Andrew D. Seidman, MD: After this patient completes the taxane, trastuzumab, and pertuzumab regimen that 90% of you chose, either doce [docetaxel], or pacli [paclitaxel], she was maintained on her trastuzumab and pertuzumab. And then after a year, while on maintenance HP [trastuzumab, pertuzumab], she experiences some growth of the breast primary, which was still in place, and in liver lesions. I’m going to ask our audience to vote on their second-line treatment choice. The first option is trastuzumab deruxtecan. The second choice is tucatinib, capecitabine, and trastuzumab. The third choice is neratinib and capecitabine. We didn’t talk about the NALA trial, and maybe we’ll revisit that. Or trastuzumab emtansine [T-DM1] as the fourth choice. Again, this patient has been on just dual antibodies for a year after a nice remission, and now she’s progressing in the breast primary and in the liver. And we are being asked where to go from here. I remember before we even had ADCs [antibody-drug conjugates], the question would be to resume the chemotherapy that you started with, once upon a time, or add a different chemotherapeutic agent onto your maintenance antibody therapy. Here, I’m going to consider this to be mature results. Let me see if the numbers are changing. More than half of responders would choose trastuzumab deruxtecan. About 10% chose the HER2CLIMB regimen of tucatinib, cape [capecitabine], and trastuzumab. It’s our fault for not calling out the NALA trial, and we can discuss that in our comments here, but nobody chose neratinib and cape [capecitabine]. And about a third chose trastuzumab emtansine. Aditya, do you want to offer some thoughts on these responses?

Aditya Bardia, MD, MPH: Yes. I would say as of a month ago, I would have considered T-DM1 the standard of care. And as per guidelines, in the second-line setting in a patient who’s had disease progression on THP [docetaxel, trastuzumab, pertuzumab] is T-DM1, and that’s based on the EMILIA results. Now, with the DESTINY-Breast03 results, where we’ve seen an improvement in both PFS [progression-free survival] and a trend toward OS [overall survival] with trastuzumab deruxtecan, and with the results being positive, there’s an inclination to consider this drug. It should be noted that at this time, the drug is not FDA-approved for this indication. But yes, we have the drug available. And for this individual patient, if you don’t want to wait for the FDA approval, which likely will happen over time, it’s not wrong to consider trastuzumab deruxtecan. In terms of the other options, tucatinib based on HER2CLIMB, that’s reasonable as well. And in terms of approval of tucatinib, it is in the second-line and beyond setting, so one could use trastuzumab, tucatinib along with capecitabine. Then finally, neratinib plus capecitabine, that’s based on the NALA trial that looked at capecitabine, lapatinib, the same control arm that was used in EMILIA, versus neratinib plus capecitabine, and showed an improvement in progression-free survival, which led to the approval of neratinib. But the incidence of diarrhea was high with the use of neratinib, and that is an adverse effect that we see with neratinib. And maybe that’s why the usage, at least in this setting, is not high. But it is an agent that could be considered in later lines.

Andrew D. Seidman, MD: Mark, I know that the DESTINY-Breast03 data are fresh. Do these results surprise you? Would you have expected a different polling result?

Mark Pegram, MD: No. I don’t necessarily say that I would expect a difference. Even though the ESMO [European Society for Medical Oncology] data are new, it may well be that the doctors who chose T-DM1 in this instance are looking at the patient’s age. Perhaps this patient has comorbidities, comedications, etc. And the therapeutic index of T-DM1 is especially high. It is a very well tolerated antibody-drug conjugate, whereas trastuzumab deruxtecan certainly has a lot of chemotherapy-like adverse effects in contrast to T-DM1. There’s more nausea, vomiting, fatigue, cytopenias. You would have to inform this patient to expect a lot more chemotherapy-like toxicities in the case of trastuzumab deruxtecan versus T-DM1, and in a balanced discussion, make the patient aware of not only the strengths of the DESTINY-Breast03 data, but also the toxicities. And the same is true for the discussion of T-DM1. In a balanced discussion, you may find there will still be some T-DM1 stragglers out there, even in the modern era, even in the wake of DESTINY-Breast03, for selected patients.

Andrew D. Seidman, MD: The next polling question will allow us to dig in on differentiation. Let’s take the next polling question. Which of the following circumstances is most likely to influence the treatment plan? We’re talking about this specific case. This is the patient who has started with taxane and HP, was on HP for about a year, and now has progressed. Are any of these circumstances main drivers of the decision? 1, visceral disease; 2, a history of interstitial lung disease; 3, perhaps the occurrence of new brain metastasis, if that were an issue for this patient. Are they all equally important and factors in driving this decision of where to go from HP? Or are none of them important, and you just are guided by the phase 3 top-level trial data? Do we nuance this? This will be interesting to see if these factors play into how our attendees feel.

This is interesting. So far, people are thinking about the big picture, all of the above. There isn’t one specific variable, visceral disease, interstitial lung disease, or brain metastasis, although those are called out separately by 8% of each. But the majority are inclined to think that all of these are important. Ruta, what are your thoughts? I asked this to you earlier, I guess, but are you surprised by this?

Ruta Rao, MD:No, not at all. I would’ve chosen all of the above as well. And when you see the answers on a question, you say, “all of the above.” But when you’re really seeing the patient in front of you, I don’t know that they’re all equal. It really depends on the patient because you could have a patient with visceral metastasis, which is 1 or 2 liver metastases, versus a patient who has a liver full of disease and abnormal LFTs [liver function tests]. And there, obviously, the visceral disease takes precedence over some of the other factors; it potentially takes precedence over even history of interstitial lung disease. Similar with brain metastases, you could have a patient with brain metastases that could be treated with local therapy versus someone who’s had all the local therapy to the brain and now is progressing in the brain only. They might have liver metastases, but those are stable. These are all equally important, but in each patient, one may become more important than the other.

Transcript edited for clarity.