Emerging Therapies for HER2-Positive Metastatic Breast Cancer - Episode 8

The Changing Treatment Landscape of HER2+ Breast Cancer

Ian Krop, MD, PhD:We have 3 drugs that were tested in roughly third- or later-line HER2-positivie metastatic breast cancer. All of them show encouraging levels of activity, including pretty dramatic improvements with tucatinib. The data with trastuzumab-deruxtecan looked very impressive in terms of efficacy. These are all things that may have a good chance of improving outcomes substantially for patients with HER2-positive metastatic disease.

There are other drugs being tested. Neratinib is another kinase inhibitor I mentioned earlier. It’s an irreversible kinase inhibitor of both HER2 and EGFR. It was tested in the NALA trial that was presented at ASCO [the American Society of Clinical Oncology Annual Meeting]. That was a trial that compared patients who had had pretreated HER2-positive disease, received either a standard of capecitabine-lapatinib or capecitabine and neratinib. And in that study the neratinib did show an improvement in progression-free survival and higher response rates compared with lapatinib-based therapy.

As expected, it also showed more diarrhea. Again, neratinib is a very potent inhibitor, so along with increased efficacy, it also seems to have increased toxicity. This toxicity generally is manageable with aggressive use of prophylactic antidiarrheals. That’s definitely something that needs to be thought about when using that drug.

In addition, there are a number of other agents being tested in earlier lines of trials—drugs in phase I development that we can talk about in the future.

One other agent that’s in clinical development right now is another antibody-drug conjugate targeting HER2. This is what’s called SYD985. This uses yet another type of cytotoxic payload along with a HER2-directed antibody. This agent has been tested in pretreated HER2-positive breast cancer in a phase I study that reported encouraging levels of activity with response rates in the 30%-to-40% range. This is interesting in that it also seems to be active in HER2 low-expressing cancers. It has an interesting adverse-effect profile in that ocular toxicity seems to be a problem in a substantial fraction of patients, so this is something that’s going to have to be managed. But the activity does look encouraging in patients who’ve already had progression on other agents. SYD985 is currently being tested in a phase III trial called the TULIP study, which is randomizing patients with HER2-positive advanced breast cancer to either this new antibody-drug conjugate or a standard-of-care regimen.

As we’ve discussed, the introduction of HER2-directed therapies has clearly improved the outcomes for patients with HER2-positive metastatic breast cancer. We have dual blockade of trastuzumab and pertuzumab chemotherapy in the first line; T-DM1 [ado-trastuzumab emtansine] in the second line; and a number of combinations of HER2-directed therapies and chemotherapy in third and later lines of therapy.

I think what’s going to change dramatically in the next year or so is the introduction of these newer agents that we discussed, like tucatinib, like trastuzumab-deruxtecan, margetuximab, and additional agents.

This is undoubtedly going to further improve outcomes for HER2-positive patients. It’s going to require the oncology community to learn how to sequence these different drugs. They have different toxicity profiles and different mechanisms of action, and how we use these interactively is going to take some work. Certainly, I think we’re going to need to learn how to personalize them for individual patients, because presumably some patients are going to benefit more from 1 versus another. But I think overall this is very good news for patients with HER2-positive metastatic disease. I think we’re all encouraged by the results that came out in 2019.

Transcript edited for clarity.