Neil Iyengar, MD: I’ll continue with her case. She did very well in the maintenance setting with fulvestrant [Faslodex] and Herceptin [trastuzumab]/pertuzumab [Perjeta]. She had stable disease for about 14 months. Now we’re into 2021 and unfortunately, after about 14 months, she developed a progression of disease in her liver and in her bone that was seen on imaging. We did at the time of progression repeat a brain MRI, and fortunately, she still had no evidence of intracranial disease. Now that we’re in 2021 and the second line, we had the opportunity to treat her with trastuzumab deruxtecan [T-DXd]. We started her with trastuzumab deruxtecan in the second-line setting and she did quite well with this agent. In fact, her first imaging at 3 months showed a complete response and so I’ll just pause there as well because I think this gives us the opportunity to talk about the evolving second-line space. And for this particular patient who was previously exposed to T-DM1 [trastuzumab emtansine] in the adjuvant setting. This is the kind of person that I felt very comfortable bringing in T-DXd based on the DESTINY-Breast03 data in the second-line setting. Of course, in that study, we saw a superior PFS [progression-free survival] and OS [overall survival] for trastuzumab deruxtecan compared with T-DM1 in the second-line setting. Now of course 50% of patients approximately were in the second-line setting in DESTINY-Breast03. The remainder was in later lines. Nonetheless, we’ve seen that trial lead to an update in NCCN [National Comprehensive Cancer Network] guidelines allowing for trastuzumab deruxtecan in the second-line space. Milana, how has your treatment in the second-line setting evolved, if at all?

Milana Dolezal, MD, MSci: I think you bring up the perfect point of what’s the role of T-DM1 now in the metastatic setting in addition to the conundrum that we have with these sort of high-risk patients who are then getting T-DM1 in the adjuvant setting. I think a few comments. One thing that we didn’t discuss in terms of HER adjuvant care was this is a triple positive patient. Would you have considered doing neratinib [Nerlynx] in that extended adjuvant setting per the ExteNET data? And you alluded to the crosstalk. We do think in terms of the estrogen positivity and HER2 positivity, there are hypotheses that there might be a bit of a seesaw in terms of maybe when you are suppressing the estrogen, the HER2 goes up. Or maybe when you’re suppressing the HER2, the estrogen goes up. And neratinib can hit all of those targets and deal with that crosstalk maybe a little bit more than tucatinib [Tukysa] can. I have been using neratinib, especially in the triple-positive types of patients, in the extended adjuvant setting. In terms of that evolving space, so she had received T-DM1 appropriately in the adjuvant setting. Now that’s not really our second line go to, and you alluded to the DESTINY- [Breast] 03 data in terms of using deruxtecan in that setting. Given that most of her disease is all-visceral, she hasn’t developed brain metastases, I think that’s appropriate to continue her on that therapy in addition to bone modulating agents as well. Presumably, she’s on Zometa [zoledronic acid] or Xgeva [denosumab]. And then what are you doing about her estrogen blockade? Are you holding off on that or where are we? It goes back to that question; she’s on chemotherapy because it’s an ADC [antibody-drug conjugate] with chemotherapy, but how are you suppressing her estrogen?

Neil Iyengar, MD: These are all such great points. Just to briefly address your first point about neratinib in the extended adjuvant setting, I fully agree. I think this is an additional agent that’s particularly attractive for hormone receptor-positive and HER2-positive diseases. We know from the subgroup analysis in ExteNET that it was the ER [estrogen receptor]-positive patients who really derived the majority of the benefit from neratinib in the extended adjuvant setting. Part of the challenge of course is that this is an older generation trial and so we didn’t have patients in that trial that had been previously exposed to things like pertuzumab and T-DM1. How that may or may not impact the ultimate outcomes, we don’t know. But as you nicely discussed, we have certainly a very robust biologic rationale for combining neratinib and hormonal therapy in the extended adjuvant setting. That being said, I could not convince this patient to do escalated therapy in the adjuvant setting and that’s why we did not use neratinib in that setting. Getting back to the metastatic setting, yes, I absolutely use bone-modifying agents. This particular patient was on Xgeva really from the start, from the finding of her bone metastasis, and finally, you raised the point about hormone therapy with an ADC. I think that’s such a great question and certainly the subject of investigation. Right now, I’m not using hormone therapy with the antibody-drug conjugates until I see some additional data. So this particular patient, we treated with trastuzumab deruxtecan alone in the second-line setting, and fortunately, as I mentioned, she had a very nice complete response.

Transcript edited for clarity.