Established Agents in Metastatic HER2+ Breast Cancer Become the Focus of Research in Earlier-Stage Disease

Because of the efficacy observed with fam-trastuzumab deruxtecan-nxki (Enhertu) and tucatinib (Tukysa) in metastatic HER2-positive breast cancer, ongoing clinical trials such as DESTINY-Breast05 (NCT04622319) and CompassHER2 RD (NCT04457596) are evaluating these agents in earlier lines of treatment, said Laura Spring, MD.

“Overall, we have a lot of new, exciting drugs in the HER2-positive [metastatic] space,” Spring said. “Of course, [these drugs] are always first approved in the advanced setting, but we need to think carefully about how to bring these agents earlier while also balancing that with toxicity.”

In an interview with OncLive®, Spring, an attending physician of medical oncology at Massachusetts General Hospital and an instructor of medicine at Harvard Medical School, discussed the influence of the findings from the DESTINY-Breast03 trial (NCT03529110) with trastuzumab deruxtecan on practice patterns in HER2positive breast cancer and updates in the management of brain metastases. She also noted the ongoing clinical trials that she is watching regarding future changes in moving therapies into earlier lines of treatment.

OncLive^®: What studies are you tracking in the HER2-positive breast cancer paradigm in 2022?

Spring: We now have several trials in the early HER2-positive breast cancer space looking at both escalation and deescalation [strategies]. [We are going to see] a balance of [research with both approaches] and [build our] understanding [of] how to integrate these new agents.

There are key issues in the field. One example is that we can see patients who have great responses to preoperative therapy, but then they may recur at some later time with brain metastases. That tells us that we need earlier use of agents that have activity in the central nervous system (CNS), which is a so-called sanctuary space. The trials looking at tucatinib and trastuzumab deruxtecan in the earlier setting are important. As an antibody-drug conjugate, trastuzumab deruxtecan is a much larger drug [molecule] than tucatinib, so it is unclear whether it will be as helpful in the prevention of brain metastases.

Other trials to watch would be CompassHER2 RD, which is looking at adding tucatinib to T-DM1 for patients with residual disease following preoperative therapy, as well as the DESTINY-Breast05 study, which is comparing the standard of care, T-DM1, with trastuzumab deruxtecan [in patients with residual invasive disease following neoadjuvant therapy].

What updates were seen in 2021 regarding the treatment of patients with CNS metastases?

Tucatinib, we know from the HER2CLIMB study [NCT02614794], does have CNS activity. Over the past year, we’ve seen additional results from the HER2CLIMB study further showing that this agent is quite active in the CNS, which is exciting news for patients. We’ve also seen results showing that trastuzumab deruxtecan can have CNS activity as well, so there is more research taking place in this area.

How did the results of the DESTINY-Breast03 trial change practice patterns in patients with HER2-positive breast cancer in 2021?

The results from the DESTINY-Breast03 study really brought the use of trastuzumab deruxtecan to the second-line setting for HER2-positive metastatic breast cancer, as it significantly outperformed T-DM1 [ado-trastuzumab emtansine (Kadcyla)] in that setting.

Prior to this study, T-DM1 was the common choice in the second-line setting. In this trial, there was 1:1 randomization to trastuzumab deruxtecan vs T-DM1. At the 2021 European Society for Medical Oncology Congress, we saw the interim results of the [DESTINY-Breast03 trial]. In the trastuzumab deruxtecan arm, the median progression-free survival was not reached vs 6.8 months in the T-DM1 arm, with an impressive HR of 0.28.

What is next for trastuzumab deruxtecan to further explore its utility?

An exciting trial to keep an eye on is DESTINY-Breast09 [NCT04784715], which is looking at trastuzumab deruxtecan in the first-line setting compared with the regimen of trastuzumab [Herceptin], pertuzumab [Perjeta], and docetaxel, which was established from the CLEOPATRA study [NCT00567190]. [The results of the DESTINY-Breast09 trial] could have significant implications, both in the first-line setting and beyond.