Novel Treatment Approaches to R/R HER2+ Metastatic Breast Cancer

Vijayakrishna Gadi, MD, PhD: Chuck, we talked a little about deruxtecan and the DESTINY-Breast03 study. Perhaps you can just remind us about tucatinib and how these recent trials are affecting our thinking on where tucatinib fits, etc.

Charles Geyer, MD, FACP: Tucatinib is a drug we’ve been interested in for a long time, but it was very challenging for the company to get the trials done. They elected to basically do the HER2CLIMB study, in a very heavily treated patient population. They had to have both antibodies T-DM1 [trastuzumab emtansine]. To their credit, they didn’t run from brain metastases. They embraced brain metastases, so to speak. There’s always been that standard saying, “We’ll let people on the stable on brain metastases.” But the thing about this study that everybody is aware of is that with any brain metastases, you can come in—almost half their patients had brain metastases, and a substantial percentage had disease that was actively progressing after prior radiation somewhere new that had been treated. There’s a lot of information on that trial because it was a large phase 3 about the subsets. Nancy has been active and has shared that information as it’s evolved. The study was designed to look at the efficacy of the drug overall, the IIT [intent-to-treat] studies. The thing that was impressive about it is that everybody was getting an acceptable regimen of trastuzumab capecitabine. For that scenario, with added tucatinib, you saw very impressive hazard ratios for the end points. Progression-free survival [PFS] hazard ratio was 0.54.

When you look at how much the progression-free survival mattered, it was only 5.6 to 7.8 months. But when you start looking at benchmark end points, like who was free or who was still alive at 2 years, you start seeing that there are subsets of patients benefiting from that. The interesting thing about the study is that the benefit is virtually the same when you look at the patients with and without brain metastases and maybe even a little better in the brain metastases population. It’s very striking, and it tells us that this is a drug that clearly has CNS [central nervous system] activity that needs to be considered. The trial was done in that third-line setting, so the big question has been, “What if in your second line, you’ve got brain metastases? Do you bring it forward? Do you use T-DXd [trastuzumab deruxtecan]?” The interesting information on the DESTINY-Breast03 study was the follow-up about their small subset of patients with stable brain metastases. We’re going to hear more about that later. But it certainly encourages us that when we’re using T-DXd [trastuzumab deruxtecan], we’re probably delivering reasonably effective therapy against CNS disease as well.

Vijayakrishna Gadi, MD, PhD: Before we return to our case, Nancy, I’m going to come to you for a second. We have a couple of other drugs out there that got extended approvals related to them. All of us are like, “Where do we use these?” For example, neratinib and margetuximab. Quick comments on those?

Nancy Lin, MD: Great question. Both of them—neratinib with NALA and margetuximab with SOPHIA—had positive phase 3 trials. But as you point out, the question is, what do you do with them in clinical practice? I think the trials were more important from a proof-of-concept standpoint than for changing our usual second- and third-line regimens. Neratinib was neratinib, and the NALA trial compared neratinib-capecitabine vs lapatinib-capecitabine, and neratinib was marginally better—the hazard ratio was 0.7, and the absolute difference is about 2 months in PFS, with no survival difference. There were some interesting findings out of NALA. Patients who had baseline brain metastases were less likely to progress in their brain.

There were some interesting hints of data in terms of benefit in the CNS. One major takeaway from the study that I took away was that we can develop better HER2 [human epidermal growth factor receptor 2] TKIs [tyrosine kinase inhibitors]. Lapatinib, which Chuck was very involved in developing, can be improved upon. By dialing in CNS activity and also better HER2 inhibition, you can improve upon first-generation HER2 TKIs. But in clinical practice, I’m typically choosing tucatinib over neratinib at least early on because of the toxicity profile and because of the survival data seen in HER2CLIMB, which wasn’t seen in NALA.

There are some big questions. Is there a role for neratinib after tucatinib or lapatinib? Is there a role for switching out the chemotherapy, in the way that we do for trastuzumab? Are we continuing trastuzumab and then switching out multiple types of chemotherapy? The problem is, with the HER2 TKIs, we don’t have a lot of combination data with other chemotherapies, and so we’re stuck with capecitabine. That really interesting. There’s an ongoing study of T-DM1 [trastuzumab emtansine]–neratinib in patients with brain metastases. It’s quite interesting, the potential to overcome T-DM1 [trastuzumab emtansine] resistance. There’s still some room left for neratinib, and there are data in HER2-mutated patients as well.

Margetuximab is a technically positive study, but the difference was quite marginal. There’s no difference in overall survival, and there was a 1-month or so difference in median PFS. Hazard ratio was very similar to NALA: 0.7 or 0.75. But it’s a proof-of-concept study in the sense that in the FF genotype, there was a benefit seen, and there was proof of concept that you can engineer trastuzumab to be more visible and more promoting of immune activation. The question is, if you use it earlier, before a patient’s immune cells are exhausted, and you tried in the neoadjuvant setting or in earlier lines, could there be a benefit? In routine clinical practice, it’s hard to come up with a major role of margetuximab in the typical HER2+ metastatic patient.

Vijayakrishna Gadi, MD, PhD: Let’s go back to our patient quickly. She had HER2-enriched de novo disease: ER [estrogen receptor]–negative, HER2+. As Chuck pointed out, she does get some variation of THP [docetaxel, trastuzumab, pertuzumab], taxane plus HP [trastuzumab, pertuzumab], presumably even subcutaneously for a while. Then 2½ years later, she completes some more scans, and there are lung metastases and bone metastases. With this in mind, we quickly talked about all these options—standard, clinical trials. Are there any changes in terms of patient factors, disease factors, treatment factors? How would you put all this together? Nancy, bone metastases vs lung metastases—does that change anything for you?

Nancy Lin, MD: If we think about, she’s been on THP [docetaxel, trastuzumab, pertuzumab]. Now you’re trying to choose second-line therapy. In general, I’m going to be reaching for trastuzumab deruxtecan because the results of DESTINY-Breast03 were so impressive. There are some exceptions. It’s more toxic than T-DM1 [trastuzumab emtansine], and there’s the ILD [interstitial lung disease] issue. For a patient who has preexisting lung disease, for a patient who may be more frail, for all sorts of more toxicity-based issues, I might still choose T-DM1 [trastuzumab emtansine] over T-DXd [trastuzumab deruxtecan] in the second line-setting. For a patient who has predominantly CNS progression, it’s not clear whether one should choose T-DXd [trastuzumab deruxtecan] or tucatinib, because the T-DXd [trastuzumab deruxtecan] data are a little more limited in terms of CNS. Patients with active CNS disease weren’t included in DESTINY-Breast03. On the other hand, HER2CLIMB wasn’t studied in the second-line setting. It’s a bit of a toss-up, and I base it on where the predominant burden of disease is. If it’s predominantly CNS-burden disease, I tend to reach for tucatinib. If it’s predominantly extracranial disease, even if there’s some CNS disease, I tend to reach for T-DXd [trastuzumab deruxtecan].

Transcript edited for clarity.