Does endocrine therapy add nothing? I don’t believe we can say that. We still use it, but I agree with Skip’s approach, and we are moving toward fulvestrant with trastuzumab based on some of the preclinical data.

HER2-directed therapy after progression on primary trastuzumab

Track 28

DR LOVE: Skip, we have a new generation of patients who have received adjuvant trastuzumab. How do you approach these patients with recurrent disease?

DR BURRIS: The key point is the interval from adjuvant trastuzumab to relapse. I think there’s some time point when you feel comfortable restarting trastuzumab and a point when you use lapatinib.

One factor that has swayed me for some patients with later relapses is the marked responses we saw when we continued trastuzumab and added lapatinib in the metastatic setting — and you feel like you’re getting an additive or synergistic effect clinically.

For example, when you treat with trastuzumab/vinorelbine and then discontinue the treatment, trastuzumab is still present in the blood. Then you add lapatinib and capecitabine, and you obtain a more dramatic response a little earlier.

This is something we did accidentally because of the trial design (Geyer 2006). The FDA allowed us to say, “We don’t know how long we need to wait for trastuzumab to be eliminated from the body. So you can begin lapatinib whenever you want.”

Anecdotally, those patients who had most recently received trastuzumab actually had a greater degree of response. I think lapatinib/capecitabine is worthy of discussion — it has been a reasonably well-tolerated combination.

Combining bevacizumab with chemotherapy in the metastatic setting

Track 39

DR LOVE: Lee, we conducted a Patterns of Care survey in which we found that about 30 percent of practicing oncologists said they were using corticosteroids when they administer nab paclitaxel. What are your thoughts about that?

DR SCHWARTZBERG: It speaks to the fact that there’s still a lot to be done in disseminating information to the community practitioners. There’s so much information out there about so many therapeutics that it’s difficult to cut through and drill down to the important issues.

This is an important issue, particularly if we move to weekly dosing of paclitaxel. If you’re using standard paclitaxel, then you’re using steroids every single week. We’re all familiar with the problems associated with that (for example, glucocorticoid-induced diabetes), which are an issue for a number of patients. There’s no reason to use steroid premedication with nab paclitaxel.

Tracks 43-44

DR LOVE: George, can you comment on the data you presented at ASCO on capecitabine and bevacizumab in the first-line metastatic setting?

DR SLEDGE: I look at capecitabine and bevacizumab and say, “In the refractory setting, we have a Phase III trial that is negative for progression-free survival (Miller 2005; [2.1]).

We also now have a front-line trial, albeit not a Phase III trial, that’s yielded distinctly miserable results, particularly in a major subset of patients with steroid receptor-negative breast cancer (Sledge 2007; XCaliBr; [2.2]).” So I don’t see a lot of data that support the use of this combination in the triple-negative subset of patients. However, I am a big fan of capecitabine and use a lot of it in my clinic.

DR LOVE: Andy, which chemotherapeutic agents are reasonable to combine with bevacizumab in a clinical setting?

DR SEIDMAN: My practice follows the highest level of evidence-based medicine. So when I use bevacizumab, for the majority of patients, I use it with paclitaxel.

There are certain unique circumstances in which paclitaxel is not appropriate, so I find the occasion to combine bevacizumab with other agents. Capecitabine would be the next most common agent followed probably by vinorelbine and gemcitabine. I don’t think I’ve ever used an anthracycline with bevacizumab for metastatic disease. Primarily, I use taxane-based therapy.

DR BURRIS: We’ve actively accrued to the RIBBON trial. So we’ve had a little experience with all of the combinations, and I don’t notice a marked difference in terms of toxicity. I’ve used bevacizumab with docetaxel, paclitaxel and capecitabine, but I had not seen the subgroup analysis from the XCaliBr trial (Sledge 2007).

That was a big difference in terms of the results in the patients with ER-positive disease and those with ER-negative disease. It’s just one trial, but we always hear about the subset of triple-negatives and you think that might be a place where antimetabolites might have a role. This turns that upside down.

DR LOVE: On the flip side, does it make you more likely to consider capecitabine and bevacizumab for patients with ER-positive disease?

DR BURRIS: Yes, I think so.

Track 46

DR LOVE: Skip, how do you approach the issue of continuation of bevacizumab upon disease progression?

DR BURRIS: It’s difficult. I have more and more patients who have finished weekly paclitaxel and bevacizumab and they’re being treated with maintenance bevacizumab. If they’re doing well and their disease is gradually regrowing, I continue bevacizumab and add a second drug. I don’t know of an ongoing trial to study this for a strategy, but it needs to be done. In patients who clearly don’t seem to be benefiting or are fighting the toxicity, it’s been an easy decision to think about discontinuing bevacizumab. In general, however, it’s been well tolerated.

DR BURSTEIN: I think that’s probably not a great strategy. We all lapsed into this behavior with trastuzumab, which perhaps was right or perhaps was wrong. Considering the concerns about some of bevacizumab’s side effects, the absolute unknowns about its role and the fact that we have a negative study in the second-line setting (Miller 2005a), it seems hard to think there’s a huge clinical advantage for continuing bevacizumab.

DR SLAMON: I respect that we need to consider long-term effects, but I hear this as a rejoinder with trastuzumab and bevacizumab from the same groups who use chemotherapy without blinking. These drugs are safe, and we know the toxicities. We can administer them safely, and I believe they should be used. If there were a way to identify a patient who was responding to bevacizumab, there seems to be little doubt that staying with the agent and adding another drug later wouldn’t also continue to benefit the patient, just as they have on trastuzumab. There are no hard data, but that’s what I would do clinically.

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