Bispecific Antibodies Hold Promise in HER2+ Breast Cancer

Bispecific antibodies like zanidatamab represent an emerging novel class of agents that could have utility in HER2-positive breast cancer, said Sara M. Tolaney, MD, MPH, who added that although the agents will likely be sequenced in the third- or fourth-line setting, ongoing trials with agents such as fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), ado-trastuzumab emtansine (T-DM1; Kadcyla), tucatinib (Tukysa), and margetuximab-cmkb (Margenza) may complicate sequencing strategies.

“The HER2-positive breast cancer landscape is very complex and competitive. We have seen a lot of movement in this setting with sequencing,” said Tolaney, chief of the Division of Breast Oncology and associate director of the Susan F. Smith Center for Women’s Cancers, a senior physician at Dana-Farber Cancer Institute, and an associate professor of medicine at Harvard Medical School.

“We are going to see more of [zanidatamab]; it is a very novel strategy to think about bispecific targeting in HER2-positive disease,” Tolaney added.

In an interview with OncLive, Tolaney discussed the mechanism of action that makes bispecific antibodies an intriguing approach in managing HER2-positive breast cancer, efficacy data with zanidatamab that were presented during the 2021 San Antonio Breast Cancer Symposium (SABCS), and her thoughts on sequencing strategies with bispecific antibodies among other agents in the paradigm.

OncLive: How could bispecific antibodies enhance the HER2-positive breast cancer armamentarium, and what data have been observed with zanidatamab?

Tolaney: It is a clever system to think about bispecific agents. One drug that we have a little bit of experience with and saw some data on from SABCS was zanidatamab. This is a bispecific antibody that targets 2 different epitopes on the HER2 receptor and results in receptor clustering so that we get downregulation of HER2, [which turns] off HER2 growth factor signaling, and enhances antibody-dependent cell-mediated cytotoxicity. I’ve always been intrigued by [this] bispecific agent. We saw some data previously looking at monotherapy activity [of zanidatamab], which is interesting because we don’t get much monotherapy activity from trastuzumab [Herceptin] or pertuzumab [Perjeta]. [Zanidatamab] does have some monotherapy activity.

At SABCS, we saw data combining zanidatamab with various chemotherapies in a small study. Interestingly, we saw a robust response rate of around 30% and a progression-free survival of around 7 months. Patients previously had trastuzumab [and] pertuzumab, most of them [had prior] T-DM1, and some of them [had prior] TKIs. [This was a] pretreated population.

Is it clear where bispecific antibodies will be sequenced if they continue to demonstrate efficacy?

Now, still THP [paclitaxel, trastuzumab, and pertuzumab] is [the standard] first-line [regimen in the metastatic setting]. Most of us think of T-DXd for most patients in the second-line setting. In the third-line setting, we are choosing capecitabine plus tucatinib and trastuzumab or T-DM1 and vice versa in the next line. We also have margetuximab as a [fifth]-line [option].

[Sequencing] becomes complicated when we have so many choices, but it is a good problem to have. In truth, as things shift, it is going to be interesting to see how these drugs perform after one another. We don’t know how T-DM1 is going to perform post T-DXd. We are going to have to learn more about how to sequence agents and get more data. However, again, the early data for bispecific antibodies seem promising and are sort of on par with what we are seeing with agents in the third- and fourth-line settings. We just need more data to see how things will shake out with a little more time in the metastatic HER2-positive space, particularly as antibody-drug conjugates are moving even earlier with the DESTINY-Breast09 trial [NCT04784715], which is exploring T-DXd in the first-line setting. More is going to come over the next few years.