Joyce O'Shaughnessy, MD: Let’s go on to the metastatic setting. Bill, you could lead us off with the standard of care. How do you see the standard of care, in the first and second line?

William Gradishar, MD: It’s an area in flux based on some of the prior comments. There are a lot of trials that are trying to position the new drugs closer to the front than the back. Everybody wants to be up front. Today if you said, what do we typically do? We tend to give a taxane with trastuzumab and pertuzumab for most patients as the first line. We still follow that for most patients with T-DM1 [trastuzumab emtansine], and most of those data were generated from randomized trials.

In the last question, the issue is, can we move up trastuzumab deruxtecan? Can we move up tucatinib and replace T-DM1 as a standalone drug as a second-line best choice? Those trials are addressing that. For most patients, at least in our practice, we would follow the standard off of a trial, CLEOPATRA-like followed by T-DM1, and enroll in some of the trials we’ve been alluding to, to see if there’s an advantage.

Joyce O'Shaughnessy, MD: Great, thank you. We’ll come back and talk about some of those different strategies for different patients. Let’s go through the data, a brief update from folks about what’s new that’s come out in 3 big new phase 3 trials that led to 3 new options in the metastatic setting—tucatinib, trastuzumab deruxtecan, and neratinib. Claudine, could you update us on what’s new with HER2CLIMB?

Claudine Isaacs, MD: We have this abundance right now of options, which is great, as Bill was alluding to. For years we knew we had good data tell us what to do in first line and second line. Then third line was sort of a free-for-all, and it was really just choosing what chemotherapy partner with trastuzumab.

In the last year, we’ve seen the approval of 3 drugs in this space. Just to remind everyone about HER2CLIMB, because I stand in awe of people who do more than just breast cancer. I can barely keep up with breast cancer let alone trying to treat a multitude of different malignancies. The HER2CLIMB trial was a randomized trial looking at the role of tucatinib, which is a HER2-specific TKI [tyrosine kinase inhibitor], and was looking at it given with capecitabine, trastuzumab, looking what it added over and above that. It showed a benefit in terms of progression-free survival [PFS]. But the thing that we have now grown used to in the HER2-positive world and the metastatic HER2-positive world is that we expect to see survival benefits. We saw it with the addition of tucatinib. There was about a 4.5-month prolongation of overall survival.

The other thing about this trial is everyone who went on the trial had to receive prior trastuzumab, pertuzumab, and T-DM1. It’s asking what I think was practical for us as clinicians because that’s how we were treating most of our patients, and it showed the benefit of adding tucatinib on top of the trastuzumab and capecitabine with that survival advantage.

The other thing that we’ve talked about already is that we know that one of the issues for our patients with HER2-positive disease is that there unfortunately seems to be a predilection for the CNS [central nervous system]. In the HER2CLIMB study, they allowed patients who had stable CNS metastasis to enroll. It turns out they actually looked for it. They mandated a screening MRI to go onto the study, and what ended up happening is around half of the patients had CNS metastases.

Now to be eligible, you had to have CNS metastases that did not require immediate local intervention. These were patients who either had known CNS metastases that were stable, were found to have CNS metastases but they were small and did not require radiation, or they had had CNS metastases, and we saw they had a bit of progression, but they didn’t need immediate intervention.

The thing that came out in the trial is that there was benefit in the subpopulation, which was a pretty large one, about half of the trial altogether that had control and had the same benefit as the patients who didn’t have CNS metastasis. Then Nancy Lin, MD, presented at ASCO [the American Society of Clinical Oncology 2000 meeting], and showed that if you looked at CNS progression-free survival, it was also prolonged substantially in the group of patients who got tucatinib, cementing that this drug had activity in patients with CNS disease. So it clearly has CNS activity. It also had benefit in patients who did not have CNS metastases. It really positioned itself with this randomized trial as a drug that we need to figure out how we sequence in our armamentarium, but one that we really want to be using.

Joyce O'Shaughnessy, MD: Great, thank you. We’ll come back. We’ll hear about the 3 trials, and we’ll come back and talk about sequencing strategies and your own experience with things. Thanks a lot. That was terrific. How about Lisa? What about trastuzumab deruxtecan? What’s new with that?

Lisa Carey, MD, FASCO: The most recent thing is the update of the DESTINY-Breast01 trial, which is the trial that generated the FDA approval for trastuzumab deruxtecan. That was updated at one of the recent meetings. Shanu Modi, MD, was presenting it, but I can’t remember where. I think it was recent, so it was at the San Antonio Breast Cancer Symposium. They looked at the outcome. This is a single-arm trial in heavily pretreated patients with HER2-positive metastatic disease at 20 months out. What they found was that, again, the progression-free survival was excellent. It was about 19 months. The range was still invaluable in the upper end. This is a very active drug with more than 50%, around a 60% response rate.

Counter to the enthusiasm is that it does have some significant toxicities, and in particular, the ILD [interstitial lung disease]. The numbers of the ILD were up a little. It was about 13% the first time it was presented, and it was about 15% this time, and they did have some deaths that were related to it, which we knew before. There’s some caution but it’s a wildly active drug, and we have to figure out if we can manage the ILD, who’s at risk for it, and trying to figure out where it goes.

Joyce O'Shaughnessy, MD: Thank you, thanks a lot. VK, what about the NALA trial?

Vijayakrishna Gadi, MD: NALA you will recall was presented at ASCO 2019, but the paper is already out, and you can read that in the Journal of Clinical Oncology. This is a funny trial and it’s a funny approval, and it’s hard to figure out how we’re going to use this in the modern world, so to speak.

This trial was designed as a comparator with lapatinib and capecitabine. This is a trial with neratinib and capecitabine. Keep in mind both molecules are small inhibitors of HER2 TKI, but also hit a lot of other tyrosine kinases as well. They’re not as clean and direct as tucatinib.

When they did the study, the trial had to be designed in a way that fully anticipated that the medians were not going to be very different. Because just inhibiting HER2 as neratinib does as opposed to the irreversible inhibition from lapatinib would mean that the biology of the disease could change over time.

What they did is they looked at landmark analyses at 12, 24 months, and so forth. Basically at those time points you see the curves separate and stay apart. When you integrate the area under those curves, and you look for a benefit for PFS, you see one. It’s modest. It’s only a couple of months, but it’s there and it’s statistically significant. This of course then gets registered with the FDA, leads to an approval, and now we have this molecule on hand.

The challenge is of course, you have now 3 HER2-targeting TKIs and how you position them. We’ll talk about this more. Tucatinib is probably a molecule that could be used first and maybe neratinib afterward. But I suspect if you get neratinib before and you’re resistant to neratinib, and this is just conjecture on my part, that you’re probably going to have cross-resistance to tucatinib.

Obviously the adverse effect profiles of these molecules are very different for that same reason, that they tend to hit multiple tyrosine kinases, so you’re going to have a lot more toxicity with neratinib. We’ll talk more about that, it’s an interesting study, and just out of necessity it had to be a funny looking trial.

Joyce O'Shaughnessy, MD: Yes. Neratinib, capecitabine is in the NCCN [National Comprehensive Cancer Network] guidelines not only for HER2-positive breast cancer metastatic, but also for patients with CNS metastasis, as is paclitaxel plus neratinib. Just so we know because we don’t go necessarily looking at the CNS NCCN guidelines that much. Those are there, so that’s helpful to be able to get for patients. Thank you guys for updating us.

Transcript Edited for Clarity