Kevin Kalinsky, MD, MS: Patients with frontline metastatic HER2 [human epidermal growth factor receptor 2]–positive breast cancer are commonly treated with the CLEOPATRA regimen, which is a taxane plus Herceptin and Perjeta. The way that study was designed is that after 6 cycles or so of receiving a taxane, you have the option of taking the chemotherapy off. That’s the frontline regimen at this point, but other regimens that are being evaluated in that frontline setting, including the role of tucatinib and trastuzumab deruxtecan. But the CLEOPATRA regimen is standard of care.

If a patient has a tumor that progresses on the CLEOPATRA regimen—even with 8 years of follow-up, a subset of patients continue to have a response or stability of disease—the options that happen in the second line include trastuzumab deruxtecan. The DESTINY-Breast03 study, which compared trastuzumab deruxtecan with T-DM1 [trastuzumab emtansine], clearly showed that T-DXd [trastuzumab deruxtecan] for various end points had a favorable outcome compared with T-DM1 [trastuzumab emtansine]. Trastuzumab deruxtecan is commonly our second choice. If you have a patient who’s had a tumor that progresses in the CNS [central nervous system], it’s not unreasonable for that second choice to be tucatinib, based on the HER2CLIMB regimen of tucatinib plus capecitabine plus trastuzumab, given that the triplet was better than the doublet without tucatinib. Those are potential second-line options.

For third line, anything goes. There’s the option of T-DM1 [trastuzumab emtansine] if a patient received prior trastuzumab deruxtecan. I would think about giving tucatinib based regimen, given that T-DXd [trastuzumab deruxtecan] and tucatinib both improved overall survival. We have other tyrosine kinase inhibitors [TKIs] like neratinib and lapatinib, but tucatinib is the preferred TKI. We don’t have much beyond real-world data about sequencing of TKI after TKI, but it’s reasonable in our patients who have CNS metastases because these TKIs can go to the CNS. We have other chemotherapy options. If a patient has a hormone receptor–positive tumor, we have the option of giving antiestrogen therapy along with HER2-targeted therapy. We always continue some form of HER2-targeted therapy with sequencing if a patient progresses on a prior line of HER2-targeted therapy. We also have margetuximab, which is approved as an option for patients after they’ve progressed on multiple lines of HER2-targeted therapy.

Let’s talk through the various agents that we give and things that we should consider. Trastuzumab deruxtecan is an intravenous infusion that’s given once every 3 weeks. The adverse effect that we’re most aware of is interstitial pneumonitis. That rate in the randomized studies—in terms of symptomatic disease and having grade 2 or higher pulmonary issues—was less than 10%, but it’s critical for us to be mindful of. In the early studies, it wasn’t something we were aware of, and some patients passed away. There were other potential adverse effects, like fatigue, gastrointestinal issues, and alopecia. That’s what we think about when we give trastuzumab deruxtecan.

T-DM1 [trastuzumab emtansine] is also targeting HER2, but it’s linked to a different chemotherapy. The adverse effects we see with that agent include hepatotoxicity, thrombocytopenia, and neuropathy, which is 1 of the ... limiting toxicities with that potential agent. Then we have TKIs. The main adverse effect with all of those is diarrhea. When we give tucatinib, it’s given along with capecitabine, which has the potential for gastrointestinal issues as well. The main thing that comes to mind with those agents is gastrointestinal issues. It’s important to think about Imodium or Lomotil and to have it handy if adverse effects develop. With our older TKIs, we see a risk for rash and often must get our dermatologist involved to help us manage those toxicities.

The other thing that I want to mention is that these are HER2-targeted agents, so often we are checking echocardiograms in the clinical studies. Those echocardiograms or MUGAs [multiple-gated acquisition scans] were done every 3 months or so. These agents have the potential for cardiotoxicity, so it’s something to be mindful of when we’re treating patients.

Transcript edited for clarity.