Research Efforts in HER2+ Breast Cancer Focused on Optimizing Novel Agents

Gregory Vidal, MD, PhD

Higher affinity HER2-targeted therapy with margetuximab, more potent TKIs such as tucatinib, and potent antibody-drug conjugates like [fam-] trastuzumab deruxtecan are all showing promise in patients with HER2-positive breast cancer, said Gregory Vidal, MD, PhD.

“Despite all of the improvements we have made with trastuzumab (Herceptin) and chemotherapy, there is a lot more to come,” said Vidal, an assistant professor, Department of Hematology/Oncology, The University of Tennessee Health Science Center.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Vidal, who is also a medical oncologist at West Cancer Center, discussed the ways in which currently available and investigational agents are being evaluated in the curative and metastatic settings of HER2-positive breast cancer.

OncLive: We recently saw data from the second interim overall survival (OS) analysis from the phase III SOPHIA trial with margetuximab. Could you provide your thoughts on these data?

Vidal: Margetuximab is similar to trastuzumab; however, the fragment crystallizable (FC) region is altered to have a higher affinity to interact with the immune system. The data we have seen with this agent are very interesting. A group of patients [who don’t benefit from trastuzumab] appear to do better with margetuximab. Overall, we do see a small improvement in progression-free survival (PFS) with margetuximab. However, we have not seen a significant improvement in OS. We’re anticipating larger trials with margetuximab.

Margetuximab has increased affinity for CD16. Could CD16 be targeted by other agents?

CD16 is a receptor that interacts with the Fc portion of the trastuzumab antibody; that interaction stimulates the immune system. Some patients have an allele that interacts really well with trastuzumab, and some patients have an allele that doesn't. Margetuximab is designed to improve that interaction [between the alleles that don’t interact well with trastuzumab].

Could you discuss the data we’ve seen with tucatinib from the HER2CLIMB trial?

Tucatinib is a TKI that inhibits the active portion of the HER2 protein. We also have lapatinib (Tykerb) and neratinib (Nerlynx). Lapatinib is reversible, and neratinib is irreversible. However, these agents are both “dirty” TKIs, meaning that they hit more than HER2. They hit HER1, 2, and 3, and some of the toxicities we see come from those [off-target effects]. Tucatinib is a more specific inhibitor of HER2, so the toxicity we’ve seen [with this drug] has been lower. We haven’t seen the data from the trial, but a press release stated that the addition of tucatinib to trastuzumab and chemotherapy versus trastuzumab and chemotherapy alone led to superior PFS and OS in patients with heavily pretreated locally advanced unresectable or metastatic HER2-positive disease. I’m looking forward to seeing the data presented at the 2019 San Antonio Breast Cancer Symposium.

Do some of these agents that are showing activity in later-line settings have the potential to be used in earlier lines of treatment?

Definitely—take tucatinib, for example. That drug is probably going to have a role in earlier lines of treatment. It will be hard to oust [current staples of treatment], such as pertuzumab (Perjeta), trastuzumab, and ado-trastuzumab emtansine (T-DM1; Kadcyla), but there will be some competition.

I suspect DS-8201 may challenge TDM-1 in the second-line setting. DS-8201 showed such great activity [in the metastatic setting], even after T-DM1 failure. The question is how DS-8201 would compare with T-DM1 in the upfront setting. Could it be superior to T-DM1? Potentially.

The FDA granted a priority review designation to DS-8201 in the metastatic setting. How could its approval impact clinical practice?

It would have a very positive impact on practice. Currently, we have trastuzumab and pertuzumab in the frontline setting, T-DM1 in the second-line setting, and the TKIs or chemotherapy with trastuzumab in the third-line setting. Toxicity is something we have to deal with in [the third-line setting]. If DS-8201 shows equal activity and less toxicity, we’ll probably push chemotherapy and [TKIs] further back to improve responses and quality of life.

Interestingly, there appears to be activity in the HER2-low population as well [with this agent], which could impact the triple-negative subtype; those patients have estrogen receptor (ER)—negative and progesterone receptor–negative disease. DS-8201 could become an option in this space, which would be exciting.

At the 2019 ESMO Congress, we also saw data from the phase II KATE2 trial with atezolizumab (Tecentriq). What are your thoughts on those findings?

Overall, it was a negative trial. Investigators tried to find a subset of patients who responded to the combination, which in this case, was the PD-L1—positive population. These patients appeared to respond better than the overall population, but it was a small population, so we’ll need to see more data.

Could you speak to some of the studies that are trying to incorporate CDK4/6 inhibitors into HER2-positive disease?

It is exciting. At the 2019 ESMO Congress, we saw data from the phase II monarcHER trial with trastuzumab, abemaciclib (Verzenio), and fulvestrant (Faslodex). The regimen was compared with standard of care trastuzumab and chemotherapy.

However, there was a third arm with abemaciclib and trastuzumab. The data showed an improvement in PFS and objective response rates with the triplet versus the other arms. I’m not surprised because the CDK4/6 inhibitors have done so well in the ER-positive space. We know that the ER-positive, HER2-positive subtype behaves a little differently than the ER-negative, HER2-positive subtype, so I wouldn’t be surprised if the CDK4/6 inhibitors find themselves in that space. This trial showed the first hint that this could happen.