Andrew D. Seidman, MD: After we have a chance to look at this, I will take some of the questions from our attendees. This is a 57-year-old woman. She presents with a left breast mass and palpable axillary nodes. We’re told that she has chronic obstructive pulmonary disease and a smoking history. She’s still an active smoker. Before starting cancer treatment, her physician opted to get pulmonary function tests that showed a mildly impaired diffusing capacity at 83% of predicted. A biopsy of the breast mass showed ER/PR [estrogen receptor/progesterone receptor]-negative, HER2-positive breast cancer. And imaging revealed 2 pulmonary nodules. She had a brain MRI that was negative. She began treatment for her de novo metastatic breast cancer with taxane, trastuzumab, and pertuzumab, followed by maintenance on the 2 antibodies. She responded, as most patients do. She had a complete response in the lung lesions. But then fast forward 10 months, she’s now progressed again in the lungs. And she does receive trastuzumab deruxtecan [T-DXd] as her second-line treatment, as was selected in the poll on a similar case by about 65% of you. Fortunately, she’s had a response now, both in the breast and lung lesion, which is a durable response.

Eighteen months later, she progresses in 1 lung lesion, and she also has a new liver metastasis seen on imaging. Again, first-line therapy with THP [docetaxel, trastuzumab, pertuzumab], maintenance HP [trastuzumab, pertuzumab]. After 10 months, progression. Has a year and a half remission on T-DXd, or trastuzumab deruxtecan. And now, we’re being asked where to go for third-line therapy of metastatic disease. If we can go to the next slide, how would you treat this patient? No. 1, is trastuzumab deruxtecan. Would you keep her on this? No. 2 is, would you switch to tucatinib, capecitabine, and trastuzumab, the HER2CLIMB regimen? No. 3, would you consider neratinib and capecitabine based on the NALA results? Or 4, would you consider the other antibody-drug conjugate, trastuzumab emtansine [T-DM1]? I’ll let you vote. Now, we’re thinking about where to go in the third-line setting for the patient who’s had taxane and HP, maintained on HP, progresses in visceral sites, has a nice year and a half remission on trastuzumab deruxtecan, and now we’re looking at third-line therapy.

This is interesting. This patient, again, had THP and then trastuzumab deruxtecan. Fifty percent, the most popular choice here, is the HER2CLIMB regimen of tucatinib, cape [capecitabine], and trastuzumab. The next most popular choice here is trastuzumab emtansine. Aditya, what do you think? Is this expected, unexpected? Is there a right answer, or is there more than one right answer here?

Aditya Bardia, MD, MPH: I can say that there’s more than one right answer. In the metastatic setting, we use therapies sequentially, and it’s about choosing one therapy. And then in the future, you’d be using the other regimens. I’m not that surprised, given the excitement around HER2CLIMB, there’s a lot of interest in utilizing tucatinib, and maybe that is what prompted the use of trastuzumab, capecitabine, and tucatinib. It’s also interesting to see the use of T-DM1. And on one hand, there could be some cross-resistance between ADCs [antibody-drug conjugates], and this patient who has disease progression on trastuzumab deruxtecan, there could be some cross-resistance to another ADC like T-DM1. But it should also be noted that in general, T-DM1 is very well tolerated. As Mark was saying earlier, patients tolerate T-DM1 very well. It does not cause much myelosuppression except thrombocytopenia, no alopecia, not much nausea. It’s very well tolerated, and it is an agent that should be used in the metastatic setting. I would personally either consider T-DM1 or tucatinib.

Andrew D. Seidman, MD: I want to get Mark and Ruta to also weigh in here on the third-line option for someone who’s progressed after THP and trastuzumab deruxtecan. How might you differentiate between these regimens, Ruta, for an individual patient?

Ruta Rao, MD:In addition to what Aditya said, the main thing is how the regimens are given. Some patients want to take oral therapy with just the trastuzumab infusion every 3 weeks, like the HER2CLIMB regimen. But for some patients, that’s just too many pills to swallow daily, and they may prefer continuing to come in once every 3 weeks for an infusion, especially this case that we’re talking about. This woman was receiving trastuzumab deruxtecan for 18 months, she was used to this routine. That’s something, definitely to discuss with the patient.

Andrew D. Seidman, MD: Mark, if there were new brain metastasis here, do you think the green bar would go up, and would that be a lead choice for you?

Mark Pegram, MD:It would. I think the green bar would be up to 100% if this patient had new brain lesions because now we have level 1 evidence from a randomized phase 3 trial of an overall survival benefit of tucatinib-based treatment with the HER2CLIMB regimen, specifically for HER2+ central nervous system metastasis. Moreover, the FDA label language for the approval of tucatinib specifically calls out those patients with HER2+ breast cancer brain metastasis as patients of particular interest for the tucatinib-based treatment. Brain metastases would be a game-changer in the answer to this question, in my opinion. Otherwise, it’s a data-free zone. I want to point out we don’t have any clinical data post-trastuzumab deruxtecan with either tucatinib-based treatment or with T-DM1. Those data still need to be generated, so I would say that in the absence of brain metastasis, it’s probably a balanced discussion between those 2 and let the patient weigh in on the decision. The other thing about the tucatinib-based treatment is you don’t necessarily need an IV [intravenous infusion] because you can give trastuzumab subcutaneously these days as well. That might be another convenience factor that might sway a patient’s decision, for example. I would argue a balanced discussion between answer 1 and 2.

Andrew D. Seidman, MD: Let’s say this patient at an initial presentation had a staging brain MRI, and she had 1 or 2 brain metastases when she first presented, and they were treated by stereotactic radiation and they remain stable. I want to differentiate here the patient with new progressive brain metastases and then the patient who may have had an earlier brain metastasis event, where they’re simply being monitored and stable. Is that a compelling reason do you think to choose a TKI [tyrosine kinsase inhibitor] over an ADC? Just simply history of treated and stable CNS [central nervous system] metastases?

Ruta Rao, MD:The ADC trials allowed patients with stable brain metastases, whereas the unique thing about the HER2CLIMB trial was that they allowed patients even with progressive brain metastases on it. That’s definitely something to take into consideration.

Andrew D. Seidman, MD: One of the questions, and Aditya or one of you may recall, I don’t know the exact number, what percentage of patients had a history of brain metastasis, recognizing that they had to be stable in DESTINY-Breast03? Does anyone recall?

Aditya Bardia, MD, MPH:Yes. It was about 20%, so 20% of patients in DESTINY-Breast03 had stable brain metastases. I would say in this patient you were referring to, I be very comfortable with trastuzumab deruxtecan because it does have activity even in patients with stable brain metastases.

Transcript edited for clarity.