Hope S. Rugo, MD: One of the questions is the order of therapy and how we would choose different treatment options. Let’s briefly hear from you how you have put these in. Assume that tucatinib and margetuximab are approved, and we've given pertuzumab in the adjuvant or neoadjuvant setting, or somebody's in the de novo metastatic setting and they've gotten both pertuzumab and T-DM1 [trastuzumab emtansine]. Of course there are patients who will have received both pertuzumab and trastuzumab emtansine in the adjuvant setting now who will get to the metastatic setting. How would you choose 1 agent to use and what sequence? Then we'll hear how the payers actually look at that. Tiffany, do you want to briefly comment on that? Why would you choose which agent in which setting?

Tiffany A. Traina, MD: From Claudine’s presentation and from what I've been thinking about, we should be looking at the tucatinib data. Obviously, we'll need to see what that label looks like and what line of therapy we'd be looking at. But the fact that there is benefit to using tucatinib and it's an overall survival benefit not limited to patients with brain metastases—there could be benefit for anybody with that prior exposure HER2-positive disease at least in the third-line setting—I lean toward the tucatinib. Although, we have to remember that’s in combination with capecitabine, in combination with trastuzumab. Despite the fact that the DS-8201, trastuzumab deruxtecan, has such a beautiful waterfall plot, it is really a single-arm, nonrandomized presentation.

I think there's great activity there, but that is balanced with the ILD [interstitial lung disease] concerns. So with the available drug before me, recognizing many of these women will have seen pertuzumab and likely trastuzumab emtansine, I lean a bit toward that overall survival advantage from tucatinib. It would be wonderful to see a time when perhaps tucatinib is able to minimize the development of brain metastases even more so than being able to treat it once they're present.

Hope S. Rugo, MD: That's a good point, and I think that was very clever of them to add trastuzumab to the combination, which my guess is it really made a difference in their ability to see large differences in overall survival with an antibody component. Priyanka, how about you? How would you use these and in what order?

Priyanka Sharma, MD: Assuming that we're making a choice in third-line setting and we have all the drugs available, another factor that would come into play would be oral versus intravenous administration, multiple drugs versus single agent, and previous risk of interstitial lung disease with other drugs in the past. That would play into the decision-making; presence of brain metastases even if they're controlled. But having a phase 3 trial that shows a survival advantage obviously makes a difference in that choice. The other factor is the DESTINY-Breast01 trial included patients that were heavily pretreated, so I would feel comfortable using the tucatinib combination in third-line setting and save trastuzumab deruxtecan for later lines of therapy since the trial population included heavily pretreated patients.

Hope S. Rugo, MD: Claudine, do you feel the same way?

Claudine J. Isaacs, MD: I do. I feel exactly the same as my esteemed colleagues here. And I guess the only thing that I would add now is occasionally we have those patients who for reasons that we don't understand have blown through all of these other treatments very rapidly. I think one of the things that really impressed me with the DESTINY-Breast01 trial was the responses that were seen in patients who’d had a lot of prior treatments and the rapid response.

In those patients where we feel we need to slam the brakes on and we don't have much time, that might be a patient population where I might move this drug up. But otherwise I think based on the phase 3 data, the survival, the benefit with brain metastases or not, I would use tucatinib as my third-line drug for the vast majority of patients.

Hope S. Rugo, MD: There are always those patients who don't tolerate capecitabine for a variety of genomic reasons. John, now we're coming back to the same area again about the oral therapy versus IV [intravenous]. This is in regard to share of cost and how we decide. If there are a lot of different treatment options available, where does the insurer fall in in terms of trying to help us and also decide what's going to be reimbursed?

John Fox, MD, MHA: First of all I'd say, especially in these late-line therapies, that the number of patients who are going to receive these therapies is relatively small in comparison to first-line therapies. Certainly, we'd prefer regimens that are replacement therapies versus add-on therapies, so instead of a 3 drug versus 2 drug, a 2 drug versus 2 drug. I was particularly interested in the HER2CLIMB study with tucatinib. This is very reminiscent of the non—small-cell lung cancer space where osimertinib, which was a second- and third-generation TKI [tyrosine kinase inhibitor] for patients who had EGFR mutations, not only treated brain metastases but also reduced the likelihood of the development of brain metastases and was subsequently approved as a first-line therapy.

We'll see if tucatinib makes that same progression from third-line to earlier-line therapies. Interestingly and just by way of analogy, in our OCM [Oncology Care Model] practices when providers are presented with that data and shown the prices of osimertinib versus erlotinib, they said, “This drug is so much better that we're going to use this even though it's costlier.” But another example is in a ROS1 mutation in non—small-cell lung cancer when comparing crizotinib and ceritinib, they said, “There is a cost difference, but we don't think there is an outcome difference, so we’re going to use the lower cost therapy.”

That’s how providers are reacting to some of these data. To go back to your question, as long as it's being used consistently with the FDA label and the NCCN [National Comprehensive Cancer Network] guidelines, there is going to be access to these therapies especially given the fact that most of these drugs, because they're new, don't have long-standing data. So we're going to defer to the oncologists in deciding which ones to use.

Hope S. Rugo, MD: That's music to our ears in many ways.

John Fox, MD, MHA: Frankly, we can't even pronounce the names of most of these drugs, let alone decide where to use them, so I think we’re going to defer to the NCCN guidelines. Unlike most guidelines, the NCCN guidelines are kept very up to date.

Hope S. Rugo, MD: This has been an interesting discussion. I think it highlighted some of the tremendous advances that we’ve seen in HER2-positive disease. And of course we're all very interested to see how this moves into the early stage setting, and how some of the very active drugs move earlier in the course of therapy to try to reproduce what we saw when we first started using trastuzumab, where we were curing patients with incurable disease.

That still remains an expansion area. And of course trastuzumab deruxtecan is being tested in patients who have a previously undefined subset of disease or HER2-low, IHC [immunohistochemistry] 1+ and IHC 2+, mainly ER [estrogen receptor]-positive but a small subset of triple-negative disease, in an ongoing randomized phase 3 trial. That's going to also provide us with a lot of interesting data in another group of patients all together for the first time.

Transcript Edited for Clarity