HER2+ mBC: Emerging Agents in the Third-Line and Higher Setting


Debu Tripathy, MD, discusses novel therapies being developed for later-line treatment of HER2+ mBC.


Sara Hurvitz, MD: Debu, there are a lot of interesting data coming out about novel therapies. Do you want to go over a few of the ones you find interesting right now?

Debu Tripathy, MD: Yes, there’s so much going on in the HER2 field, a lot of new antibody-drug conjugates [ADC]. And then some antibodies that are very differently designed, for example, zanidatamab is one that is generating a lot of excitement. It’s a bispecific antibody, or I should use the term biparatropic. It binds 2 distinct epitopes, and it results in clustering of HER2 in the membrane in a different pattern than you see with other antibodies. It’s unclear what the mechanism of action is, whether the clustering may induce the immune system better, or maybe it affects the signaling itself. But it has shown activity in phase 1 trials, not only in breast, but other HER2-positive cancers, as a single agent. In patients with refractory breast cancer, responses have been seen in about the 20% range, 20% to 25%.

We recently reported at ASCO [American Society of Clinical Oncology annual meeting] breast, a neoadjuvant study with single-agent zanidatamab, so chemotherapy-free, and we’re seeing pathologic complete response rates very early in the first cohort. So this is a drug now that is going to move forward both in the I-SPY trial, in the neoadjuvant setting, and in the advanced setting as well. There was an interesting study in hormone receptor-positive and HER2-positive [cancer using] zanidatamab, palbociclib, and fulvestrant presented last year at San Antonio [Breast Cancer Symposium] that did also show some compelling activity.

Then there are other antibody-drug conjugates, as I mentioned, trastuzumab duocarmazine, which uses an antimicrotubule payload. That study did show an improvement in PFS that met its end point. It does have some distinct toxicities, as do other ADCs, such as keratitis, or ocular symptoms that range from dry eyes to other ocular injury. [These are] generally reversible, but this is an issue. These are active and are going to be moving forward.

There was an interesting study reported of dalpiciclib and pyrotinib, so a CDK [cyclin-dependent kinase] inhibitor with a TKI, tyrosine kinase inhibitor, also showing activity. The PATINA study that was mentioned earlier is looking at adding a CDK in the hormone receptor-positive subtype. They’re doing it at the maintenance therapy phase, and I think they fully accrued, but it’ll probably be reading out soon. That’s just a handful that we have time to discuss. I’ll say one more thing because there has been a lot of interest in CAR [chimeric antigen receptor] T-cell therapy with HER2. Some of the early experience showed that this could be dangerous, they saw some cardiac toxicities. But now they have modulated and changed how the HER2 is presented, and there’s renewed interest in immune effects targeting with this type of technology.

Sara Hurvitz, MD: Absolutely. You mentioned the pyrotinib data, and there have been a lot of studies out of Asia looking at pyrotinib. I think my main concern is the severe diarrhea that’s been reported. It looks along the lines of neratinib or worse. I think if they can figure out how to improve that, maybe we’ll be seeing more studies here with it. It’s certainly interesting and a very potent TKI. If they could make it HER2-specific, maybe….

Debu Tripathy, MD: There are some new super HER2-specific TKIs that are in early development, so I think we are going to be seeing some that have a higher affinity, for example, than tucatinib. These are entering testing.

Sara Hurvitz, MD: To be determined. More data are forthcoming.

Transcript edited for clarity.

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