Advanced Breast Cancer - Episode 9

Advanced HER2+ BC: Phase III HER2CLIMB and DESTINY-Breast01


Debu Tripathy, MD: Let’s start by discussing your impressions and thoughts of the tucatinib study. That’s obviously the 1 that’s closest to changing practice. It’s a registrational phase III trial. Adam, do you want to start?

Adam M. Brufsky, MD, PhD: Clearly it will change practice. I think the biggest difference for tucatinib and neratinib—let’s not forget about neratinib—in terms of the IC50 [half maximal inhibitory concentration] for the...tyrosine kinase, they are about the same. The nice thing about tucatinib is because it’s not EGFR specific at all—you can really increase the dose. If you increase the dose in the phase I to the point where they can get penetration in a lot more areas than neratinib. That’s the biggest difference between the HER2CLIMB trial and the NALA study, which should show a benefit as well.

They probably both are equally potent in terms of preventing or at least preventing and treating brain metastases. However, 1 is a lot less toxic, and because you can give that a longer time, that’s probably why you saw the survival benefits. Clearly, it’s likely going to change practice. The issue is, when is it going to be approved? Remember, breast cancer is a global problem. While it will probably be approved quickly in the United States—we’ll probably be able to get it within the next 6 to 9 months—who knows when it will be available around the world.

We still have lapatinib and we have neratinib, which have likely been approved in other countries for at least extended adjuvant therapy. Don’t forget about those. Even though this probably will change the standard of care around the world, it likely will be a slow process. For me, I think that it will be 1 of my go-to third-line regimens when it’s approved, absolutely.

Joyce A. O’Shaughnessy, MD: Yeah, I totally agree. I think it’s a game changer. Because of the survival advantage, I think it will be positioned in my practice right after T-DM1 [trastuzumab emtansine], where I used to use capecitabine and trastuzumab. Not uncommonly there, it will be with tucatinib. Though the patients with brain metastasis did very well, and some of them had multiyear improvements in their brain, the trial was positive for survival in the overall population. It really is for the entire patient population. I think it’s going to be my go-to regimen right after T-DM1.

Adam M. Brufsky, MD, PhD: But Joyce, the question I ask is, was that overall survival benefit driven by the brain metastases population?

Debu Tripathy, MD: Well, it turns out that…

Adam M. Brufsky, MD, PhD: In the nonbrain metastases as well, but I mean it’s…for everybody, I get that.

Debu Tripathy, MD: The analysis, it showed for PFS [progression-free survival], it definitely did. They didn’t show survival specifically for the brain group.

Adam M. Brufsky, MD, PhD: I don’t know the answer. I’m just asking, I’m raising it.

Hope S. Rugo, MD: What they showed was the overall survival, not PFS in brain, that’s going to be at a later date. But it was overall survival in people who entered the study with a history of or active brain metastasis. That group had improved overall survival. We don’t actually know what the activity is in the brain, but it certainly suggested that it must be doing something if those people are living longer than if they got capecitabine and trastuzumab.

Adam M. Brufsky, MD, PhD: But how do people die of this disease? How do they die? They die of brain metastases usually.

Hope S. Rugo, MD: Mostly they do. It’s going to be helpful to know what the data are, and we’ll see that soon, I believe. I think survival turns out to be the gold standard, after all. It’s an easy end point relative to PFS. The fact that they show survival benefit—interestingly, a survival benefit that’s greater than the PFS benefit. It really has a bigger impact, which is so interesting because I think of that as an antibody-mediated effect. There’s some interaction between trastuzumab and tucatinib here that has to be driving that differential. I’d go with Joyce. I think a survival benefit wins, and I would go with that as next therapy.

Obviously, there are people who can’t tolerate capecitabine and people who won’t be able to tolerate tucatinib. I’m sure a small percentage. Although I have to say, the discontinuation rate was really low so it’s a great option.

Debu Tripathy, MD: It was low...obviously.

Hope S. Rugo, MD: Then we still have the trastuzumab deruxtecan which I say differently than you.

Adam M. Brufsky, MD, PhD: I like TrasD [trastuzumab deruxtecan].

Hope S. Rugo, MD: T-DXd [trastuzumab deruxtecan] actually works well. That drug is going to be really interesting. Having had a patient now on it for longer than she was on T-DM1 in that same phase II trial, it’s going to be an important option for patients. Although the lack of survival benefit, we’ll probably use it next line; it’s going to move up relatively quickly. It will be interesting to see what we find.

Ian E. Krop, MD, PhD: Actually, the FDA has given trastuzumab deruxtecan a priority review.

Adam M. Brufsky, MD, PhD: Correct.

Ian E. Krop, MD, PhD: So it actually may be available…

Adam M. Brufsky, MD, PhD: I’m talking more about tucatinib.

Ian E. Krop, MD, PhD: Right. No, I’m saying they both may be available soon.

Adam M. Brufsky, MD, PhD: I’m not sure about the tucatinib.

Hope S. Rugo, MD: We’ll have to figure out order.

Ian E. Krop, MD, PhD: Yeah, right. So tucatinib.

Adam M. Brufsky, MD, PhD: Definitely the TrasD yes.

Ian E. Krop, MD, PhD: Right. Good, we’ve coined a new name.

Hope S. Rugo, MD: TrasD? Yeah. It has 4 names already.

Adam M. Brufsky, MD, PhD: It has 4 names…

Ian E. Krop, MD, PhD: I think the brain metastasis obviously is an issue. In the trastuzumab deruxtecan study, patients who had higher brain metastases still had very good response rate and very good progression-free survival. But those were treated brain metastases, whereas with the HER2CLIMB study there was a mix. My clinical experience is that there are 2 kinds of patients with HER2 [human epidermal growth factor receptor]—positive brain metastases. One are the patients who have a few lesions that show up in the first year or 2 of their disease. You do SRS [stereotactic radiosurgery], and you never hear from them again in terms of brain metastases. Then you have the patients whom you treat it with SRS, and 6 months later they have another 1. You end up with whole brain, which you try to avoid, yet their brain becomes…

Joyce A. O’Shaughnessy, MD: Leptomeningeal.

Adam M. Brufsky, MD, PhD: That’s how they die. They die of dementia from the whole-brain leptomeningeal, right.

Ian E. Krop, MD, PhD: Right. But there are patients who never get brain metastases, and there are patients for whom their brain metastases aren’t a clinical issue. For those patients, my guess is I’m going to lean more toward doing trastuzumab deruxtecan because of the very high response rate and long progression-free survival. There are 2 randomized trials that will hopefully report out relatively soon, and we can look at it those data too. As the data mature for both trials, it will help us to hear how to sequence these. But the bottom line is, we’ll be using both drugs for our patients.

Adam M. Brufsky, MD, PhD: The bottom line is, we’re excited about third-line and beyond therapy. I mean, that’s with survivals. When would we ever think we’d be talking about this?

Debu Tripathy, MD: We have a wealth of drugs.

Transcript Edited for Clarity