ADCs, TKIs, and others expand treatment options in HER2 + metastatic breast cancer

“The field of HER2-positive breast cancer is at a rapid pace with several new drug indications, just in the past year [alone], Pegram said. “The data from HER2-positive metastatic breast cancer is arriving at such a pace that with every meeting there are important new updates, some of which may influence clinical practice. “

In an interview with OncLive^®, Pegram, Suzy Yuan-Huey Hung Full Professor of Medical Oncology, Associate Dean for Clinical Research Quality at Stanford University School of Medicine, Associate Director of Clinical Research at Stanford Comprehensive Cancer Institute and Medical Director of Stanford Clinical Translational Research The Stanford Medicine unit is developing the latest data on HER2-positive metastatic breast cancer.

OncLive^®: What recent developments in HER2-positive metastatic breast cancer are you most excited about?

Pegram: There is still a great unmet need [to integrate novel therapies to the treatment paradigm for] HER2-positive metastatic breast cancer. Feedback on the original trastuzumab adjuvant [Herceptin] trials in Europe, North America and the Breast Cancer Research Group global studies with 3 years of follow-up, they all had exceptional disease-free survival data of around 80%, and we declared success. After 10 years, however, all trials had a relapse rate of around 25%. Also, if you look at the mortality results in these trials, most of the mortality events were due to metastatic breast cancer.

The CLEOPATRA trial [NCT00567190] pertuzumab regimen [Perjeta], trastuzumab and docetaxel for the first-line treatment of HER2 + metastatic breast cancer has been the norm. This is a very high bar to beat in terms of clinical research, although there are a few ongoing attempts that have started recently.

There is also the possibility of using endocrine therapy in combination with targeted therapy on HER2. [for this patient population.] A number of clinical trials have examined the combination of ER and HER2 targeted therapies, derived from EGF30008 [NCT00073528], RELEVANT [NCT01491737], TANDEM [NCT03517540], and ALTERNATIVE tests [NCT01160211]. All these [trials] were combinations of anti-HER2 and anti-estrogen therapies and were found to be effective.

At the ASCO annual meeting in 2021, a group of Chinese researchers conducted a phase 3 randomized trial of hormone therapy plus trastuzumab vs chemotherapy plus trastuzumab, as the first-line treatment for [this patient population]. Surprisingly, the hormone therapy plus trastuzumab arm performed well, statistically meeting its non-inferiority criterion in the study design. It was quite remarkable for both progression-free survival and overall survival. However, this predates the pertuzumab era, so it remains to be seen whether the same logic can be applied with dual antibody therapy. There are some patients for whom chemotherapy may not be applicable due to comorbidities, such as advanced age, or simply patient preference, but we now have a large body of data indicating that these patients are doing well.

[There have also been efforts examining] in addition to the CLEOPATRA regimen for patients with ER and HER2 expression. The PATINE trial [NCT02947685] review the combination of palbociclib [Ibrance] with anti-estrogens during the maintenance phase of a CLEOPATRA-type diet. The EPIK-B2 test [NCT04208178] look at alpelisib [Piqray] in ER- and HER2-positive patients who also harbor PIK3CA mutations, also following a CLEOPATRA type scheme in the maintenance phase.

With antibody-drug conjugates [ADCs], there are distinctions between ado-trastuzumab emtansine [TDM1; Kadcyla] and fam-trastuzumab deruxtecan-nxki [Enhertu]. [The 2 agents] are chemically and structurally linked, [but they have] different payloads. For example, the payload of trastuzumab deruxtecan with a significant spectator effect, which may explain some of its impressive clinical results.

[Additionally,] in the pivotal DESTINY-Breast01 trial [NCT03248492], the agent had extremely impressive response rates in a group of patients with [multiple] previous treatment lines. Additionally, there was an update at the ASCO 2021 annual meeting on anecdotal activity with this agent in patients with HER2 positive breast cancer and brain metastases from the clinical trial. DESTINY-Breast01. Objective responses were documented by the RECIST criteria, and these responses tended to be durable for a period of several months. This suggests that ADCs may play a role in the future of HER2-positive breast cancer and brain metastases, and dedicated trials in this space are underway.

[In patients with HER2-low disease], which accounts for about half of all breast cancers, there are now trials with trastuzumab deruxtecan. These trials are compared to the current standard of care. It will be exciting to see if this new ADC has activity in a new frontier of HER2-low breast cancer.

There is also an ADC [in development] from Bolt Therapeutics which has an immunological payload which is a Toll-like 7/8 receptor agonist, which will attempt to boost anti-tumor immunity with ADC instead of using a chemotherapy payload.

[Finally, we saw updated results from the] HER2CLIMB trial [NCT02614794] at ASCO 2021, at the annual meeting, and their OS data still looks strong with long-term follow-up.

In terms of integrating these new therapies into clinical practice, what patient characteristics and other factors do you consider?

One of the key factors when deciding which effective HER2-targeting therapy to use at any given time during the course of metastatic disease is the adverse reaction profile. [We must] explain them to patients, as there may be more than one option at a time. We don’t want to do [treatment decisions] based only on efficacy, but rather on efficacy divided by toxicity or therapeutic index. It is essential to try to use these drugs in a way that maximizes the quality of life of the patients, as well as the quantity of life.

What other areas of unmet need are important to keep in mind?

The real challenge with HER2-positive metastatic breast cancer is that it is incurable, with the exception of the rare responders. However, these are anecdotal and rare. This is always the highest unmet need. We do not have a cure strategy for HER2-positive disease when it metastasizes, and this is partly because half of these patients will develop brain metastases. We need dedicated studies of all new agents targeting HER2, especially in this population, to see which ones will be effective. We already have this data for tucatinib, in the form of a randomized phase 3 trial, but we do not yet have this level of evidence for other agents targeting HER2.

Other [areas of investigation] include the combination of other classes of drugs, which may have a favorable impact on the results. For example, there is a growing body of literature on combining CDK4 / 6 inhibitors with targeted therapy on HER2, which is the focus of the PATINA trial. Given the extraordinary results we have seen in ER-positive disease with the addition of CDK4 / 6 inhibitors, if we can take advantage of this kind of leap in terms of new technology, with a new target, in a new space open, there are preclinical data with combinations of therapy targeting HER2 and CDK4 / 6 inhibitors [that looks promising]. From a scientific point of view, this combination should work.

The other combination that could be provocative would be to test immune checkpoint inhibitors plus HER2 targeting agents. There was phase 2 randomized KATE2 [NCT02924883] trial examining T-DM1 with or without atezolizumab (Tecentriq). A subset analysis, which examined only the PD-L1-positive subset, appeared to show a signal of efficacy with this combination. Now there is the ongoing KATE3 phase 3 randomized trial [NCT04740918], which will directly test this hypothesis.

These are the opportunities of the future [in terms of] explore the activity of new drug classes in the HER2 space.