Treatment of HER2+ Metastatic Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: Let’s move on a little bit to something where, I think, there’s a lot of agreement internationally, and that’s the treatment of metastatic disease. I think, that at this point in time, based on the CLEOPATRA data, most people will give THP—trastuzumab, pertuzumab, and a taxane. And I have a feeling that the taxane, what’s used, may depend on what part of the world we’re in. Do most physicians in Europe use docetaxel as opposed to paclitaxel?

Michael Untch, MD: Well, actually, to be very honest, in Germany, most of us use weekly paclitaxel. We like that because it’s very effective. The side effects are quite low. So, 3-weekly docetaxel is not the most used schema in Germany for treatment of metastatic breast cancer. Now, this is how the study was done. And then, obviously, this is the labeled definition. There is a second trial that has used weekly paclitaxel and was also positive. Most of us in Germany use the double combination, trastuzumab/pertuzumab, with weekly paclitaxel in the metastatic setting.

Hope S. Rugo, MD: How do you schedule your paclitaxel? I think one of the difficulties with many people is that if you give 3 on, 1 off, they have to come in on their week off to get pertuzumab variably.

Adam M. Brufsky, MD, PhD: Right, it’s an excellent point.

Michael Untch, MD: Yes, that’s a good point. We are very, very trained in doing neoadjuvant trials, as you’ll remember with the GeparSepto trial, which was published early this year in the Lancet Oncology. And, in that trial, we used continuous 12 weeks of weekly paclitaxel in one arm and, in the other one, nab-paclitaxel. By the way, it was positive for nab-paclitaxel. And, also, we used a double combination, the way it is used. So, the patients, yes, were coming weekly to get their taxane regimen and they were receiving the double combination in a 3-weekly fashion.

Hope S. Rugo, MD: But, you can’t do that forever in metastatic disease, so you have to give a break.

Michael Untch, MD: That’s correct.

Hope S. Rugo, MD: We’ve tended to go maybe a couple of cycles with 3 on, 1 off and then switched to 2 on, 1 off, which is less drug. What do you do, Adam?

Michael Untch, MD: That’s practical. Yes, I agree.

Adam M. Brufsky, MD, PhD: I agree; 2 on, 1 off is practical.

Ahmad Awada, MD, PhD: I think, basically, we had to choose here: weekly paclitaxel or every 3 weeks? But, usually we like to do 3 weeks out of 4 for the reason you mentioned; 2 weeks is more easy for the patients, but less drug.

Hope S. Rugo, MD: Yes.

Adam M. Brufsky, MD, PhD: So, the next question is really on second-line therapy. In the United States, I think T-DM1 is clearly the standard of care. Is it the same in Europe in second-line, T-DM1?

Michael Untch, MD: Exactly, yes. I was part of the EMILIA trial and I was very impressed when I saw those data. I think that is still one of the standards we have to beat.

Adam M. Brufsky, MD, PhD: Right, I agree. And so, lapatinib/capecitabine use, has that gone down in Europe? I know in the United States it has.

Ahmad Awada, MD, PhD: The development of T-DM1 pushed lapatinib-based therapy, let’s say, to later lines of therapy in combination with chemotherapy or in combination with trastuzumab. So, both approaches were pushed a little bit later.

Michael Untch, MD: But, I know countries in Eastern Europe where virtually T-DM1 is not available because of the economic problem, and there, one of the possible standards of care is the combination of lapatinib and capecitabine.

Hope S. Rugo, MD: I think when we give it, we usually give all three drugs — trastuzumab, lapatinib, and capecitabine. That would be harder in some of the countries where they don’t, for a lot of financial issues.

Adam M. Brufsky, MD, PhD: Right. So, the last question, before we move on to novel therapies for HER2—which are very exciting data—really one of, I think, the big disappointments of the last year that we hinted at a little bit was the fact that MARIANNE was not a positive trial. Again, as we know, MARIANNE was a study of docetaxel/trastuzumab versus T-DM1 alone versus T-DM1/pertuzumab in first-line therapy. And, essentially, the progression-free survivals were all within the 14- to 16-month range. None were statistically superior to the other, and so the question is: why was that negative? It was supposedly a negative trial.

Ahmad Awada, MD, PhD: I would like to do, here, a general comment. T-DM1 is the superb drug in terms of efficacy, in terms of side effects, and in terms of the tolerance for the patient. When we have a superb drug, we start to expect the drug to give superb results, super results, even more than the drug could give because, going back to your question about neoadjuvant, it’s a little bit less than expected. I think T-DM1 was given in first-line in the neoadjuvant setting. This is a chemotherapeutic agent. I think what we observed is what we should expect normally, but due to the really very good results in second-line, later-line therapy, we expect more in the first line, more in the neoadjuvant setting. And, now, we face the results. So, T-DM1 is a superb, active drug, but we should not expect this drug to give an outstanding super result.

Adam M. Brufsky, MD, PhD: Right. I agree, but now we’re caught because we have THP, which is superior to TH, and we have T-DM1, which is equivalent to TH. So, we’re kind of stuck. Now, what do we do?

Ahmad Awada, MD, PhD: I think standard of care, based on the survival result of the CLEOPATRA trial, is the first-line therapy from the breast cancer. But, I should admit that 10% of these patients only receive trastuzumab in the adjuvant setting. That means 90% didn’t receive it, and that’s the problem in this trial. Nevertheless, if we take the whole package of dual HER2 inhibition with taxane, I think this is really a valid option for first-line therapy.

Hope S. Rugo, MD: And, the thing is that MARIANNE really did include three times more patients who had been exposed to adjuvant trastuzumab. So, these cross-trial comparisons are difficult because we keep marching ahead with our standard treatments. And, the trials, of course, just suffer from having been developed when they were. I think that the bottom line is that, in the future, most people will receive pertuzumab in the early-stage setting, so this won’t really be an issue. And, hopefully, we’ll just have increasingly less patients arriving into metastatic disease.

Adam M. Brufsky, MD, PhD: I think there were data, just recently published in JCO, where they actually looked at the response to T-DM1 in patients who had already had pertuzumab as first line, and it was not as good as you would think. You guys have any comment on that?

Hope S. Rugo, MD: That’s what I thought, too. I reviewed that paper before it was accepted and I thought it was actually interesting. It was MD Anderson and Yale. They went back and looked at their data sets and said, “Okay, who previously had pertuzumab?”. People still had a response and it was still a reasonable PFS, but it wasn’t very long. And, it’s interesting. The more treatment you give before you give your new drug, the less well it’s going to work. You just develop all sorts of resistance mechanisms, and, I think, we all expect that. But, I think, the paper was still important because it showed that you could get some benefit from T-DM1 after pertuzumab.

Adam M. Brufsky, MD, PhD: So, you look at it in a positive way. I agree. I think it’s more of a positive spin.

Hope S. Rugo, MD: And, it was a retrospective assessment.

Adam M. Brufsky, MD, PhD: Correct. It wasn’t really prospective data.

Michael Untch, MD: I would like to add one more point, Adam. We have learned from the metastatic MARIANNE trial and the neoadjuvant KRISTINE trial that we cannot have the double combination, trastuzumab/pertuzumab, with chemotherapy. I think the answer will be given by the KATHERINE study because in that study, we used the optimal anti-HER2 therapy with chemotherapy in the neoadjuvant setting. And, in patients with residual disease at the end of the neoadjuvant therapy, who are the ones that have the highest risk for recurrence, are treated either with the standard of care, which is adjuvant trastuzumab, or with T-DM1. That study has been finished. We’re going to see the results, and probably if the study is positive, we know the answer that in trastuzumab-resistant patients, then we might use T-DM1. That might be the wisest sequence, so let’s wait for that.

Adam M. Brufsky, MD, PhD: No, that’s an excellent design. I hope that works. I think we’re all looking very forward to that.

Transcript Edited for Clarity