AVEREL: Bevacizumab in HER2+ Metastatic Breast Cancer

Kathy D. Miller, MD; Luca Gianni, MD

Disclosures

December 19, 2011

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Introduction

Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at Indiana University School of Medicine, in Indianapolis. This is Medscape Oncology Insights in Breast Cancer, coming to you from the 2011 San Antonio Breast Cancer Symposium.

Joining me today is Dr. Luca Gianni, Medical Oncology Director in the Department of Medical Oncology at the San Rafael Cancer Center, in Milan. Luca, thank you for coming in today.

Luca Gianni, MD: Thank you.

AVEREL: Two Drugs, Two Targets

Dr. Miller: I would like to talk to you about the AVEREL trial,[1] which you led and reported. This is a study looking at the addition of bevacizumab as a component of the initial therapy in patients with HER2-positive metastatic disease. This is a subset that was excluded from all of the previous trials that we have been talking about. Why look at bevacizumab in this subset of patients?

Dr. Gianni: There is very strong support in preclinical models indicating that there is a cross modulation between the vascular endothelial growth factor and HER2. Indeed, there are very nice models of HER2-positive disease, where the administration of trastuzumab and bevacizumab concomitantly results in synergistic activity. Phase 1 and phase 2 studies in women with HER2-positive breast cancer showed very promising results,[2] and so we thought it was appropriate to test this hypothesis in a formal way.

Dr. Miller: I remember that early phase 1 and 2 study, looking at just the 2 antibodies without chemotherapy.

Dr. Gianni: Yes.

Dr. Miller: It was really quite striking that almost half of the patients seemed to benefit, even with just the antibody therapy.

Dr. Gianni: Yes, and as always, with a relatively small trial, you may have results that are very promising in the beginning and then they are not confirmed. In this case there also was a phase 2 trial in which chemotherapy was added to the 2 monoclonal antibodies. The additional benefit of this was seen, but it was not controlled. So we needed a control.

Dr. Miller: The AVEREL trial really put this hypothesis to the test, looking at a trastuzumab-based regimen with or without bevacizumab. What chemotherapy regimen and what patient population did you target for this trial?

Dr. Gianni: The decision was to adopt what many considered the most active combination, and that is docetaxel, as the chemotherapy backbone, at 100 mg/m2, associated with trastuzumab. We decided to give this therapy every 3 weeks, for a minimum planned number of 6 cycles, and in the therapeutic arm with bevacizumab, the same chemotherapy was administered. All treatments were to be continued until progression, which means that in the combination with bevacizumab arm, the patients continued on bevacizumab and trastuzumab after completing the 6 cycles of chemotherapy, whereas in the case of the control arm, they continued with trastuzumab single agent.

Dr. Miller: I want to ask you a little bit more about the chemotherapy. Many of the trials in the HER2-negative population suggested continuing the chemotherapy and the bevacizumab, but with docetaxel at 100 mg/m2, 6 cycles would certainly be doable, but going much beyond that would start to run into toxicity difficulties.

Dr. Gianni: I completely agree. Docetaxel is a very good drug. On the other hand, beyond 6 cycles it becomes difficult to handle, especially by the patient. Toxicity becomes prominent, and dealing with this toxicity can be very difficult. Other drugs can be continued for a more prolonged time, but not in the case of docetaxel, or it is not something that we would advise.

Dr. Miller: These patients were getting their first trastuzumab-based regimen for advanced disease. Many of our patients now receive trastuzumab in the adjuvant setting. Was that something that was allowed in these patients?

Dr. Gianni: Yes, but the patients who had received trastuzumab at an earlier stage, as an adjuvant therapy, were in the minority, around 10%. This is easily understandable because the trial started in 2006, when trastuzumab was not on the market, anywhere in the world, for this indication, and so it [use of trastuzumab as an adjuvant therapy in metastatic breast cancer] built up slowly, as it penetrated the market. As an indication for breast cancer, it is now common in many parts of the world.

A Clear-Cut Improvement in PFS

Dr. Miller: So tell us, what did you find? Was there benefit by targeting 2 different pathways rather than the same pathway?

Dr. Gianni: There was a clear sign -- a prolongation of progression-free survival. This prolongation was clear-cut, it was around 3 months. The control arm fared better than we expected, which in a way, is good, and the statistical analysis was a bit complicated. It was complicated because it relied on 2 possible types of assessments, one is the investigator assessment, which mimics what happens in everyday practice, because the physician makes decisions about continuing or not continuing the treatment, and the other one is the standard suggested by the regulators at the US Food and Drug Administration, which is the independent review committee assessment.

The 2 assessments basically had the same numerical value of about 3 months prolongation of progression-free survival. The difference by the investigators is not statistically significant, whereas that of the independent review is statistically significant.

Dr. Miller: What about some of the other indicators of benefit? I am sure you looked at overall response rate in this population.

Dr. Gianni: For overall response rate, there was a trend towards an improvement by addition of bevacizumab on the order of a 5% improvement, according to the investigators and on the order of 10% by the independent review committee. It is striking that the level of activity, even before the addition of bevacizumab, was very high, on the order of 70% objective responses.

Dr. Miller: That is quite amazing, because if you add 10% or more to that, you really have only a minority of patients who are progressing the first time you are assessing their disease, which is quite unusual, in a metastatic setting.

Dr. Gianni: Exactly, and it should be pointed out that the strong starting point of chemotherapy with trastuzumab in this indication is so good that it leaves little room for benefit in these patients. This is good news, because we have active treatment, but it makes life more complicated in terms of demonstrating additional benefit from newcomers.

The Toxicity Factor

Dr. Miller: Whenever we talk about adding a new therapy, we have to think about bad things that can happen, and the toxicities as well. Those phase 1 and 2 studies that we mentioned earlier raised a potential concern about cardiac toxicity. I am sure you must have been looking at that carefully in this group of patients.

Dr. Gianni: We have been very proactive in assessing the cardiac toxicity of this combination with the addition of bevacizumab. If you look at the so-called serious adverse events (grade > 3) and 3 adverse events, the incidence tends to be higher with the addition of bevacizumab, on the order of 5%, whereas in the case of the control treatment, incidence is on the order of 2.5%. The difference is mostly, if not exclusively supported by a higher incidence of so-called "non-symptomatic events." If you look at the bad part, which is the symptomatic events, they were the same order of magnitude with either treatment, so the addition of bevacizumab apparently did not cause a major worsening of the cardiac toxicity of the combination.

What Is Next for Bevacizumab?

Dr. Miller: Where are you headed with this combination now? A huge amount of controversy has surrounded bevacizumab and what to do with it, and now we have another study in a population that we have not had data, showing pretty similar benefit to what has been seen in the studies that we have been arguing about.

Dr. Gianni: It needs to be put in context. In the case of HER2-positive disease, the number of therapeutic options is really expanding, and some of them provide really outstanding benefits to patients, so what would have been welcomed 5 years ago as a very important opportunity -- the improvement in progression-free survival we observed in the AVEREL trial -- doesn't excite us as much today. This does not mean that there is not a benefit. As we have seen in the AVEREL trial, as in other trials that include bevacizumab, we need to understand whether any subgroup of patients clearly benefits from the addition of bevacizumab, and whether there are others in whom the administration of bevacizumab doesn't add much.

Dr. Miller: Did the AVEREL trial collect tissue blocks or blood specimens, to try and help identify that subgroup of patients?

Dr. Gianni: That approach, which is crucial for understanding modern oncology medicine, was optional, and not associated with relatively good success. Only 160 of more than 400 patients enrolled into trial were compliant with this request. We had tumor blocks, and blood and serum from these 160 patients, and information is emerging that we think might be very interesting.

Dr. Miller: Before we leave today, I have to remind us all that we do studies in the metastatic setting partly to improve the treatment of patients with metastatic disease, but also to think about what therapies might be effective and moved into the adjuvant setting. An adjuvant trial is looking at adding bevacizumab to HER2-targeted therapy as well. You have also been participating in that trial. How has that trial been going, and do we have any expectations yet as to when we might see those important results?

Dr. Gianni: The trial has just recently completed enrollment. We are no longer participating in the trial, but I have obviously kept an eye on this combination, and as far as I know, they will need another 12 months or longer to have the first analysis of the results.

Conclusion

Dr. Miller: Luca, thank you for coming in and going through these results with us today, and thank you to our audience for joining us for this addition of Medscape Oncology Insights. This is Kathy Miller at the 2011 San Antonio Breast Cancer Symposium.

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