Virginia Kaklamani, MD, DSc: For the agents that we have in the third- and fourth-line settings, I’ll divide them into 3 different groups. We have tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib. Of those, tucatinib is the 1 more targeted toward the HER2 [human epidermal growth factor receptor 2] compared with the other 2. That’s why it has the least toxic profile compared with lapatinib and neratinib. All 3 agents can cause some diarrhea, with tucatinib causing less. We combine these agents with capecitabine. With tucatinib we’re also going to add trastuzumab; that’s a triple drug combination. Capecitabine can also cause diarrhea. When you combine 2 agents that are prone to causing diarrhea, you’re going to increase the risk of diarrhea in this patient population. Those are tyrosine kinase inhibitors, which means they work on the tyrosine kinase domain of HER2 and block HER2 that way.

The second category is antibodies. Here we have trastuzumab, pertuzumab, and margetuximab. Typically, pertuzumab is being used in the first-line setting. We also have trastuzumab or margetuximab in combination with chemotherapy. This is where we’re going to think about cardiac toxicity. Trastuzumab can cause a lowering of the ejection fraction, so we’re going to check the cardiac function. But with the types of chemotherapies that we pair trastuzumab with, the risk of cardiac toxicity is low.

Finally, we have antibody-drug conjugates, such as T-DM1 [trastuzumab emtansine] and T-DXd [trastuzumab deruxtecan], which work in the sense that they have the trastuzumab-based antibody but also a payload, a toxin, on them. This payload is released into the cancer cells…and the surrounding cancer tissue. That’s the main reason antibody-drug conjugates work: because of the payload associated with the antibody.

The major toxicity from T-DM1 [trastuzumab emtansine] is thrombocytopenia, but the major toxicity from T-DXd [trastuzumab deruxtecan] is nausea. The toxicity from T-DXd [trastuzumab deruxtecan] that we all talk about is interstitial lung disease [ILD], which is seen in 10% to 15% of patients receiving T-DXd [trastuzumab deruxtecan]. That’s because it’s the 1 that worries the most. And it can happen early, within 3 to 4 months and as late as 11 months or so after treatment. Our patients have to be aware of that potential toxicity so we can identify it early, stop the medication, and treat the patient appropriately. Depending on what the grade of ILD is, we may then be able to restart the T-DXd [trastuzumab deruxtecan].

When we try to decide which treatment to give our patients in the third-line setting—assuming that in the first-line setting they’ve received THP [docetaxel, trastuzumab, pertuzumab] and in the second-line setting they’ve received T-DXd [trastuzumab deruxtecan]—we’re looking at oral agents, such as tyrosine kinase inhibitors and antibodies in combination with chemotherapy. We have to look at whether we think a patient can reliably take oral medications and if that patient is able to call us if there are adverse events from these oral medications. If we think something is appropriate for the patient, I favor tucatinib as my third-line option because of the overall survival benefit that hasn’t been seen with margetuximab, for example. Some patients would rather have IV [intravenous] medications. Others would rather come to the office. Physicians would rather know that they’re able to give the medication—when they’re giving it, how the patient is receiving it, and so forth.

Another consideration is alopecia. Some of the agents that are going to be given in combination with chemotherapy can cause alopecia. For example, we’re picking trastuzumab in combination with a taxane. Assuming the patient is on this regimen for a while, they’re likely going to develop alopecia. But if we give them tucatinib and capecitabine, they are not likely going to lose all their hair but may have some hair thinning. This is extremely important, and that’s why we discuss the options with patients. We discuss the adverse events associated with each regimen, and we let our patients decide what they think they want to do next.

Something else that’s important is the disease burden that we’re dealing with. If there are brain metastases, especially active brain metastases, I’d favor tucatinib because that’s where the data are very strong. If a patient has high-volume disease and I need an agent that’s going to give me a quick response, I may pick tucatinib. But if there’s a patient who’s prone to developing diarrhea, I likely won’t use a tyrosine kinase inhibitor. I might use an antibody plus other chemotherapy. A lot of factors play into this decision, and this is a conversation that we have for patients.

Transcript edited for clarity.