Perspectives on Systemic Therapy for Breast Cancer - Episode 11
Adam M. Brufsky, MD, PhD, FACP: We’re going to switch gears and talk about triple-negative breast cancer, and I think one of the first things that I’d like to talk about—and it’s great, I’ve got Hope Rugo sitting next to me, who did one of the trials and still is continuing on one of the very, very important trials of this topic—is what do we do about nanoparticle paclitaxel? We’ve had this drug now for probably 10, 15 years already. We had initial data from your CALGB trial. You updated at San Antonio. Do you want to talk about that again?
Hope S. Rugo, MD: CALGB 40502, now an Alliance trial, was a randomized phase III trial of patients in first-line chemotherapy for metastatic breast cancer, and patients were randomized to receive paclitaxel, nab-paclitaxel, or ixabepilone as weekly therapy—3 on, 1 off—with bevacizumab. And the majority of patients received bevacizumab; it was the current standard of care at the time that this study was designed. Even when we made it optional, everybody went on bevacizumab because it was available to them. The nab-paclitaxel dose, which was discussed for 2 years before the study opened, was based on a phase II Russian study that was actually published with Bill Gradishar as the first author. They had one arm that was 150 mg/m2 and one that was 100 mg/m2, using that weekly schedule of nab-paclitaxel. They showed superiority in terms of response, PFS, and tolerance in the 150 mg/m2 arm, but that was a relatively small phase II study in a place where patients didn’t have options for other therapy and didn’t get multiple lines of therapy, unlike our patients. In our trial, 150 mg/m2 was too toxic. Ixabepilone was inferior and also had some toxicity, although less hematologic toxicity. But ixabepilone was clearly inferior.
When we updated our data and looked at the subsets of ER-positive and ER-negative patients, it was interesting: We still showed that nab-paclitaxel was certainly the best-tolerated drug. In the overall population, paclitaxel was the standard arm. Nab-paclitaxel was about similar but not superior, and ixabepilone was inferior. If one also looked at overall survival, ixabepilone was inferior. But when we looked at the subset analysis of ER-positive and triple-negative disease—we had a smaller section of patients who had triple-negative breast cancer, under 30%—it looked like the triple-negative patients who received nab-paclitaxel had superior outcome than those who receive paclitaxel. Again, ixabepilone is still inferior, so we put that off to the side. And in ER-positive disease, that wasn’t the case: Paclitaxel was superior. I was thinking to myself—and it’s really hard to go back in a retrospective subset analysis and look at that—that if you had ER-positive disease, you have other options, lots of options. So, maybe people were more willing to drop the drug faster. With paclitaxel, they stayed on for longer. Some of the people stayed on paclitaxel for 2 years in that study.
Adam M. Brufsky, MD, PhD, FACP: Did you see that? Did you actually see the dose intensity less in the ER-positive group?
Hope S. Rugo, MD: Actually, when we look at it, it was very hard to assess. It looked like the dose intensity and dose reductions were similar. I just think it’s hard to assess exactly what people are doing and why. We had so many more patients with ER-positive disease than ER-negative disease. But we did look at it, and it didn’t look different overall. But what we did see was that by cycle 3 for nab-paclitaxel, almost everybody had dose reduced and people had dropped out. Regardless of that, we saw this superiority in the triple-negative group, which is fascinating.
Adam M. Brufsky, MD, PhD, FACP: What kind of superiority? What was it, PFS, OS?
Hope S. Rugo, MD: It was looking at PFS. OS is a little harder in a trial like that but there was a difference that still favored nab-paclitaxel, and ixabepilone was inferior. Also presented right next to our presentation was GeparSepto, and remember, these were all looking at subsets in trials that are farther out. So, these are hypothesis generating. They would need to be further assessed. But in GeparSepto, which is looking at neoadjuvant nab-paclitaxel, they also showed that 150 mg/m2 was too toxic and dropped to 125 mg/m2. But they did show, in their looking at event-free survival, superiority with the nab-paclitaxel group, both in the ER-positive and in ER-negative groups—actually maybe a little more in the ER-positive patients, it’s hard to say—versus paclitaxel. I think it’s hard to know what to take home from both of those trials. I’m interested in everybody’s thoughts on it. I think that clearly, 150 mg/m2 should never be used in nab-paclitaxel. It’s way too toxic. I think 100 mg/m2 is our general standard, and 125 mg/m2 may have some benefits in some settings. A study that was done by Luca Gianni that looked at a 3 on, 1 off schedule in the neoadjuvant setting showed no superiority with nab-paclitaxel.
Adam M. Brufsky, MD, PhD, FACP: But it was a 3 on, 1 off schedule. That’s why I asked that question.
Hope S. Rugo, MD: They got less drug overall compared with the GeparSepto trial. Is that really what the difference is in the triple-negative population? It’s hard to know. With our trial in the metastatic setting, I think we’ve shown in triple-negative breast cancer that if you give a more intensive chemotherapy in patients who are chemotherapy responsive, they may do better. That’s not in everybody, but they may do better. You may overcome some resistance. So, should we be using nab-paclitaxel instead of paclitaxel? I think it’s a hard call. I think it’s clearly a very useful drug for our patients. We have a low threshold for switching, and we certainly use it in the metastatic setting. But I think that these data as of yet aren’t enough to say that you should always be using nab-paclitaxel.
Francisco Esteva, MD, PhD: I was very impressed by the GeparSepto study, where patients were randomized to paclitaxel versus nab-paclitaxel followed by AC in both groups. Particularly in the triple-negative population, the pCR, pathologic complete response rate, was much higher. But interestingly, even if patients did not achieve pCR, the event-free survival was significantly better for patients treated with nab-paclitaxel compared to paclitaxel. So, I thought that was intriguing. 125 mg/m2 is too much. I use 100 mg/m2. It’s not FDA approved. This was not an FDA registration trial, but I’m very intrigued.
Adam M. Brufsky, MD, PhD, FACP: So, are we moving our practice?
Hope S. Rugo, MD: The events were small, and it was not planned to be looked at exactly that way, so I find it hard to believe.
Francisco Esteva, MD, PhD: The PFS was significant.
Hope S. Rugo, MD: I just find it hard to believe that the chemotherapy you get before surgery matters for that cancer.
Francisco Esteva, MD, PhD: It might.
Lee Schwartzberg, MD, FACP: But you might be moving up the RCB-3s to RCB-1s.
Hope S. Rugo, MD: You may.
Adam M. Brufsky, MD, PhD, FACP: That’s exactly right.
Hope S. Rugo, MD: I think it’s still a response criterion.
Francisco Esteva, MD, PhD: But it’s not just the pCR.
Komal Jhaveri, MD, FACP: I agree with Hope. I think at this point I don’t know how to take home the data from these 2 trials to change my practice right away. I think we do need some kind of validation, at least in the early stage setting, to be able to justify a 75% grade 1/2 peripheral neuropathy from nab-paclitaxel. The dosing of 150 mg/m2 changed over to 125 mg/m2. With event-free survival, we really did not see the difference in the hazard ratios broken down by the doses that the patients received.
Adam M. Brufsky, MD, PhD, FACP: It’s hard to do. I think there were not enough patients in that.
Hope S. Rugo, MD: And the events were small.
Komal Jhaveri, MD, FACP: And events were so small. Outside of a clinical trial, I’m not sure I am going to personally change my practice to utilize nab-paclitaxel.
Adam M. Brufsky, MD, PhD, FACP: But will there be more clinical trials of this kind?
Hope S. Rugo, MD: No, there won’t be.
Adam M. Brufsky, MD, PhD, FACP: Because Celgene are now into CAR T-cells, but are they going to still work on this?
Komal Jhaveri, MD, FACP: Right, but a standard.
Francisco Esteva, MD, PhD: I’m still using weekly paclitaxel and AC as the standard, but based on this presentation at San Antonio, my threshold to switch…
Adam M. Brufsky, MD, PhD, FACP: Has decreased.
Francisco Esteva, MD, PhD: Right.
Lee Schwartzberg, MD, FACP: Do you all think it’s a dose effect or a drug effect? Is there something inherently different about nab-paclitaxel? We heard the whole story about SPARC and all that.
Adam M. Brufsky, MD, PhD, FACP: But SPARC never really panned out.
Komal Jhaveri, MD, FACP: I think partly dose.
Lee Schwartzberg, MD, FACP: It’s dose, right?
Hope S. Rugo, MD: I think it’s better to give a drug that is within protein than within solvent.
Adam M. Brufsky, MD, PhD, FACP: It’s a delivery issue.
Francisco Esteva, MD, PhD: I think it’s a better option. Obviously, it’s more expensive.
Komal Jhaveri, MD, FACP: More toxic, more expensive.
Lee Schwartzberg, MD, FACP: Because we’re going to have to use steroid premeds.
Hope S. Rugo, MD: The neuropathy rate is lower. Actually, if you use 100 mg/m2 for 12 weeks, the neuropathy rate in the long run is probably lower than with paclitaxel because you don’t have the Cremophor. I think I agree. I was just saying that to a patient. I was trying to get authorization for somebody who already has grade 2 neuropathy on weekly paclitaxel in the neoadjuvant setting, for which of course I had to do a peer-to-peer for in the middle of clinic. But the patient got the nab-paclitaxel and I think that that’s a reasonable thing to do.
Adam M. Brufsky, MD, PhD, FACP: The bottom line is that whereas it was relatively negative a couple years ago, I think it’s beginning to shift a little bit. I think we have less of a barrier to use it
Hope S. Rugo, MD: Yes, I think that’s a good summary.
Lee Schwartzberg, MD, FACP: So, how do you incorporate carboplatin into that?
Adam M. Brufsky, MD, PhD, FACP: That’s a great question.
Transcript Edited for Clarity