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To summarize, I consider HER2 TKIs to be a very reasonable choice for treating patients with HER2-positive MBC in the third-line setting and beyond. The neratinib data are interesting and the tucatinib data are particularly strong. The ADC, trastuzumab deruxtecan, is a major new therapy in the third-line setting, and I suspect it will likely move to earlier settings. These earlier settings could include the postneoadjuvant setting where T-DM1 is now the standard of care; the second-line therapy for residual disease (DESTINY-Breast03); and treatment for HER2-low disease (DESTINY-Breast04). The benefit of margetuximab is unclear, but it may be of use in patients who are CD16A-158F carriers.
Nurses and pharmacists play key roles in the multidisciplinary team caring for patients with HER2-positive MBC, particularly regarding managing and counseling patients on toxicities. Of the therapies we discussed here, there are 2 with important AEs of interest: the pan-HER TKI neratinib, which is associated with diarrhea; and T-DXd, which is associated with ILD.
The diarrhea associated with neratinib can be quite severe and lead to treatment discontinuations. However, it is manageable with dose escalation of neratinib and prophylactic antidiarrheals (ie, loperamide with or without budesonide or colestipol); these preventive strategies markedly reduced the incidence of high-grade diarrhea in patients receiving neratinib.[17,24,25]
The ILD associated with T-DXd can be fatal, which is why it is important to counsel patients on prompt reporting of respiratory symptoms (eg, cough, dyspnea). However, we have effective toxicity management algorithms in place that rely on monitoring, starting steroids immediately upon suspicion of ILD, and, depending on grade, either holding treatment, modifying the dose, or discontinuing treatment.
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