Sara A. Hurvitz, MD: It’s very well established that sequencing should be paclitaxel, trastuzumab, pertuzumab in the frontline setting for HER2-positive metastatic breast cancer, and in the second line, trastuzumab emtansine. The sequence is established based on well-developed, well-run phase III randomized trials that showed a significantly improved progression free survival [PFS] and also overall survival compared with standard therapy at the time. After that, it really is a mishmash of choices, and of course we take into consideration the hormone receptor status of the tumor and the patient’s performance status and comorbidities when making a treatment recommendation in the third-line setting and beyond.

I personally really like trastuzumab and vinorelbine, a very old-fashioned regimen that has great efficacy. I’ve had patients take this regimen for years without having disease progression or needing to hold therapy for toxicity. It tends to be very well tolerated. Capecitabine-based regimens, as well, in combination with trastuzumab or lapatinib are certainly appropriate and are easier for patients because of the toxicity profile and lack of hair loss. And then any chemotherapy as a single agent that’s standardly used for breast cancer can be paired with a HER2-targeted agent.

Joyce O’Shaughnessy’s data looking at trastuzumab and lapatinib together are compelling in the later-line setting. We certainly have data to support pairing of endocrine therapy with HER2-targeted therapies as well in the later-line setting. I think through most of 2019, that was our standard regimen available. We have new data coming out that I think are going to define beyond the second-line setting even further for us.

William J. Gradishar, MD: In patients with first-line metastatic disease, we typically use a CLEOPATRA-like regimen, which means we’re going to be using early on trastuzumab and pertuzumab with a taxane. Among those are patients who ultimately developed a progression of their disease, because we’re not curing those patients. At the time they do develop progression of disease, the question then becomes, “What do we do with them?” And in that situation, if they haven’t received T-DM1 before, that’s generally viewed as the standard second-line therapy.

There are patients where, if they had received preoperative chemotherapy in an earlier stage setting and had residual disease, it’s conceivable that at that point they’ve already had pertuzumab and trastuzumab, and then they’re going to get T-DM1 [trastuzumab emtansine]. At some later date, if they develop metastatic disease, the question then becomes how do we go about treating them? If the distance between the prior therapy and the development of metastatic disease is fairly long, I think the slate is generally fairly clear, and you could consider any of those agents again.

Typically, if somebody has already been through pertuzumab and trastuzumab, as well T-DM1, it’s very much the Wild West in the sense that there isn’t a clear recommendation right now. We’ll talk, I’m sure, about what the next line of therapy would be. And as a result, if you look at guidelines, what you see is that a number of different chemotherapy drugs could be combined with trastuzumab, and there are also older regimens that are still viable options, including lapatinib and capecitabine, or even in certain situations lapatinib and trastuzumab. There are many different options, and it’s a choice in many ways among equals. When talking to or evaluating a given patient, decide what their comorbidities are and what their preexisting toxicities that continued from prior therapy are, then look at what your options are, and decide what’s best for that patient.

Ian E. Krop, MD, PhD: Clearly the introduction of HER2-directed therapy, such as trastuzumab, pertuzumab, and T-DM1, has greatly improved the outcomes of patients with HER2-positive metastatic breast cancer. Right now, the standard of care for first-line patients is a taxane with trastuzumab and pertuzumab based on the CLEOPATRA data. That study showed substantial improvements in progression-free and overall survival with relatively modest increases in toxicity by adding pertuzumab to a chemotherapy and trastuzumab regimen. That, in my mind, is the clear standard of care for first-line patients.

In the second line, similarly, the EMILIA trial demonstrated the superiority of T-DM1 over capecitabine and lapatinib. Therefore, T-DM1, which is typically quite well tolerated in the metastatic setting, in my mind is the standard of care in the second line.

In the third line and later, there really is no clear standard of care. I think the take-home message in that setting is that it’s important to continue the HER2-directed therapy, either trastuzumab or in certain cases lapatinib, in addition to chemotherapy. In general, I don’t think there’s a strong preference for 1 chemotherapy over another, and I typically leave that up to patient preference. Drugs like capecitabine, gemcitabine, vinorelbine, and eribulin all make good partners for trastuzumab. Capecitabine and lapatinib also is an option as well. You can use trastuzumab with lapatinib in select patients. Endocrine therapy plus HER2-directed therapies is also an option for those patients who are estrogen receptor positive as well as HER2 positive. But generally we just rotate the chemotherapies and continue the HER2-directed therapy. Unfortunately, the efficacy of those regimens is relatively limited and new therapies are definitely needed for that third- and later-line setting, where there is not a clear standard of care.

Transcript Edited for Clarity