Sequencing in Hormone-Driven Metastatic Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: Where does fulvestrant fit in with everybody’s practice? Denise, when do you use fulvestrant now?

Denise A. Yardley, MD: I think I’m somewhat mixed on when I’m using fulvestrant. I’ve looked at various studies. I’d certainly say my first-line treatment for endocrine-positive patients in the metastatic setting is a CDK4/6 combination. And then I have moved fulvestrant into that setting for most of my patients. Although I have to say, we participated in the TRINITY-1 trial, which looked at adding ribociclib after a CDK4/6 inhibitor—either immediately if they progressed or they could have had interval chemotherapy—and added everolimus to that combination with exemestane.

And so I think from my experience on that trial—because it wasn’t blinded and we’re in the data assessment phase—patients did very well with adding everolimus, adding the CDK4/6 ribociclib with exemestane. I think that it’s a time when we’re really reexploring what to do because of the paradigm shift. Now we have all the data from the BOLERO-2 trial, and that was not in a CDK-naïve population. So, how do we go back and look at everolimus in that patient setting? I think it’s a time when we’re searching through clinical trials to keep these patients moving forward so we can really understand what’s the next-best sequencing, if there is going to be one.

Adam M. Brufsky, MD, PhD: Any other comments, Carlos?

Carlos L. Arteaga, MD: Yes. I think the FALCON study, which showed fulvestrant being compared with an AI, tells me that the way we should consider treating an ER-positive tumor first is not with estrogen deprivation but with something that eliminates ER physically or functionally—like an independent ER function. So, to me, what those data do is stimulate me to at least find a better SERD, a better down regulator.

Adam M. Brufsky, MD, PhD: And there are some oral SERD trials going on now.

José Baselga, MD, PhD: And I agree with Carlos. I think in my mind, this is a very dynamic time because it is a time of paradigm shift. But in my mind, fulvestrant is the best anti-estrogen we have these days, and the data are beginning to accumulate. The FALCON study, to me, was a big eye-opener. I tend to move it to first-line whenever I can.

Adam M. Brufsky, MD, PhD: So, most people would think about fulvestrant and a CDK—is that what we’re saying?—as first-line therapy.

Carlos L. Arteaga, MD: Several of us have been saying that the better partner for a targeted therapy has been fulvestrant.

Adam M. Brufsky, MD, PhD: Yes. So, then say you progress on that. Now what’s the role of everolimus? I guess it’s called the old one, even though it’s only from 2012. It’s not that old.

José Baselga, MD, PhD: Let’s remember one thing about everolimus: In the BOLERO-2 study that we presented, the hazard ratio was 0.46.

Adam M. Brufsky, MD, PhD: That’s pretty good.

José Baselga, MD, PhD: Now, I think everolimus had the issue and has the issue that it takes expertise in how to use it because mucositis can be a very limiting toxicity and requires people to be very careful. So, I think that if you see physicians who are used to using everolimus, they do an OK job. They don’t get in trouble. It’s all about making sure you check mucositis early on. These are patients who don’t go to clinic 6 weeks later—it’s too late. You need to monitor them earlier. But I think it has a role, clearly. Now, what happens with CDK4/6 is this—it’s a contingent scenario. We don’t know the answer to this, but it does play a role, and I use it all the time, mostly in the second-line setting. I think fulvestrant data are also coming along very powerfully.

Kimberly L. Blackwell, MD: So, I use it quite a bit. The PrECOG study at San Antonio was very helpful in showing this improvement in PFS when you layer everolimus on top of fulvestrant. I will say one thing that’s somewhat clinically relevant: Most of us who use a lot of the drug are using dexamethasone swish-and-spit solutions. Now that has been published in The Lancet, and it significantly reduces grade 3/4 mucositis to single-digit amounts.

But my observation, since I’ve started using it, is that I’m seeing more rash and other side effects because the mucositis usually appeared early, and I would see these patients at 2 to 3 weeks just to see how they’re doing. But now with the swish-and-spit, I’m not seeing the mucositis. And so, I’ve actually pushed the time that I see patients back to about a month. They’re usually coming in for their bone health agent anyway.

But I’m convinced that I’m seeing more rash because before, we would see the mucositis early, and then we would dose-reduce. Now we’re preventing the mucositis and patients are staying on a higher dose. So, you just have to be aware. That’s one thing that fell off my radar screen—the rash. I perceive, as a single investigator study, that we’re seeing more of the rash because we’re not dose-reducing early because of the mucositis.

Adam M. Brufsky, MD, PhD: I’ve always been a fan for dose reduction, I’ve got to tell you. You were in the BOLERO-2 trial; you know it. I don’t know why you picked 10 mg. You could have done 5 mg. We can’t say that: The FDA-approved dose is 10 mg. On the other hand, I’m just not sure that 10 mg was necessary. What are your thoughts on that? I’m really curious.

José Baselga, MD, PhD: We have multiple examples in oncology—clinical trials were done pushing the full dose. Capecitabine would be an example. Everolimus as well. So, I think there is nothing wrong with being very, very eager to go down on the dose because the data between 10 mg and 5 mg are totally unclear. At the end of the day, the proportion of patients who drop to 5 mg occurs at a very high number. So, I would have a very low threshold to go down on the dose.

Adam M. Brufsky, MD, PhD: So, Kim, when your patients get rash, do you drop to 5 mg then?

Kimberly L. Blackwell, MD: Yes. Sometimes I’ll drop to 7.5 mg. It really depends on the grading of the toxicity. Just like with capecitabine, I don’t like to drop it to the lowest level. I like to go down and then see. I do think—I agree with José—that you have to see these patients back. Just like we learned with the CDK4 inhibitors, it’s no different. You can’t just let them run loose for 2 months.

Adam M. Brufsky, MD, PhD: Usually, you’ll have a 2-week appointment after.

Kimberly L. Blackwell, MD: Yes, somewhere between 2 to 3 weeks, although I might be pushing that back a little bit because I’m not seeing the mucositis.

Transcript Edited for Clarity