The Ongoing Role of Everolimus in ER-Positive MBC

Transcript:Sunil Verma, MD, MSEd, FRCPC: I think there are some data that are going to be coming out at San Antonio this year, hopefully, that look at post-progression treatment.

Adam M. Brufsky, MD, PhD: That’s what I was about to get to, exactly.

Sunil Verma, MD, MSEd, FRCPC: And how do these patients do? In PALOMA-3, we have the data on post-progression treatment as to what they received and how long they stayed on treatment. So, that information, hopefully, we’ll be able to share at the end of the year. Because it really tells you then, whether you are able to maintain the benefits that you have gained, and if the biology of disease is no different or is there continued benefit? I think that is going to then tell us whether there is a survival gain that’s going to be in the same range as we were seeing with the PFS gain.

Adam M. Brufsky, MD, PhD: Let me turn that in two ways. First of all, the first question for post-progression treatment—I think there is some kind of noise out there—and some use it in patients who have progressed on palbociclib and letrozole, and then they get fulvestrant and palbociclib. Is that a reasonable strategy?

Sunil Verma, MD, MSEd, FRCPC: No. Without any trials, that’s not a reasonable strategy.

Adam M. Brufsky, MD, PhD: Right. Are there trials that are testing that though?

Sunil Verma, MD, MSEd, FRCPC: There are trials looking at that right now. There are trials looking at the role of continued suppression of CDK4/6 with palbociclib beyond progression. So, there is a randomized study which is evaluating it, but I think in clinical practice we should not be doing it.

Adam M. Brufsky, MD, PhD: You shouldn’t do it. Carlos, is there science behind that that would support it or not?

Carlos L. Arteaga, MD: Not that I’m aware, but I can speculate that maybe for those tumors that develop ER mutations, maybe the combination may be better. I want to go back to this issue of the whether we should treat everybody with a CDK4 inhibitor and an anti-estrogen therapy upfront. And I think that this is an effective targeted therapy. We know that from the history of cancer therapy, every time we move a therapy early to the disease, we are more likely to change or in fact we do change the natural history of that disease. The fact that you start early doesn’t mean that you may not have to continue it forever. You may add the CDK4 inhibitor for a short period of time, allowing you to maybe reprogram that disease and then stop the therapy. So, maybe that would be an option because there is toxicity and there is also cost. I think we can fix the cost. It’s harder to fix toxicity.

Adam M. Brufsky, MD, PhD: Right. Getting back, one of the last things I want to talk about before we move on to another type of breast cancer, is really where does this leave other targeted agents like exemestane and everolimus? We’re going to have data hopefully from PALOMA-3 on treatment with, I’m assuming, exemestane and everolimus among the many different therapies we have. Is that still a viable option after progression on a CDK4 inhibitor?

Sunil Verma, MD, MSEd, FRCPC: Yes. I think most certainly the challenges as we have learned as we plug and play new therapies in, we don’t have the prospective evidence to the same degree. But in the sequence of treatment, exemestane and everolimus are still an option to consider for patients who have had a CDK4/6 inhibitor, patients who have had single agent therapy previously. And Dr. Rugo has presented some data at the ASCO meeting looking at prophylactic steroid mouthwash that—Joyce, you’re a part of as well—shows pretty significant reduction, nearly 60% reduction in the occurrence of stomatitis. I think we’re getting, after many years, comfortable in managing those side effects that really concern us, and I think that’s a big one.

Joyce A. O’Shaughnessy, MD: Yes. I think that’s one to emphasize because though the word is getting out, it’s still not fully out that there’s just no reason to have any stomatitis or any more than grade 1 stomatitis. Because in Hope’s use of the elixir of the dexamethasone solution—and we’re doing a trial with prednisolone solution, as well as a separate one, which is our Miracle Mouthwash with hydrocortisone crushed up into it—that requires compounding, which is a little bit more cumbersome—which is why we’re doing a randomized trial versus prednisolone. We’ll have those data at San Antonio. But Hope’s trial is down to 2% grade 2 stomatitis and no grade 3; but the key is to start from day 1. It’s swish and expectorate 3 or 4 times a day, and you only need to do it for the first 6 or 8 weeks because then after that, the stomatitis incidence goes way, way down. And then patients could just use it PRN (pro re nata). I really liked Hope’s bottom line from her abstract, which is this is a new standard of care. I totally agree with that.

Sunil Verma, MD, MSEd, FRCPC: Thinking back now, if I remember in BOLERO-2, the discontinuation rate was close to 18%. It was high and if a strategy such as that was implemented, could we have seen even better results? Could we have seen more patients stay on therapy for a longer period of time?

Joyce A. O’Shaughnessy, MD: Yes, from a therapeutic standpoint.

Sunil Verma, MD, MSEd, FRCPC: So, it just tells you how important it is for us to even actually ameliorate some of these side effects right at the beginning, and have these strategies before we launch into big trials where I think most of the benefit may have been muted because these patients weren’t really managed that well.

Carlos L. Arteaga, MD: Adam, I want to go back to the question of everolimus and exemestane at progression. I agree with what Sunil said. However, we have to remember that we are creating a very new disease. Any time that we have a very effective therapy in the metastatic setting, that cancer is going to go through some Darwinian evolution and try to come up with some mechanisms we just don’t know. I think we have a responsibility and the tools to identify those mechanisms. These are patients that should be re-biopsied, whose tumors should be re-sequenced to understand that biology. Because, if you think about it, in the history of mankind, breast cancers have never seen this, ever. I should have said womankind.

Adam M. Brufsky, MD, PhD: There are some men who have breast cancer, too.

Carlos L. Arteaga, MD: So, we’re creating new nature that we have to interrogate while we try some of these options that you allude to.

Sunil Verma, MD, MSEd, FRCPC: But we have to understand it prospectively, evaluate it.

Carlos L. Arteaga, MD: Correct.

Sunil Verma, MD, MSEd, FRCPC: We’re doing a trial in Canada, where we’re basically monitoring these patients prospectively as they go through this journey. Because I think we need that prospective evolution to say what is happening to the natural history of breast cancer when they have been exposed to CDK4/6 and what happens to these patients when they get PI3 kinase inhibitors. And I think you need that prospective evaluation.

Carlos L. Arteaga, MD: Now, remember that ER-positive breast cancer is encumbered by a number of somatic alterations at the time of diagnosis. These are data from the TCGA (The Cancer Genome Atlas) and other databases. So, that cancer had, at its disposal, a number of alterations that she or he, whatever the sex of the cancer is, can usurp, and upregulate, and use.

Transcript Edited for Clarity