Ian E. Krop, MD, PhD: Currently, in terms of how we choose our therapies for HER2 [human epidermal growth factor receptor 2]—positive metastatic disease, it’s very clear that for first-line therapy, trastuzumab-pertuzumab, and chemotherapy should be the standard of care, and in second-line, T-DM1 [trastuzumab emtansine]. Again, the data are very clear for those. In third- and later-line settings, the standard of care is really not clear, and based on patient-preference cycling through 1 of the many different chemotherapies that are available is very reasonable. The important point is to continue your HER2-directed therapy, either using trastuzumab or lapatinib.

I should point out that at least my preference, based on the available data, is that single chemotherapies should be preferred rather than doublets. There really are no data to say that using combination chemotherapy in addition to HER2-directed therapy is more efficacious in the long run than using sequential single agents, and definitely using doublets of chemotherapy increases toxicity. I think using sequential single agents makes the most sense, and you can get reasonable efficacy from doing that.

What we’re all excited about is that there clearly are several new drugs that are going to be approved, or are likely to be approved, in that third- and later-line setting. At that point we’re going to have to, as a community, figure out how best to sequence these new agents. But right now, chemotherapy sequentially, along with HER2-directed therapy, should be what we’re doing.

William J. Gradishar, MD: One of the challenges is going to be how to employ all these different drugs that we’re likely to have available to us. Obviously, when you have 2 drugs or 1 drug, it’s very easy decision making; you just use what you’ve got. But if you’ve got 5 or 6 or 7 different things, how do you optimize treatment?

I think 1 of the drivers of decision making is going to be overall survival. When you look at the trials that have been conducted to date, 1 of the reasons we use a taxane, trastuzumab-pertuzumab, as a first-line therapy is that it very clearly has a survival advantage. And that is employed as first-line therapy for most, not all, patients, and T-DM1 typically follows with the same justification. There was a survival benefit that was demonstrated in the trials evaluating T-DM1.

As we go forward post pertuzumab-trastuzumab and T-DM1, we’ll have another group of drugs that I expect to be on the scene soon, and we’ll have to determine whether they offer an advantage over other standard options, which would typically be trastuzumab and chemotherapy de jour, whatever you want to use. And what we’re seeing in the trials that we’ve talked about today is that these drugs have a lot of activity. They’re unique in design, like antibody-drug conjugates or bioengineered trastuzumab, which may more selectively identify certain subsets of HER2-positive disease in which it would be more advantageous to use a drug like margetuximab. And there may be patients for whom you select a certain drug based on where their disease is. If somebody has CNS [central nervous system] metastases, use tucatinib if you have it available.

I think part of the decision making is going to be based on characteristics of the patient and what they’ve received in the past, and applying the menu of drugs you have available to that given patient. The other thing that’s going to impact this is that so many patients are getting, based on the APHINITY trial, pertuzumab and trastuzumab in the adjuvant setting, and that may dictate what comes first. It may not be pertuzumab and trastuzumab if they develop metastatic disease.

If somebody gets preoperative therapy with trastuzumab and pertuzumab but happens to have residual disease, they’re going to get T-DM1. So if they relapse quickly, they’ve already gotten 3 of the most active drugs. You may make a decision not to go back to them but use 1 of the newer drugs. It’s going to be an issue where the clinician has to look holistically at what the patient has gotten, what the time frames are, and what the clinical situation is: brain metastases, no brain metastases, or other comorbidities that may determine what the best choices for that patient are when they develop metastatic disease.

Sara A. Hurvitz, MD: It’s going to be very interesting to see how the sequencing and management of HER2-positive metastatic breast cancer changes in 2020, because I believe we saw some real practice-changing data emerge at the end of 2019. I do believe we are going to have tucatinib and DS-8201 [trastuzumab deruxtecan] available very shortly. So a natural question is, how do we utilize this in our standard-of-care practice of patients with metastatic breast cancer? We’ve not yet seen data that pushes out frontline use of THP [paclitaxel, trastuzumab, pertuzumab], and I believe that remains the standard regimen in the first-line setting; nor have we seen data that should push out T-DM1. Both of those regimens and therapies have been supported by phase III randomized trials that have shown survival benefit. Keeping in mind, the frontline therapy of THP is now associated with an OS [overall survival] of 5 years almost, so I don’t think we have good enough data yet to bump that regimen. We need to actually go head-to-head in a trial before we do so.

Where it gets a little dicier and is less backed by evidence is, if we have both tucatinib and DS-8201, how do we choose our third-line regimen, our fourth-line regimen? I think many of us will utilize the CNS metastases data that we saw and that will continue to emerge from HER2CLIMB. I would be compelled to probably sequence tucatinib earlier in a patient who has CNS metastases. But if a patient has a lot of disease in their body and I really need a response, I might use DS-8201 earlier, given that objective response rate was so high. It was especially high if you look at the subgroup of DESTINY-Breast01 patients who had fewer than 3 lines of therapy, where there is now greater than 70% objective response rate. The truth of the matter is, all our patients are going to receive both these therapies ultimately when their disease progresses. So we don’t have data to tell us that 1 way is right for every patient who is having disease progression.

Transcript Edited for Clarity