Kevin Kalinsky, MD, MS: There are several factors when we think about treatment [for metastatic breast cancer]. What is a patient willing to accept? Is a patient willing to accept the potential for alopecia? Does the patient have a preference of an oral pill? I have some patients who live hours away or outside the country, so coming in to get infusions is a challenge. Those are some factors. What is the patient willing to accept? Some patients have a prior history of pulmonary disease, like ILD [interstitial lung disease]. I have a patient who has HER2 [human epidermal growth factor receptor 2]–low disease and had CDK4/6 inhibitor pneumonitis, and we’ve been concerned about giving her trastuzumab deruxtecan. Not that it’s the same mechanism of action, but this is a patient who has required oxygen utilization, so it’s something to be mindful of. If the patient has neuropathy, do we want to expose them to T-DM1 [trastuzumab emtansine] at that point? Or do we give them something else that keeps the disease at bay and gives a little time before introducing another potentially neurotoxic agent.

The other thing is about CNS [central nervous system] disease. Some of the monoclonal antibodies that we give include pertuzumab. Given that they’re bulky agents, I don’t know how well they penetrate to the CNS. With a tucatinib-based regimen and other TKIs [tyrosine kinase inhibitors] we have clear data that you can have good CNS penetration. That’s 1 thing that may lead me to give a TKI earlier. We have interesting data that have been published with trastuzumab deruxtecan. This also has CNS activity. Its payload is a topoisomerase inhibitor, and that’s a class of agents that can have good activity within the brain. This has been shown in specific cohorts of patients with CNS metastases. Those are some of the considerations that we think about when we’re deciding our next step for a patient.

In that second line, do we use trastuzumab deruxtecan or the HER2CLIMB regimen, with tucatinib capecitabine, and trastuzumab? The factor that leads me to use T-DXd [trastuzumab deruxtecan] is a patient who has a significant visceral disease and needs a remarkably fast response. The response rate with that agent is fast, durable, and impressive. If I have a patient with several liver metastases or symptomatic lung disease, it’s clear that I should think about using trastuzumab deruxtecan. If I have a patient who’s young and needs whole-brain radiation therapy, I don’t love giving whole-brain radiation therapy to a patient unless she or he really needs it. There are data from the HER2CLIMB regimen that show that giving this regimen could delay the initiation of radiation therapy. There was a subset of patients who had active untreated brain metastases. We have clear data in that context, so that makes sense. In the HER2CLIMB regimen, 50% of patients had brain metastases, which is a large population, and overall survival advantage was seen across the entire population. We have large data for patients with HER2 metastases. I tend to use the HER2CLIMB regimen. I have colleagues who use trastuzumab deruxtecan, even for patients with brain metastases because of the ease of every-3-week infusions. We have larger, more robust data with the triplet combination with tucatinib. That’s why I favor doing that.

The other caveat is the patient’s history. If they have significant gastrointestinal issues, I lean toward trastuzumab deruxtecan. If they have significant pulmonary issues, I lean toward a tucatinib-based regimen. It’s important to reiterate that it’s a question of what you sequence first. Hopefully, patients get second line and then go on to get third line. There are other studies…looking at the combination of the 2. We have a lot of agents at our disposal, and sometimes the patient or patient preferences help define the sequence of those drugs.

Transcript edited for clarity.