HER2+ mBC: Impact of T-DM1 and T-DXd Beyond the Frontline Setting

Shared insight on the roles of trastuzumab emtansine and trastuzumab deruxtecan in relapsed/refractory HER2+ metastatic breast cancer.

Vijayakrishna Gadi, MD, PhD: I’m going to transition us to a different phase of the discussion that’s focused on treatment beyond the first line. Let’s say this patient who we just discussed gets good mileage out of this—3, 4 years of stable time. We’re up to the second line because of some progression event. Maybe we have a ton of agents to talk about in the second line and beyond. I’ll start with Michelle. Can you go through some of the things that have caught your eye? How is KATHERINE affecting what we might do in the second line? Just update us on what we’ve learned from EMILIA and the mechanism actions of some of the things we’ve been doing for years in that second line.

Michelle Melisko, MD: Obviously, KATHERINE has had 1 of the greatest impacts on clinical practice of early stage HER2 [human epidermal growth factor receptor 2]–positive breast cancer since the approval of Herceptin and Perjeta years ago. Everyone knows the structure of this trial: patients who had residual disease after neoadjuvant chemotherapy were randomized to continue on trastuzumab or get T-DM1 [trastuzumab emtansine], and the use of T-DM1 [trastuzumab emtansine] resulted in an 11% reduction in invasive disease-free survival at 3 years. That’s a pretty dramatic outcome and improvement for those patients with HER2-positive breast cancer who didn’t achieve a pathologic complete response with their neoadjuvant chemotherapy.

Recognizing that there will be a larger population of HER2+ patients who’ve been exposed to T-DM1 [trastuzumab emtansine] or Kadcyla in the post-neoadjuvant and adjuvant setting, we wonder how effective Kadcyla will be in the metastatic setting. Until the last couple of years, the first line would be the CLEOPATRA regimen. Upon progression patients would go on Kadcyla under most circumstances based on the EMILIA trial, which randomized Kadcyla to lapatinib and capecitabine and found that Kadcyla was superior with about a 4-month advantage in terms of progression-free survival.

Now we have the data that compares Kadcyla and HER2 with trastuzumab deruxtecan in the second-line setting, showing that trastuzumab deruxtecan has phenomenal efficacy with the median time to progression and progression-free survival not reached. This is going to be a game changer in our practice. It’s going to get harder and harder to identify patients for these trials because if we carry things out, and we expect that we’re going to get 2 to 2½ years of stability with first-line treatment. In the second-line treatment, the new standard is likely going to be trastuzumab deruxtecan. Those patients may get another 2 to 3 years.

What’s next? To leave some other trials to talk about the data on tucatinib and HER2CLIMB. Going back to what Nancy said before, it’s about the role of CNS [central nervous system] imaging for these patients. In my experience, where we fail—at least in the CLEOPATRA taxanes and dual HER2-targeted antibodies—is in the brain. That’s often a good first line of progression. We’re very excited about the potential for trastuzumab deruxtecan to have some CNS activity. We know that tucatinib does, but it’s going to be a big question: how do we image the brain other than having a very low threshold, as Nancy mentioned? I have a bunch of patients who are really pushing, they want their brain MRI every 6 months, and I usually acquiesce. I’ve had patients who are percolating along, doing great, and then they call in with slight dizziness. I had someone last week with a 5-cm brain metastasis who showed up with her only presentation—a little dizziness. My staff wanted to give her some meclizine and tell her she had an inner ear infection. I was like, “No, you have to get an MRI.” I have a very low threshold. That’s where challenge like remains.

Charles Geyer, MD, FACP: It’s amazing how variable symptoms are between patients with different volumes of disease in those cases, and that’s what’s so concerning about it. You’ll have people come in with relatively minimal symptoms. It’s like, “Ha.” When you’re doing that every 6 months, Michelle, are you talking about your patients once they develop recurrent disease? Even if they’re systemic only and it’s looking good, you’re still saying you check the MRI every time? I don’t think that’s unreasonable at all.

Michelle Melisko, MD: It’s obviously not guideline driven. Nancy mentioned this trial in Toronto. We’re going to pick up more brain metastases, and then that’s going to set people out on a screening every 2 to 3 months. It’s not going to be very cost-effective, but it may improve people’s quality of life to not have to go through, obviously, whole-brain radiation or to have a big brain metastasis resected. I’m not dogmatic about it, but I have 5 or 6 women who have prolonged stable disease systemically on HER2-targeted therapies, and I order it at intervals of about every 6 months. Of course, as Nancy said, there’s a very low threshold to order a brain MRI on any HER2+ patient and triple-negative patient that shows up with a subtle neurological symptom.

Transcript edited for clarity.

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