Joyce O’Shaughnessy, MD: Taking out the crystal ball, how do you think the curative setting might change? What other newer agents do you think might make their way into the curative setting? Second, is there any role for the T-DM1 [trastuzumab emtansine]–pertuzumab KAITLIN regimen? Is there any patient who maybe that would help? Maybe they just have comorbidities or what have you. It wasn’t as effective as the TCHP [docetaxel, trastuzumab, pertuzumab, carboplatin] in the KAITLIN trial. It’s not a standard of care, but do you see any role for that for any patients? Do you think about that at all? What agents do you think will maybe move up in the future?

Lisa Carey, MD, FASCO: I do think that for our optimization, personalization, and tailoring efforts, we have a couple of trials that are actually trying to leverage this pCR [pathologic complete response] thing, right? There’s CompassHER2-pCR, which is an ECOG-ACRIN trial. In Europe there’s the DECRESCENDO trial, which is a very similarly designed trial in which they’re giving just a taxane and HP [trastuzumab, pertuzumab]. If the patient achieves pCR, they just get the HP and never get additional chemotherapy.

Those are maneuvers in which we serially try to eliminate the chemotherapy, right? You could argue what we should eliminate. Do you eliminate pertuzumab? Do you eliminate the duration of the HER2 target? When you poll patients, they want us to get rid of the chemotherapy. One thing we did take away from KAITLIN is that although the pCR was different—and this is a small number, but it looked like it didn’t matter a huge amount whether you got a pCR through a T-DM1P [trastuzumab emtansine–pertuzumab] mechanism or a more traditional TCHP mechanism—they all had about the similar event-free survival. There is an argument, a testable hypothesis, that pCR achieved by whatever is pCR. Then we have to figure out who can we get away with just giving anti-HER2 therapy with endocrine therapy. There have been trials of this, and there’s always a low but real pCR rate. If we could figure who they are, that’s a way forward.

Because it’s a trial that’s about to open and we’re super excited about it for those who have residual disease—as we were just saying, there are groups in the residual disease setting who in spite of KATHERINE, in spite of T-DM1 still have a high relapse rate. You may remember that KATHERINE did not have an impact on brain mets. There’s an Alliance trial that is about to open that is with residual disease is T-DM1, or the same with tucatinib, and so it’s a very straight up. Can we build on that in high-risk residual disease?

Joyce O’Shaughnessy, MD: That’s great. Hopefully it’s going to be a strategy for both cure and brain. What do you think VK?

Vijayakrishna Gadi, MD: Lisa, I have 1 other thing. With these trials you mentioned, the 1 other neat feature is in the correlative work. They’re using circulating tumor DNA as a measure of deep molecular remissions. I hope that something like a deep molecular remission would track well with pCR. For those who didn’t, you can see the circulating tumor DNA that still suggests there might be cancer cells. Then having some adaptive therapy, based on that in some of these novel agents used, would be a future possibility. That’s really early science. I was heartened to see the collection of those specimens so we can assess for those things.

Lisa Carey, MD, FASCO: The things that were—the integrative biomarker that’s in these is actually the intrinsic subtype. Some are more HER2 driven than others, so we may get a little more bang for the buck out of looking more closely at the tumor. Also, I would argue, although it’s a secondary thing: exploratory, immune microenvironment, getting back to Claudine’s comment about TILs [tumor-infiltrating lymphocytes].

Joyce O’Shaughnessy, MD: Thank you. I want to mention the DESTINY-Breast05 trial too. We have tucatinib trying to improve overall outcome, but also brain, and then the DESTINY-Breast05. It’s just opened, T-DM1 vs TDXD—that’s trastuzumab deruxtecan. Just a head-to-head, and there’s a head-to-head going on in the metastatic, which we don’t know the answer to. It just opened in the curative setting as well. We don’t know much about TDXD [trastuzumab deruxtecan] in the brain. That’s still an unknown area, but another candidate isn’t it for the curative setting.

Transcript Edited for Clarity